Upload
leminh
View
231
Download
6
Embed Size (px)
Citation preview
Malaria Centre Report 2010-11
London School of Hygiene &
Tropical Medicine
London School of Hygiene and Tropical MedicineKeppel Street
LondonWC1E 7HT
http://malaria.lshtm.ac.uk/[email protected]
Copies of this report may be obtained on the website or by writing to the address above.
Cover images (clockwise from top): Modelling the dispersal of resistance mutations at codons 437 and 540 of the dhps gene in 2000 and 2005. Courtesy of Cally Roper & Inbarani Naidoo; Children in Lower Moshi. Copyright Teun
Bousema; Sporulating oocyst on Plasmodium berghei-infected Anopheles stephensi midgut. Copyright Annie Tremp & Hans Dessens; DTM&H students in laboratory 24 February 2011. Copyright London School of Hygiene & Tropical Medicine.
Bi-annual Report2010-11
Contents
Director’s message 2Executive Summary 3Global Relevance 4
Capacity Strengthening 6Parasite Biology 10Immunology & Vaccination 22Drug Development, Deployment and Resistance 30Epidemiology 42Clinical Trials & Studies 60Vector Studies 78Social & Economic Research 92
Publications 114Members 130Abbreviations 134
2 Director's Message
London School of Hygiene & Tropical Medicine
Despite the global decline of mortality caused
by malaria, the estimated number of deaths
remains unacceptably high, particularly as infants
and pregnant women are most susceptible. Death is
just one of many outcomes; the World Health Organ-
isation (WHO) estimates that there are over 216M
people infected with malaria. For those who survive,
the longer term effects of the disease vary, with some
struggling to contribute to their household’s eco-
nomic survival. With the decline of malaria-caused
mortality comes the risk that governments, funders
and policy makers become complacent about this
devastating disease.
The plasmodium parasite has shown itself to be
highly adaptive to changing contexts and preventa-
tive drugs. With such an opponent it is clear that
the best approach must be coordinated and multi-
facetted. The London School of Hygiene & Tropical
Medicine’s Malaria Centre has led the way in bring-
ing together researchers expert in a wide range of
disciplines to work in a concerted way on malaria,
looking at the disease at population, household and
the individual levels and at the pathogen’s funda-
mental biology and life cycle. Using their expertise,
Centre members actively engage with policy devel-
opment at both country and global levels, working
with governments and international bodies such as
the WHO.
This report highlights some of the significant de-
velopments over the last two years which have been
made possible by the Malaria Centre’s leadership
and partnerships, most importantly with collabora-
tors in malaria-endemic countries. In particular, the
Professor Baron Peter Piot
Director, LSHTM
report highlights the strength that lies in its mem-
bership, not least Brian Greenwood (Page 113),
whose life-long contribution to this field has un-
doubtedly played a major role in his being awarded
both a knighthood and the Canadian Gairdner Prize.
As the Centre becomes more mature, its impor-
tance as an international Centre of excellence grows.
In many ways, the Centre represents the very best
that LSHTM can offer and leads the way in bringing
an integrated, cross-disciplinary approach to a prob-
lem of global significance.
Malaria is a disease that remains a puzzle to hu-
manity. One of the major challenges that the Centre
and all those working in this important field face, is
to ensure that this major killer is not overlooked in
the post-2015 period, and remains a priority in the
era following the Millennium goals.
Executive Summary 3
Malaria Centre Report 2010-11
T he headlines from the frontline of malaria
control continue to paint a mixed picture. On
the one hand, a marked decline in mortality in the
last 10 years is evident. However, new analyses of
data have suggested that global mortality estimates
for malaria may be higher than previously thought.
This immediately draws attention to one of the great
challenges currently facing those working in ma-
laria control: reliable data for the monitoring and
evaluation of systems and approaches. Therefore,
the challenge remains to identify regional or coun-
try specific factors associated with success and fail-
ure to further optimise the current tools for malaria
control. Similarly, malaria elimination is an increas-
ingly well established concept and an aim for many
countries. However, this is tempered by the increas-
ing realisation that it will not be easy to achieve in
the vast majority of endemic settings. Indeed, with
reports of increasing levels of mosquito resistance
to pyrethroid insecticides following on the heels of
parasite resistance to anti-malarial drugs, the more
pragmatic goal is to sustain the gains made in recent
years while preserving the long-term effectiveness
of our best malaria control tools.
Developing and refining the tools needed to con-
trol and eliminate malaria is clearly a high priority
but similar emphasis is required in guiding the use
or change in use of any approach. There is also a
need to develop new tools and approaches, and to
draw them together into a coherent framework to
monitor progress. The effects will not only manifest
as changes in biological endpoints but also as social,
financial and health system performance indicators.
Addressing these complex issues requires the inter-
action of many partners from academic, manufactur-
ing, governmental and non-governmental sectors to
define research questions and influence policy. With
its breadth of discipline, multiple overseas partners
and interactions that range from the World Health
Organisation to local secondary schools, the LSHTM
Malaria Centre is uniquely placed to contribute to
this and catalyse malaria research. This report cov-
ers work done on basic biology and the identifica-
tion of potential targets for new drugs, vaccines and
insecticides; the testing of these products in field
settings; the social and economic evaluation of in-
terventions; and their relevance to policy. The ulti-
mate endpoint is translational research that can be
implemented by governments and those involved in
malaria control programmes wherever the disease
exists.
Chris Drakeley
Director, Malaria Centre
4 Global Relevance
London School of Hygiene & Tropical Medicine
Evidence of this translational approach is pro-
vided in this report. One example is how the appli-
cation of high throughput techniques for the identi-
fication of molecular markers associated with drug
resistance has led to a simple algorithm for malaria
control programme managers to determine whether
they should deploy Intermittent Preventative Treat-
ment (IPT) for malaria in infants. A seasonal IPT ap-
proach in older children – now renamed as Seasonal
The key strength of the London School of Hy-
giene and Tropical Medicine (LSHTM) Malaria
Centre is its members and partners. The Centre com-
prises more than 200 members and has collabora-
tors and research partners in more than 30 countries
encompassing a wide range of malaria endemicities
and ecological settings. The main research focus is
malaria but interactions with researchers investigat-
ing other vector borne and infectious diseases facili-
tate the sharing of ideas to optimise approaches for
disease control. Within LSHTM, the Malaria Centre
has close ties with the Diagnostic Centre, Vaccine
Centre and Public Health & Entomology Group. Col-
lectively, this research encompasses basic parasite
biology, vector and human studies through to imple-
mentation and policy related studies with a strong
emphasis on translational research.
Malaria Chemoprevention (SMC) - has been further
evaluated in a series of field studies and modeling
exercises which have contributed to its recent adop-
tion as policy by World Health Organisation (WHO).
Some further examples of malaria research with
global relevance are:
■ Studies of the geographical distribution of
parasite proteins associated with erythrocyte inva-
sion and how this distribution may influence vac-
cine design.
■ Laboratory investigations into the dynamics
of both B and T cell populations in naturally exposed
individuals resident in different transmission levels
as well as those who have been vaccinated with the
RTS,S malaria vaccine.
■ A range of studies to monitor the threat of
drug resistance to artemisinins; clinical and labora-
Countries where Malaria Centre members work.
tory trials continue to attempt to identify the para-
site genes associated with resistance and the effects
on parasite transmission. Social and economic stud-
ies also aim to identify what the drivers behind the
development of resistance at the population level
are.
■ Vector control research that builds on the
long standing relationship with the WHO in evalu-
ating new brands of Long Lasting Insecticidal Nets
Global Relevance 5
Malaria Centre Report 2010-11
(LLINs) and with the Bill & Melinda Gates Founda-
tion in developing alternative insecticides to the py-
rethroids for Indoor Residual Spraying (IRS). Along
with the introduction of IRS in many African coun-
tries under the President’s Malaria Initiative, studies
are also presented on interventions where LLINs are
combined with IRS and on integrated vector man-
agement which incorporates supplementary ap-
proaches such as larviciding and repellents.
■ A variety of studies of the science of surveil-
lance including those evaluating the best tools or
combination of tools to identify infection and expo-
sure to infection. Furthermore, studies that investi-
gate what survey approaches in schools, health fa-
cilities or communities – and over what geographical
scale - will generate the most appropriate informa-
tion for malaria control programmes.
■ Social and economic research that centres on
work that improves our understanding of the patient
provider interactions in terms of both diagnosis of
malaria using rapid diagnostic tests and treatment
with artemesinins, as well as the economic evalua-
tion of the impact of malaria and community based
delivery systems.
The work of the Malaria Centre provides a highly
conducive environment for supporting the develop-
ment of scientists of all disciplines and capacity de-
velopment is a central component of our activities.
Capacity development comes in a variety of guises;
conventional teaching, training within specific re-
search projects or dedicated post-graduate training
programmes. One example of the latter, the Malaria
Capacity Development Consortium, is run in part-
nership with 5 African Universities and is also de-
signed to promote support and supervision of re-
search students.
In addition to research, Centre members provide
a range of services that contribute to the diagnosis,
treatment and research of malaria. These include in-
secticide and repellent testing through ARCTEC (at
LSHTM) and PAMVERC (in Africa) and drug quality
testing services as well as diagnosis and treatment
of malaria through the Hospital for Tropical Diseases
and the Malaria Reference Laboratory.
Communicating research findings and raising
awareness of malaria research and development
continues to be a major focus of the Centre. Activities
around World Malaria Day have included press brief-
ings to scientific and mainstream media on major
research and future challenges while our 1930s tea
dance for World Mosquito Day highlighted the his-
torical discoveries that have shaped malaria control.
In addition to fielding routine media enquiries, the
Centre has also produced a range of dissemination
outputs including educational videos for secondary
schools and podcasts on research specific areas reg-
ularly made available via the updated website.
Dissemination also encompasses the important
advisory roles that member of the Malaria Centre
have to policy makers in the UK and abroad. In par-
ticular, members have continued to provide advice to
the WHO and National Malaria Control Programmes
in malaria endemic countries. Members have also
authored or contributed to reports produced by UK
Department for International Development and the
UK All Parliamentary Group of Malaria and Neglect-
ed Tropical Diseases.
6 Capacity Strengthening
London School of Hygiene & Tropical Medicine
Building on the successes of previous years, mem-
bers of the Malaria Centre have continued to play an
important role in strengthening research capacity
in malaria endemic countries, particularly in Sub-
Saharan Africa. Members have been working with
partners to build key competencies in numerous col-
laborating institutions, networks and consortia. Al-
though focusing on malaria, capacity strengthening
activities have had a wider impact on health research
development in collaborating institutions due to the
strategic nature of collaborations, the engagement
of key stakeholders, and the implementation of ac-
tivities that address identified development needs of
institutions. All these activities accord with the mis-
sion of LSHTM.
Training malaria health researchers
In 2010/2011, 34 students completed the Epide-
miology and Control of Malaria module, and 13 stu-
dents graduated with PhD degrees focusing on ma-
laria. These included PhD students from malaria en-
demic countries who are based in LSHTM overseas
collaborating institutions where they play a key role
in transferring new technology and other skills to
their peers. The majority of PhD students that have
graduated continue to work on malaria or in related
areas and the Centre ensures that they remain part
of the Malaria Centre network through the website,
mailing list and opportunities to attend the annual
Malaria Centre meeting.
Members also play an active role in the supervi-
sion and/or co-supervision of students from the Ma-
laria Capacity Development Consortium (MCDC) and
from a number of partners from consortia within the
Wellcome Trust’s African Institutions Initiative.
The Distance Learning Malaria Module contin-
ues to attract significant interest with 82 students
registering on the module in 2010/2011. The re-
cently updated module is also available, via the Ma-
laria Centre website, as an open-access education
resource to students and researchers from all over
the world who are interested in gaining a broader
understanding of malaria. Since its launch, over 800
individuals have registered and accessed the online
module.
Members of the Malaria Centre, together with
partners from the University of Groningen and Royal
Tropical Institute are being funded by the Nether-
lands Initiative for Capacity Development in Higher
Education to work in partnership with the Ifakara
Health Research Institute in Tanzania to develop a
Masters in Research for Public Health.
Summary
Capacity Strengthening 7
Malaria Centre Report 2010-11
Malaria Capacity Development Consor-tium
MCDC strengthens both individual and institutional
malaria research capacity in Africa. Working in part-
nership, the consortium of 5 African Institutions and
3 European Institutions currently supports 18 Afri-
can scientists who will gain their PhD’s from their
host institutions. Students receive a wide ranging
support package which includes local primary su-
pervision, co-supervision from one of the EU part-
ners, opportunities to spend up to one year in their
co-supervisors EU institution and a comprehensive
career development programme supported by an
educational advisor based at Université Cheikh Anta
Diop in Dakar. MCDC also supports an active cohort
of 29 established malaria researchers through its
“Investigators” programme. Activities for Investiga-
tors focus on supporting them, as necessary, to es-
tablish their careers within their home institution.
Support has been provided for continuing career
development activities via a Personal Development
Planning (PDP) programme, a grants scheme and an
innovative mentoring programme.
This extensive network of over 40 malaria re-
searchers is maintained through both the MCDC
Community (an online resource centre) and via an-
nual consortium meetings. Having demonstrated
the benefits of PDP and mentoring to early stage
researchers, MCDC is now working with its African
partners to embed these activities within each insti-
tution as part of its institutional strengthening ob-
jective.
In Focus: MCDC Mentoring Programme. ■ 28 mentees and mentors matched
■ mentoring agreement formalizes the process
■ frequency and mode of meetings decided between the mentor and mentee
■ one face-to-face meeting per year encouraged
■ web-based support and training materials developed and available as an open access resource at:
http://mentorship.mcdconsortium.org/mentoring
■ mentor training workshop jointly developed and delivered with the College of Medicine, Malawi
8 Capacity Strengthening
London School of Hygiene & Tropical Medicine
MCDC’s approach to institutional capacity
strengthening for its partner’s PhD programmes has
been based on meeting the needs for each partner
as identified, in 2009, by a Baseline Needs Assess-
ment exercise. Activities at each institution, tailored
to address their specific needs include: the devel-
opment of comprehensive, accessible, up-to-date
regulations and handbooks, improved supervisor
training and mentoring and a formal induction and
research skills courses. A follow-up assessment is
shortly to be undertaken to evaluate this aspect of
the programme.
MCDC has, over the last two years, worked with
its partners to facilitate PhD supervisor training
courses at four of its African partner institutions and
has recently developed a Training of Trainers course
for PhD supervisors and a mentors training course
in conjunction with the College of Medicine and The
Malawi-Liverpool-Wellcome Trust Clinical Research
Programme in Malawi. Over 100 staff have benefit-
ted from these training courses with attendees from
institutions outside the MCDC partnership including
those from the Wellcome Trust’s African Institutions
Initiative (SACIDS, SNOWS, CARTA and (THRiVE).
Networks, consortia and multi-cen-tre field trials.
Staff and students from the Centre continue to play
key roles in a number of malaria research consortia
and multi-centre trials. Contributions to the work of
MalariGEN are being made by members of the Centre
working under the auspices of the Joint Malaria pro-
gramme in North Eastern Tanzania. Growing inter-
est in the development of strategies to control adult
and larval stages of Anopheles mosquitoes (e.g. IVCC,
PAMVREC) has led to the establishment of a num-
ber of field centres in West and East Africa where
many of these studies are conducted. Work plans
for projects conducted by these various consortia
incorporate the transfer of skills and technology to
local project staff with the appropriate training be-
ing delivered either in country, or, through scientific
exchange visits to LSHTM.
MCDC Meeting Kilifi, Kenya, 2009.
Capacity Strengthening 9
Malaria Centre Report 2010-11
A primary objective of the ACT consortium is
to evaluate a range of strategies for the delivery of
ACT, and to provide evidence which will maximise
their public health impact. A core team of scientists,
including Malaria Centre members, provide social
science, economic, and statistical support to the con-
sortium projects. Capacity in social science has been
strengthened by Malaria Centre members who have
supervised a team of junior scientists based at the
Infectious Disease Research Collaboration in Ugan-
da.
Malaria Centre members have played key roles
in the Phase 3 trial of the RTS,S vaccine in Tanzania
and Ghana, providing mentorship to the local Prin-
cipal Investigators and supporting the significant
infrastructure and training programmes that have
provided field and laboratory staff with the neces-
sary expertise to conduct such large scale, high qual-
In Focus: Understanding what National Malaria Programmes mean when they talk about operational research.Operational and Implementation Research have received increased attention in recent years. Large donors,
such as the Global Fund to fight HIV/AIDS, tuberculosis, and malaria have prioritised Operational Research
(OR) as an activity that needs to be undertaken to improve programme quality and effectiveness. Despite
donor support for OR for malaria programmes, emphasis has been on providing research outputs which
inform global malaria policies such as Artemisinin-based Combination Therapy efficacy or effectiveness
of different Rapid Diagnostic Tests rather than local, programme-based OR to provide evidence for taking
programmes to scale.
Members of the Malaria Centre (Caroline Lynch & Kirstin Banek) are helping to identify how different
groups involved in the conduct, management and funding of research define operational and implementa-
tion research. In addition they are seeking to understand which groups prioritize OR and whether, and at
what programmatic levels, OR results are used.
ity vaccine studies. In a similar vein, staff have men-
tored project coordinators and assisted local staff to
lead on large multi-centre trials investigating Sea-
sonal Malaria Chemoprevention in Mali and Burkina
Faso, and Intermittent Screening versus Treatment
of Malaria in Pregnancy - in Burkina Faso, Mali, the
Gambia and Ghana (MiP consortium).
The funding environment in which the Malaria
Centre’s capacity strengthening activities are con-
ducted has changed significantly during the period
covered by this report. Donors are now investing
heavily in programmes which strengthen capacity
in health systems in malaria endemic countries and
one of the main challenges faced by the Malaria Cen-
tre is how to make the best use of its resources in
meeting these changing needs.
10 Parasite Biology
London School of Hygiene & Tropical Medicine
Summary
Several aspects of malaria parasite biology are un-
der investigation by members of the LSHTM Malaria
Centre and their many collaborators. The work in-
cludes: studies on Plasmodium falciparum popula-
tion genetics and merozoite invasion mechanisms
here in the UK and in West Africa, measurement
of immune responses in children to transmissible
stages of Plasmodium falciparum in Ghana, stud-
ies on genetic epidemiology using next generation
DNA sequencing, as well as genetic and biochemical
analysis of life cycle stage-specific proteins of Plas-
modium falciparum and rodent malaria parasites.
This is a particularly exciting time for malaria scien-
tists with technology emerging that allows us to in-
tegrate data obtained for single proteins with global
microarray and proteomic data and also with whole
genome datasets at the population level. All of these
approaches ultimately aim to generate and inform
new disease interventions by means of understand-
ing the biology of the parasite and its complex inter-
actions with its human host and mosquito vector at
the molecular level.
One of the major problems with tackling malaria,
especially in parts of Africa, is that within a single
species, Plasmodium falciparum (the most lethal
form), there are a multitude of genetically diverse
parasite ‘strains’ whose surface proteins or antigens
are distinct. Therefore a vaccine targeting these pro-
teins that effectively kills one strain will not kill most
of the others. It is therefore vitally important that
we are aware of the extent of variation and identify
which antigens are the best ones to target with vac-
cines. Population genetic approaches are being used
in David Conway’s laboratory to address these im-
portant issues. The team is also exploring (in a study
in Ghana) the possibility that during infection, the
parasite switches its mode of invasion of red blood
cells, in response to the host immune response. A rel-
atively recent discovery that the Conway group were
involved in was the finding that a species of malaria
parasite (Plasmodium knowlesi) previously thought
to infect only macaques, in fact causes disease in hu-
mans. One of the important implications of this work
is that malaria caused by this species might have an
animal reservoir where a mosquito picks up gameto-
cytes from a macaque and can then pass on the infec-
tion (following development to the sporozoite stage)
to a human as it takes a subsequent blood meal.
LSHTM has a long term interest in the transmis-
sible forms of malaria. One of Colin Sutherland’s
current projects involves assessment of the levels
of antibodies to these forms (gametocytes) in Gha-
naian school children. A unique and exciting aspect
of this study is that it is measuring antibodies that
react with malaria parasite proteins displayed on
the outside of the infected red blood cell. It is im-
Parasite Biology 11
Malaria Centre Report 2010-11
portant to know whether antibodies to this class of
parasite proteins can kill gametocytes - if they can
they would render the child non-infective. Mimick-
ing such a natural immune response with a vaccine
would block transmission of malaria between indi-
viduals in the population by killing gametocytes in
the vaccinated individual. This approach contrasts
with conventional transmission blocking strategies
which require antibody titres to remain sufficiently
high in the mosquito midgut following a blood meal
to block gamete or ookinete development rendering
only the mosquito non-infective.
Several members of the Malaria Centre, in collab-
oration with Taane Clark are taking advantage of the
so-called next generation sequencing technologies
which allow us to determine hundreds of whole ge-
nome sequences in a relatively short time. Until re-
cently, analysis of genetic diversity was restricted to
examination of just a few selected loci, however, we
can now compare entire genomes in just a minute
fraction of the time it took to decode the first ever
Plasmodium genome. This has enormous implica-
tions for a whole range of malaria parasite studies
that aim to relate genetic changes to alterations in
function or phenotype and to inform work on drug
treatment and vaccine design.
Hans Dessens’ research team is working on an
intriguing family of proteins (LCCL proteins) that
play an important role in development of the malar-
ia parasite within the mosquito vector. Some of these
unique proteins reside in a very curious organelle
known as the crystalloid. This was identified many
years ago, but only now is its composition and func-
tion under close scrutiny here at LSHTM. Since the
crystalloid and its components are not found in the
host, it is possible that it may be the target of a future
novel anti-malarial strategy.
David Baker’s group is interested in a particular
biochemical pathway that plays an important role
in triggering key parasite life cycle transitions. The
so-called ‘cGMP signalling system’ has several enzy-
matic components. One aspect of the team’s work is
to understand how these components work at the
molecular level: how exactly does this signalling
system cause a blood stage schizont to rupture and
how does it activate a gametocyte to allow gametes
to emerge? Recent findings have led directly to the
second aspect of the work which involves exploring
these components as targets for new anti-malarial
drugs. The first evidence of resistance to artemisinin
derivatives was detected some time ago now, and so
it is crucial that the drug discovery pipeline yields
some entirely new chemical structures with new
modes of action for use in future combination thera-
pies. Inhibitors of protein kinases or cyclic nucleo-
tide phosphodiesterases might fit this need.
12 Parasite Biology
London School of Hygiene & Tropical Medicine
Population genomic signatures of balancing selection and novel antigen characterization in Plasmodium falciparum.
LSHTM Investigators: David Conway, Kevin Tetteh, Lindsay Stewart, Ian
Cheeseman & Elizabeth Deerhake.
External Investigators/Collaborators: Alfred Amambua-Ngwa, Nata-
lia Gomez-Escobar, Muminatou Jallow & Omar Janha (Medical Research
Council, The Gambia); Dominic Kwiatkowski, Magnus Manske, Susana
Campino & Bronwyn MacInnis (Wellcome Trust Sanger Institute, UK);
Chris Newbold (University of Oxford, UK); Anthony Holder & Ellen Knuep-
fer (National Institute for Medical Research, UK).
Funding Body: Wellcome Trust & Medical Research Council, UK.
Acquired immunity in vertebrates maintains polymorphisms in endemic pathogens, leading to identifiable signatures of balancing selection. To survey for genes under such selection in Plasmodium falciparum, we generated paired-end short-read sequences of parasites in clinical isolates from an en-demic Gambian population, which were mapped to the 3D7
reference genome to yield high quality genome-wide coding sequence data for 65 isolates.
Excluding sub-telomeric regions, 2853 genes contained 3 or more single nucleotide polymorphisms for analysis of polymorphic site frequency spectra, and the outlying minori-ty of genes with signatures indicating exceptionally interme-diate frequencies were identified. Such signatures were most common in genes with peak expression at the merozoite stage that invades erythrocytes, the strongest signature be-ing in the msp3-like gene PF10_0355. Analysis of msp3-like transcripts in 45 clinical and 11 laboratory adapted isolates grown to merozoite-containing schizont stages revealed sur-prisingly low expression of PF10_0355. In diverse clonal par-asite lines the protein product was expressed in a minority of mature schizonts (<1% in most lines), and subclones of one line cultured separately had a spectrum of positive frequen-cies (0.9 to 7.5%), indicating phase variable expression of this polymorphic antigen. This and other identified targets of balancing selection are now prioritised for functional study and vaccine candidacy.
Map of municipality.
Parasite Biology 13
Malaria Centre Report 2010-11
Alternative molecular mechanisms for erythrocyte invasion by Plasmodium falciparum in Ghana.
LSHTM Investigators: David Conway.
External Investigators/Collaborators: Gordon Awandare (University
of Ghana, Ghana); Seth Ogusu-Agyei (Kintampo Health Research Centre,
Ghana); Abraham Oduro (Navrongo Health Research Centre, Ghana).
Funding Body: Royal Society-Leverhulme Africa Award.
Development of a blood stage vaccine is hampered by inad-equate understanding of the mechanisms by which the para-site invades erythrocytes and evades immune responses. The invasive merozoite stage of Plasmodium falciparum has an extensive array of ligands, each interacting with one or more receptors on the erythrocyte surface. The identity of sialic acid (SA)-independent erythrocyte receptors were unknown until Dr Gordon Awandare and colleagues identified comple-
ment receptor 1 (CR1) as the major SA-independent invasion receptor, and subsequent studies implicated the Rh4 protein of Plasmodium falciparum as the ligand for CR1. We propose that one mechanism by which Plasmodium falciparum mero-zoites evade immune responses is by altering ligand gene expression that allows a switch in invasion phenotypes as antibodies targeting the existing mechanisms are developed.
The current study involves analysis of clinical isolates from different endemic sites to addresses the following aims:
■ To determine the erythrocyte invasion phenotypes of Ghanaian Plasmodium falciparum isolates and their rela-tive dependence on different receptors including CR1.
■ To determine the impact of selection by host anti-bodies on gene expression profiles of Plasmodium falciparum ligands involved in SA-independent invasion.
■ To identify polymorphisms in parasite genes associ-ated with escape from anti-SA ligand antibodies.
Gordon Awandare studying erythrocyte invasion by malaria parasites in his lab at the University of Ghana.
14 Parasite Biology
London School of Hygiene & Tropical Medicine
Malaria parasite population structure and adaptation on the edge of endemic distribution in Africa.
LSHTM Investigators: Craig Duffy & David Conway.
External Investigators/Collaborators: Hampate Ba (Recherches en
Santé Publique, Mauritania); Ambroise Ahouidi (Cheikh Anta Diop Uni-
versity, Senegal); Dominic Kwiatkowski (Wellcome Trust Sanger Institute,
UK); Manoj Duraisingh (Harvard University, USA).
Funding Body: Medical Research Council, UK.
We are investigating population genetic structure and pheno-types of Plasmodium falciparum under selection at the north western extreme of its African range in Mauritania, where endemicity persists despite limited and highly seasonal rainfall that restricts transmission. We predict that, genetic divergence between populations of Plasmodium falciparum in different areas of Mauritania will be high due to genetic
drift with small effective population sizes, and restricted gene flow among endemic foci. This is being investigated by microsatellite and whole genome sequence polymorphism analyses.
We also predict that the selective landscape will be strik-ingly different from elsewhere, leading to measurable effects including the following:
■ Low levels of acquired immunity in the human pop-ulation will reduce diversifying selection on merozoite inva-sion ligands so these will be less diverse and skewed towards the use of a preferred primary ligand.
■ Alleles under strong positive selection will increase to high frequencies in local populations before sporadic gene flow events allow them to spread so there will be major local differences in drug resistance.
Understanding these processes in terms of demographic and selective constraints on the parasite will guide targeting of existing control tools including antimalarial drugs and de-velopment of new tools including vaccines.
Mauritania desert town with malaria.
Parasite Biology 15
Malaria Centre Report 2010-11
Population genetic structure of Plasmodium falciparum across a region of diverse endemicity in West Africa.
LSHTM Investigators: Victor Mobegi, Taane Clark & David Conway.
External Investigators/Collaborators: Ambroise Ahouidi (Cheikh Anta
Diop University, Senegal); Kovana Marcel Loua (The National Institute of
Public Health, Guinea); Alfred Amambua-Ngwa, Judith Satoguina & Davis
Nwakanma (Medical Research Council, The Gambia); Dominic Kwiatkows-
ki (Wellcome Trust Sanger Institute, UK).
Funding Body: Medical Research Council, UK.
Malaria parasite population genetic structure varies among areas of differing endemicity, but this has not been system-atically studied across Plasmodium falciparum populations in Africa.
Ten polymorphic Plasmodium falciparum microsatellite loci were genotyped in 268 infections from eight locations in four West African countries (Republic of Guinea, Guinea
Bissau, The Gambia and Senegal), spanning a highly endemic forested region in the south to a low endemic Sahelian re-gion in the north. We assessed proportions of mixed geno-type infections, genotypic diversity among isolates, multilo-cus standardised index of association, and inter-population differentiation. Each location had similar levels of pairwise genotypic diversity among isolates, although there were many more mixed parasite genotype infections in the south. Genetic differentiation between populations was low and an overall test for isolation by distance was not significant. Al-though proportions of mixed genotype infections varied with endemicity as expected, population genetic structure was similar across the diverse sites. Very substantial reduction in transmission would be needed to cause fragmented or epi-demic sub-structure in this region. Genome sequences from one of the Guinean sites are now being analysed to compare signatures of selection with those detected in a less endemic region in The Gambia.
Distribution of Tajima’s D values (genes under balancing selection have high values of this index) for each of 2853 Plasmodium falciparum genes with 3 or more SNPs in a Gambian population. (Values are plotted according to the order of the genes along each of the 14 chromosomes).
16 Parasite Biology
London School of Hygiene & Tropical Medicine
Estimating selection on Plasmodium falciparum drug resistance alleles in an endemic population over a 25 year period.
LSHTM Investigators: David Conway, Paul Milligan, Colin
Sutherland & Brian Greenwood.
External Investigators/Collaborators: Davis Nwakanma,
Eniyou Ereiro, Alfred Amambua-Ngwa & Margaret Pinder
(Medical Research Council, The Gambia).
Funding Body: Medical Research Council, UK.
Using archived blood samples, we surveyed drug resistance polymorphisms in The Gambia over a 25 year period from 1984 when resistance was unknown locally through periods of gradual fail-ure of chloroquine therapy and increasing use of sulphadoxine-pyrimethamine until eventual introduction of Artemisinin-based Combination Therapy. At the first survey there were no drug resistance alleles detected at two of the loci (crt and dhps) and very few isolates contained re-sistance alleles at the other two loci (mdr1 and dhfr). Proportions of isolates with resistance al-leles increased progressively over subsequent surveys, reaching peaks for the chloroquine resistance alleles crt 76T (76%) and mdr1 86N (78%) in the year 2000, and for antifolate resis-tance dhfr alleles (94%, mostly as a triple com-bination of 51I, 59C and 108N) and dhps 437G (86%) in 2007 and 2008 respectively. To analyse allele frequencies, we counted one allele at each locus per isolate, and estimated 95% confidence intervals. Changes in allele frequencies occurred at different times and rates over the period, and the data fit closely a very simple model for each locus with assumed fitness costs and a change in selection coefficients reflecting historical change in therapeutic use. We are exploring the fit be-tween these historical selection data and signa-tures of selection at these loci derived from ge-nome wide polymorphism data in a population sample taken at the end of the period.
Proportions of Plasmodium falciparum infected individuals with each allele at 4 drug resistance loci in 8 different surveys in Farafenni between 1984 and 2008.
Parasite Biology 17
Malaria Centre Report 2010-11
M/S hybrid forms of Anopheles gambiae throughout 2 years at a site in The Gambia.
Minimal genomic differentiation between putative incipient species of Anopheles gambiae with extensive interbreeding at ecologically diverse sites in West Africa.
LSHTM Investigators: David Conway.
External Investigators/Collaborators: Davis Nwakanma, Musa Jawara,
Samson Awolola & Majidah Adiamoh (Medical Research Council, The Gam-
bia); Lassana Konate, Ngayo Sy & Ibrahima Dia (Cheikh Anta Diop Univer-
sity, Service de Lutte Antiparasitaire and Pasteur Institute, Senegal); Ama-
belia Rodrigues (Bandim Health Project, Guinea Bissau); Kovana Marcel
Loua (National Institute of Public Health, Guinea); Daniel Neafsey, Emily
Lund & Marc Muskavitch (Harvard University, USA).
Funding Body: Medical Research Council, UK, Foundation for the National
Institutes of Health/Gates Grand Challenges in Global Health.
M and S molecular forms of the major African malaria vector Anopheles gambiae are widely considered as incipient spe-cies with strong reproductive isolation, with M/S hybrids rarely seen except in a few sites in the extreme west of Af-rica. We undertook new surveys of 12 sites in four contigu-
ous countries in this region, with a total of 3499 Anopheles gambiae identified and genotyped.
High frequencies of M/S hybrid forms were seen at each site, ranging from 5% to 42%, and there was a large spectrum of inbreeding coefficient values from 0.11 to 0.76 (spanning most of the range expected between the alternative extremes of panmixia and assortative mating). At a site in The Gambia that was sampled each month for 2 years, M/S hybrid forms were seen throughout, and a genome-wide scan with an Af-fymetrix 400,000 single nucleotide polymorphism (SNP) microarray showed marked differentiation between M and S forms only in the pericentromeric region of the X chromo-some that contains the molecular form-specific marker lo-cus. Such minimal inter-form genomic differentiation was also seen in such a scan of two other populations, in Senegal and Guinea Bissau. These results clearly indicate that M and S forms are not strongly isolated in this part of Africa.
18 Parasite Biology
London School of Hygiene & Tropical Medicine
Plasmodium knowlesi: reservoir hosts and tracking the emergence in humans and macaques.
LSHTM Investigators: David Conway.
External Investigators/Collaborators: Balbir Singh, Kim-Sung Lee,
Paul Divis, Siti Khatijah Zakaria & Roynston Julin (Universite Malaysia
Sarawak, Malaysia); Janet Cox-Singh (St George’s Hospital, UK); Asmad
Matusop (Sarawak State Health Department, Malaysia).
Funding Body: Wellcome Trust & Malaysian Ministry of Science, Technol-
ogy and Innovation.
We previously described Plasmodium knowlesi, a malaria parasite originally thought to be restricted to macaques in Southeast Asia, as a significant cause of human malaria. More recently, to extend understanding of the epidemiology and evolutionary history of Plasmodium knowlesi, we examined 108 wild macaques for malaria parasites in the Kapit District of Sarawak, Malaysia, and sequenced the circumsporozoite
Genealogical network of Plasmodium knowlesi mitochondrial genome haplotypes sampled from human and macaque hosts in Malaysia. (Numbers in larger circles represent number of haplotypes and unnumbered circles represent a single haplotype. Each line connecting the circles represents a mutational step and black dots missing intermediates).
protein (csp) gene and mitochondrial (mt) DNA of parasites from macaques and humans.
We detected five species of Plasmodium (Plasmodium knowlesi, Plasmodium inui, Plasmodium cynomolgi, Plasmo-dium fieldi and Plasmodium coatneyi) in long-tailed and pig-tailed macaques. Macaques had a higher number of Plasmo-dium knowlesi genotypes per infection than humans, and di-verse alleles of the Plasmodium knowlesi csp gene and certain mtDNA haplotypes were shared between both hosts. There were no mtDNA lineages associated exclusively with either host.
Furthermore, our analyses of the mtDNA data reveal that Plasmodium knowlesi is derived from an ancestral parasite population that existed prior to human settlement in South-east Asia, and underwent significant population expansion approximately 30,000-40,000 years ago. These results in-dicate that human infections with Plasmodium knowlesi are not newly emergent and that knowlesi malaria is primarily a zoonosis with wild macaques as the reservoir hosts.
Parasite Biology 19
Malaria Centre Report 2010-11
Genomic epidemiology using Plasmodium falciparum whole genome sequencing data.
LSHTM Investigators: Francesc Coll, Mark Preston, Nuno Sepulveda,
David Baker, Teun Bousema, David Conway, Chris Drakeley, Cally Roper,
Colin Sutherland & Taane Clark.
External Investigators/Collaborators: Samuel Assefa, Thomas Otto,
Magnus Manske, Susana Campino & Dominic Kwiatkowski (Wellcome
Trust Sanger Institute, UK).
Next generation sequencing technologies are generating many millions of short sequences (reads). These are lead-ing to near complete Plasmodium falciparum (Pf) genomes, through alignment to the reference genome (3D7, 23Mb) and de novo assembly. Many hundreds of Pf isolates have been sequenced including samples contributed by members of the Malaria Centre, and the resulting raw data are becoming publically available.
At the Malaria Centre, we have established data analysis pipelines and are currently involved in several areas of re-search, including: cataloguing of structural variation across the Pf genome, estimating the multiplicity of infection, de-tecting regions under selective pressure, estimating recom-bination breakpoints and identifying important genetic mo-tifs in hotspots, summarising Pf population structure and developing genetic barcodes for implementation in high
Allele frequencies on a map.
Longitudinal immune responses to Plasmodium falciparum gametocytes in Ghanaian school children.
LSHTM Investigators: Bismarck Dinko, Maha Saeed, Teun Bousema &
Colin Sutherland.
External Investigators/Collaborators: Harry Tagbor & John Larbi
(Kwame Nkrumah University of Science and Technology, Ghana).
Funding Body: Ghana Education Trust Fund.
Malaria transmission-reducing interventions are key compo-nents of malaria control and elimination. However, little is known about the immune responses directed at circulating Plasmodium falciparum gametocytes in humans. We set out to determine patterns in gametocyte surface antigen (GSA) antibody prevalence and seek stronger evidence for specific immune suppression of gametocytes.
Flow cytometry is being used to detect antibodies recog-nising cultured 3D7a mature gametocyte-infected erythro-cyte surface in plasma from asymptomatic malaria parasite positive children from a rainforest region in Ghana. These children were treated with dihydro-artemisinin piperaquine, and plasma collected weekly for 1 month. By microscopy, 8.9% (15/168) of the children enrolled carried gametocytes at enrolment and 20% of them developed gametocytes dur-ing subsequent follow-up. More than 50% of the gametocyte-positive children tested to date carry antibodies to GSA. Fur-ther longitudinal flow cytometry will enable understanding of the dynamics of GSA development following treatment of asymptomatic malaria.
throughput assays, and an assessment of Pf evolution using mitochondrial and apicoplast genomes.
To support this work, stand-alone software has been developed to view genomic variation (“VarB”), and identify and display regions under selection, as well as recombina-tion breakpoints (“SelectionVista”). We have also developed web-based tools to view variants.
Further information may be obtained from www.patho-genseq.org.
20 Parasite Biology
London School of Hygiene & Tropical Medicine
Using next-generation sequencing technologies to identify Plasmodium falciparum genomic variation.
LSHTM Investigators: Nuno Sepúlveda, Mark Preston, Colin Sutherland,
David Conway & Taane Clark.
External Investigators/Collaborators: Samuel Assefa, Susana Campino
& Dominic Kwiatkowski (Wellcome Trust Sanger Institute, UK).
Funding Body: Bill & Melinda Gates Foundation.
Structural variations (SVs), such as copy number variations (CNVs), in the Plasmodium falciparum (Pf) genome have been associated with important health-related phenotypes, including anti-malarial drug resistance. Therefore, there is a great interest for human health in detecting and catalogu-ing SVs across the Pf genome. Genotyping array platforms, such as comparative genomic hybridization (CGH), have been widely used but could only detect a limited set of SVs. With the advent of next-generation sequencing technologies (NGTs), there is now the full capacity to characterise many types of SVs across the whole genome using the same data.
NGTs yield many millions of short sequences per sample, and data from hundreds of isolates are publically available.
We developed novel statistical methods in order to iden-tify SVs using paired-end mapped sequence alignments and the resulting genomic coverage. These new approaches have the advantage of dealing with the high AT-content of Pf ge-nome that usually affects the analysis due to uneven genomic coverage. We applied these methods to 6 well-characterised laboratory strains from different geographical origins and compared the results with the literature.
We confirmed several loci identified by CGH technolo-gies, including a large amplification at the PfMDR1 locus in the Thailand-origin Dd2 strain and another at the GTP cy-clohydrolase I locus across different strains but comprising different length. We also found other SVs that were not de-tected by previous technologies. These await experimental validation.
Ongoing work aims to extend the analysis to a large col-lection of field isolates, complemented by experimental vali-dation, and the development of a web-based exploratory tool for the research community.
Copy number variation in the GTP cyclohydrolase I, MDR1, and GECO/GEXP1 locus across three laboratory strains (GB4, Dd2 and 7G8) from different geographical origin (Ghana, Thailand and Brazil, respectively).
Parasite Biology 21
Malaria Centre Report 2010-11
The roles and modes of action of a Plasmodium LCCL protein family in sporozoite development and transmission.
LSHTM Investigators: Johannes Dessens, Sadia Saeed & Annie Tremp.
Funding Body: Wellcome Trust.
Malaria crystalloids are unique organelles of as yet unknown function that are present only in the mosquito-specific ooki-nete and early oocyst stages of the parasite. We have spatially and functionally linked crystalloid formation in Plasmodium berghei to the parasite protein PbSR, a member of the Plas-modium LCCL protein family composed of six modular mul-
Functional analysis of the Plasmodium falciparum cGMP-dependent protein kinase.
LSHTM Investigators: David Baker, Christian Flueck & Eloise Thompson.
External Investigators/Collaborators: Mike Blackman (National In-
stitute for Medical Research, UK); Manoj Duraisingh, (Harvard School of
Public Health, USA); Andrew Tobin (University of Leicester, UK).
Cyclic GMP signalling mediated by the cGMP-dependent pro-tein kinase (PKG) plays important roles in several stages of the malaria parasite life-cycle. This study aims to identify the molecular mechanisms by which Plasmodium falciparum protein kinase (PfPKG) mediates release of malaria parasites from red blood cells.
Investigating the Potential of Phosphodiesterases as a Target for Anti-malarial Drug Discovery.
LSHTM Investigators: Laura Drought, Paul Bowyer & David Baker.
External Investigators/Collaborators: Tanya Parkinson (Medicines for
Malaria Venture).
Funding Body: Biotechnology and Biological Sciences Research Council
(CASE studentship with Pfizer as industrial partner).
Cellular signalling plays a key role in the growth and devel-opment of Plasmodium parasites. As the life cycle progresses parasites sense changes in their environment and respond accordingly. Cyclic nucleotides are important mediators of signalling, as secondary messengers they affect many down-stream targets which have a variety of functions in the cell. Their levels must be tightly controlled for the parasites to
This new project has the following aims: ■ Identify the repertoire of parasite proteins phos-
phorylated by PfPKG in the blood-stages of the life-cycle us-ing a quantitative proteomic approach
■ Determine whether the cGMP-activated PfPKG acts upstream of the calcium-dependent protein kinases CDPK5 and CDPK4 in a single pathway, or whether they are part of parallel pathways during merozoite and gamete release, re-spectively
■ Determine whether PfPKG regulates secretion from parasite apical organelles required for egress/invasion.
complete their life cycle. The balance in a cell are determined by two groups of enzymes, cyclases and phosphodiester-ases (PDEs) which, create and breakdown these molecules respectively. These enzymes have proved to be important targets for drugs that treat a range of disorders in humans. Little is known about the malaria parasite PDEs. There are four Plasmodium PDE homologues, PDEα-δ, of which only one, PDEβ, is expected to be essential in the asexual blood stages of the parasite life cycle. This project firstly aims to expand our knowledge of how PDEs contribute to regulation of parasite life cycle progression, but will also investigate whether selective inhibitors of parasite PDEs could be used in anti-malarial chemotherapy.
tidomain proteins involved in sporozoite development and infectivity.
We have also shown more recently that at least two other LCCL protein family members are targeted to the crystalloids in a similar way to PbSR. These results extend the similarities between the LCCL proteins, and provide strong supporting evidence that members of this protein family work in concert and are involved in the same molecular process. This proj-ect aims to investiate the molecular interactions of the LCCL protein family members to elucidate their precise roles and modes of action and in this process.
22 Immunology & Vaccination
London School of Hygiene & Tropical Medicine
Members of the LSHTM Malaria Centre conduct fun-
damental research into the cellular and molecular
basis of immunity to malaria and the contribution of
immune responses to malarial pathology as well as
translational research on vaccines and on the use of
serology for mapping malaria transmission. Work
encompasses epidemiological studies, ex vivo and in
vitro studies of human cells and work in experimental
model systems.
Here, we summarise recent studies designed to
understand the complex immunomodulatory conse-
quences of infections, such as the role of T cell regu-
latory receptors in inhibiting T cell effector function
and ameliorating severe malarial pathology. A par-
ticular highlight is the demonstration that the heme-
oxygenase pathway of heme detoxification (which is
essential for preventing oxidative tissue damage dur-
ing malaria infections) acts to impair the normal mat-
uration of bone marrow neutrophils. This neutrophil
dysfunction underlies the increased susceptibility of
malaria-infected hosts to gram-negative (and particu-
larly non-typhoid Salmonella) bacteraemia and pro-
vides the first mechanistic explanation for the well
described clinical association between severe malar-
ial anaemia (and other forms of haemolytic anaemia)
and bacteraemia.
Other studies include recent epidemiological
studies in Africa to investigate the capacity of natural-
ly acquired antibodies to neutralise the inflammatory
activity of malarial “toxins”, to characterise the dy-
namics of acquisition and retention of malaria specific
memory B cells in an area of very low and seasonal
malaria endemicity, and to better understand the re-
lationship between asymptomatic infections and the
maintenance and boosting of anti-malarial antibodies
(with a particular emphasis on the longevity of anti-
body responses that reduce transmission of malaria
between humans to mosquitoes). Results are also
presented of a study in Thailand designed to estimate
the longevity of malaria specific T cell-mediated im-
munity. This type of data is essential for improving our
understanding of naturally acquired immunity and for
setting benchmarks by which we can assess vaccine-
induced immunity.
Finally, members continue to provide intellectual,
technical and logistic support to the very large Phase
3 clinical trial of the RTS,S vaccine, the very first phase
3 trial of a malaria vaccine, and were delighted that
the initial analysis of the trial outcomes confirmed the
results of the numerous phase 2 trials, with the vac-
cine conferring approximately 50% protection against
clinical malaria episodes. Importantly, our analysis
of cellular immune responses induced by the vaccine
identified several new and highly sensitive markers of
antigen-specific T cell responses that may be useful in
future studies to determine the magnitude and dura-
tion of these responses and assist in the search for im-
munological correlates of protection.
Summary
Immunology & Vaccination 23
Malaria Centre Report 2010-11
Human immune responses that reduce the transmission of Plasmodium falciparum in African populations.
LSHTM Investigators: Teun Bousema, Colin Sutherland, Eleanor Riley,
Geoffrey Targett & Chris Drakeley.
External Investigators/Collaborators: Thomas Churcher (Imperial
College London, UK); Bert Mulder (Microbiology Laboratory Twente, The
Netherlands); Louis Gouagna (L’Institut de recherche pour le développe-
ment, France).
Funding Body: Wellcome Trust and European Union.
Malaria-infected individuals can develop antibodies which reduce the infectiousness of Plasmodium gametocytes to bit-ing Anopheles mosquitoes. When ingested in a bloodmeal together with gametocytes, these antibodies reduce or pre-vent subsequent parasite maturation in the insect host. This transmission blocking immunity is usually measured in human sera by testing its effect on the infectivity of gametocytes grown in vitro. Here we evaluate evidence of transmission-blocking im-munity in eight studies conducted in three African countries. Plasmodium falciparum gametocytes isolated from each individual were fed to mosquitoes in both autologous plasma collected with the parasites, and permissive serum from non-exposed do-nors. Evidence of transmission reducing effects of autologous plasma was found in all countries. Experiments involving 116 Gambian children (aged 0.5–15 years) were combined to determine which factors were associated with transmission reducing immune responses. The chances of infecting at least one mosquito and the average proportion of infected mosquitoes were negatively associated with recent exposure to gametocytes and sampling late in the season. These results suggest that effective malaria transmission-reducing antibodies do not commonly circulate in African children, and that recent gametocyte carriage is required to initiate and/or boost such responses.
The relationship between gametocyte density by microscopy and the proportion of infected mosquitoes. Light grey circles indicate the proportion of infected mosquitoes after feeding on blood samples with control serum; dark grey circles indicate autologous plasma. The sizes of the circles are proportional to the number of mosquitoes dissected for a given range of game-tocyte densities.
The dynamics of malaria-specific antibody responses in relation to microscopic and submicroscopic Plasmodium falciparum infections.
LSHTM Investigators: Carla Proietti, Federica Verra, Michael Bretscher,
Patrick Corran, Eleanor Riley, Teun Bousema & Chris Drakeley.
External Investigators/Collaborators: Andrea Crisanti (Imperial Col-
lege London, UK); Raffaele Ronca & Bruno Arca (Federico II University,
Italy); Bernard Kanoi, Betty Balikagala & Tomas Egwang (Medical Bio-
tech Laboratories, Uganda).
Funding Body: European Comission-FP7 Marie Curie Actions.
Understanding of the dynamics of antibody responses against malaria infection, and in particular, the effect of im-mune boosting on the acquisition and maintenance of natu-rally acquired immunity, is essential for the interpretation of findings from cross-sectional and even longitudinal studies.
We examined the effect of microscopic and sub-micro-scopic malaria infections on malaria-specific antibody acqui-sition and explore the dynamics of antibody responses in re-lation to malaria infections in longitudinal cohorts from high endemic area of Apac, Uganda.
500 individuals were selected (250 <5years, 125 <10years, and 125 adults) and followed throughout the transmission season. At three time-points, plasma was col-lected and antibody responses against Plasmodium falci-parum AMA1, MSP-1, MSP-2 and CSP and Anopheles-specific gSG6 were determined. Antibody responses against all anti-gens were associated with current submicroscopic infections with Plasmodium falciparum. Individuals with no parasites had the lowest antibody levels but no difference was seen in antibody levels between individuals with patent or submi-croscopic infections. This suggest that in this endemic set-ting, low density infections are important for maintaining antibody levels.
24 Immunology & Vaccination
London School of Hygiene & Tropical Medicine
Neutralization of malaria glycosylphosphatidylinositol in vitro by serum IgG from malaria exposed individuals.
LSHTM Investigators: Brian de Souza, Kevin Couper,
Patrick Corran, Lucy Okell, Tom Doherty, Colin Suther-
land & Eleanor Riley.
External Investigators/Collaborators: Channe Gowda
(Pennsylvania State University, USA); Geoff Pasvol (Impe-
rial College London, UK).
Funding Body: Wellcome Trust.
Parasite-derived glycosylphosphatidylinosi-tol (GPI) is believed to be a major inducer of the pathways leading to pathology and mor-bidity during malaria infection and has been termed a malaria “toxin”. The generation of neutralising anti-GPI (“anti-toxic”) antibodies has, therefore, been hypothesised to be an im-portant step in the acquisition of anti-disease immunity to malaria. However to date the GPI-neutralising capacity of antibodies induced during natural malaria infection has not been evaluated. We have developed an in vitro mac-rophage-based assay to assess the neutralising capacity of malarial GPI-specific IgG. We demonstrate that IgG from Plasmodium falciparum-exposed individuals can signifi-cantly inhibit GPI-induced activation of macrophages in vitro, as shown by reduced TNF production and attenuation of CD40 expression. The GPI neutralising capacity of individual IgG samples was directly correlated with anti-GPI antibody titre. IgG from malaria-exposed individuals also neutralised the macrophage activating effects of Plasmodium falciparum schizont extract (PfSE) but there was only a poor correlation between PfSE neutralising activity and anti-GPI antibody titre, suggesting that PfSE contains other macrophage activating moieties in addition to GPI. In conclusion, we have established an in vitro assay to test the “toxin” neutralising activity of anti-malarial antibodies and have shown that anti-GPI antibodies from malaria immune individu-als are able to neutralise GPI- induced macrophage activation; however the clinical relevance of anti-GPI antibodies remains to be proven given that malarial schizonts contain other pro-inflammatory moieties in addition to GPI.
IgG from malaria immune individuals neutralises GPI-induced TNF production. Neutralization of GPI-induced TNF release from macrophages after incubation with endotoxin-free IgG. Each point represents the mean percentage TNF reduction (±SD) of IgG samples from control (open symbols) and immune subjects (solid symbols) from at least three separate experiments. The horizontal dotted line shows the cut-off level for neutralizing activity; values below this cut-off are clas-sified as “non-neutralizers”. The regression line shows a significant (p<0.001) association between neutralization and anti-GPI antibody titre.
Dynamics of the breadth and magnitude of circulating memory B cell responses to Plasmodium falciparum in an area of low malaria transmission.
LSHTM Investigators: Sarah Nogaro, Eleanor Riley, Julius Hafalla, David
Conway & Kevin Tetteh.
External Investigators/Collaborators: Michael Walther & Brigitte
Walther (Medical Research Council, The Gambia); Edmond Remarque
(Biomedical Primate Research Centre, The Netherlands).
Funding Body: Medical Research Council, UK.
Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly im-munogenic or that the development of effective immune re-sponses to malaria may be impaired. To begin to test these two hypotheses, we carried out two age-stratified cross-sec-tional surveys of anti-malarial humoral immune responses in a Gambian village where Plasmodium falciparum malaria transmission is low and sporadic. Circulating antibodies and memory B cells (MBC) to four malarial antigens were mea-sured using ELISA and cultured B cell ELISpot. The propor-tion of individuals with malaria-specific MBC and antibod-ies, and the average number of antigens recognised by each individual, increased with age but the magnitude of these
Immunology & Vaccination 25
Malaria Centre Report 2010-11
The magnitude of the malaria antigen-specific MBC response does not increase with age. The magnitude of Ag-specific serum IgG (A–E) and of Ag-specific MBC responses [expressed as %MBC (F–J) or expressed as MBC/PBMC (K–O)] are shown for individuals who showed evidence of previous malaria exposure. Box plots indicate the 25th, 50st and 75th percentile, with whiskers representing the 10th and 90th percentiles. Outliers are denoted by a spot. P values are given for Kruskal-Wallis tests.
responses did not. Malaria-specific antibody levels did not correlate with either the prevalence or median number of MBC, indicating that these two assays are measuring differ-ent aspects of the humoral immune response. Among those with immunological evidence of malaria exposure (defined
as a positive response to at least one malarial antigen either by ELISA or ELISpot), the median number of malaria-specific MBC was similar to median numbers of diphtheria-specific MBC, suggesting that the circulating memory cell pool for malaria antigens is of similar size to that for other antigens.
26 Immunology & Vaccination
London School of Hygiene & Tropical Medicine
Duration of effector and memory T cell responses to malaria in an area of low malaria endemicity.
LSHTM Investigators: Eleanor Riley, Julius Hafalla & Lucy Okell.
External Investigators/Collaborators: Jiraprapa Wipasa, Supachai
Sakkhachornphop, Chaisuree Suphavilai, Kriangkrai Chawansuntati. (Re-
search Institute for Health Sciences, Thailand); Witaya Liewsaree (Office
Disease Prevention and Control, Thailand).
Funding Body: Wellcome Trust.
Immunity to malaria is widely believed to wane in the ab-sence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. To test this assumption, we have analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of Plasmodium falciparum and/or Plasmodium vivax in the past 6 years.
The magnitude of T cell IFN-γ responses declines with time since last infection for those infected with Plasmodium falciparum, but not those infected with Plasmodium vivax.
CD4+ T cell effector memory (CD45RO+) IFN-γ (24 hours ex vivo restimulation) and cultured IL-10 (6 day secre-tion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-γ-producing effector memory T cells declined signifi-cantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years. In sharp con-trast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. Our observations have clear implications for understanding the immunoepidemiology of naturally ac-quired malaria infections and for malaria vaccine develop-ment.
Immunology & Vaccination 27
Malaria Centre Report 2010-11
Phase III Trial of RTS,S/AS01 Malaria Vaccine Candidate in African Children.
LSHTM Investigators: Daniel Chandramohan, Chris Drakeley, Brian
Greenwood, Seth Owusu-Agyei & David Schellenberg.
External Investigators/Collaborators: The RTS,S Clinical Trials Part-
nership.
Funding Body: PATH Malaria Vaccine Initiative.
RTS,S/AS01 is the most advanced malaria vaccine candi-date which has progressed through phase II clinical trials to a multi-centre phase III study. This is being conducted by a broad partnership involving researchers from 11 research centres in 7 countries in sub-Saharan Africa, their associated northern partners, GSK and the Malaria Vaccine Initiative at PATH. The study has recruited 15,460 children in two age categories – 6-12 weeks and 5-17 months old at the time of dose 1 – and randomised them to receive either RTS,S or a
comparator vaccine. The primary endpoint is efficacy against clinical malaria and secondary endpoints include efficacy against severe disease, efficacy in different transmission set-tings and the role of a booster dose.
Results of the primary endpoint analysis during 12 months of follow-up in the 5-17 month age category were published in 2011. RTS,S efficacy against clinical malaria was 55.8% (97.5% CI, 50.6 to 60.4), with 0.55 episodes of clinical malaria per person-year in the control group and 0.32 epi-sodes per person-year in RTS,S recipients). Efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5). Overall, serious adverse events occurred with a similar frequency in the two study groups. The rate of generalized convulsive seizures after RTS,S/AS01 was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). The primary endpoint for children in the younger age category will be evaluated towards the end of 2012, and complete trial results are expected to be available for review by policy makers in 2015.
Cellular immune responses induced by immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine.
LSHTM Investigators: Amir Horowitz, Julius Hafalla, Elizabeth King,
Denise Dekker, Patrick Corran, Chris Drakeley, Lorenz von Seidlein & El-
eanor Riley.
External Investigators/Collaborators: John Lusingu (National Institute
for Medical Research, Tanzania); Amanda Leach, Philippe Moris, Joe Co-
hen & Johan Vekemans, (GlaxoSmithKline Biologicals, Belgium); Tonya Vil-
lafana (PATH Malaria Vaccine Initiative, USA); Philip Bejon (Kenya Medi-
cal Research Institute/ Wellcome Trust Programme, Kenya).
Funding Body: PATH Malaria Vaccine Initiative.
RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum, is undergoing clinical trials. We con-ducted an analysis of cellular immune response to compo-nent antigens of RTS,S – hepatitis B surface antigen (HBs) and Plasmodium falciparum circumsporozoite (CS) protein – among Tanzanian children in a Phase IIb RTS,S/AS01E trial. We observed that RTS,S/AS01 E vaccinees make stron-ger T cell IFN-γ, CD69 and CD25 responses to HBs peptides than do controls, indicating that RTS,S boosts pre-existing HBs responses. T cell CD69 and CD25 responses to CS and CS-specific secreted IL-2, were augmented by RTS,S vaccina-tion. Importantly, more than 50% of peptide-induced IFN-γ+ lymphocytes were NK cells and the magnitude of the NK cell CD69 response to HBs peptides correlated with secreted IL-2 concentration. CD69 and CD25 expression and IL-2 secretion
Relative contribution of T cells and NK cells to the total IFN-g response to HBs and CS peptides in RTS,S/AS01E vaccinated subjects. PBMCs from RTS,S/AS01E vaccinees (n = 80) were cultured with HBs or CS peptides for 24 h and analysed by flow cytometry. (Top) An example of the gating strategy to identify IFN-g+ cells and then to determine the proportion of these cells that are either T cells (CD3+), NK cells (CD3-, CD56+) or CD3-CD56- cells for HBs-stimulated cells from one vac-cinated subject. (Bottom) Bar charts indicate the absolute number (mean/SD per 105 PBMCs) of IFN-g+ cells that are NK cells, T cells or CD3-CD56- (DN, double negative) lymphocytes among HBs-stimulated (filled bars) or CS-stimulated (open bars) PBMC.
may represent sensitive markers of RTS,S-induced, CS-spe-cific T cells. The potential for T cell-derived IL-2 to augment NK cell activation in RTS,S-vaccinated individuals, and the relevance of this for protection, needs to be explored further.
28 Immunology & Vaccination
London School of Hygiene & Tropical Medicine
We found that the expression of CTLA-4 and PD-1 on T cells correlates with the extent of pro-inflammatory respons-es induced during PbA infection, being higher in C57BL/6 than in BALB/c mice. However, antibody-mediated blockade of either the CTLA-4 or PD-1/PD-L1, but not the PD-1/PD-L2, pathways during PbA-infection in ECM-resistant BALB/c mice resulted in higher levels of T cell activation, enhanced IFN-γ production, increased intravascular arrest of both par-asitised erythrocytes and CD8 T cells to the brain, and aug-mented incidence of ECM. Thus, in ECM-resistant BALB/c mice, CTLA-4 and PD-1/PD-L1 represent essential, indepen-dent and non-redundant pathways for maintaining T cell homeostasis during a virulent malaria infection. Moreover, neutralisation of IFN-γ or depletion of CD8+ T cells during PbA infection was shown to reverse the pathologic effects of regulatory pathway blockade, highlighting that the aetiol-ogy of ECM in the BALB/c mice is similar to that in C57BL/6 mice. In summary, our results underscore the differential and complex regulation that governs immune responses to malaria parasites.
The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to acute Plasmodium-induced immune pathology.
LSHTM Investigators: Julius Hafalla, Kevin Couper & Eleanor Riley.
External Investigators/Collaborators: Brian de Souza (University Col-
lege, London); Carla Claser & Laurent Renia (Singapore Immunology Net-
work, Singapore); Georges Grau (The University of Sydney, Australia).
Funding Body: Wellcome Trust and The Royal Society.
The balance between pro-inflammatory and regulatory im-mune responses in determining optimal T cell activation is vital for the successful resolution of malaria infections. Dur-ing chronic infections, this balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L1, which dampen effector responses. However, their role in acute infections, such as malaria, remains less clear. Thus, we determined the contribution of CTLA-4 and PD-1/PD-L to the regulation of T cell responses during Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM) in susceptible (C57BL/6) and resistant (BALB/c) mice.
Regulation of effector T cell responses by IFN-γ during Plasmodium berghei ANKA infection.
LSHTM Investigators: Ana Villegas-Mendez, Brian de Souza, Tovah Shaw,
Rachel Greig, Eleanor Riley & Kevin Couper.
Funding Body: Biotechnology and Biological Sciences Research Council.
IFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection but the role of IFN-γ in shaping the effector CD4+ and CD8+ T cell response has not been examined in detail. To address this, we compared the effector T cell re-sponses in wild-type and IFN-γ-/- mice during Plasmodium berghei ANKA infection.
The expansion of splenic CD4+ and CD8+ T cells was not affected by the absence of IFN-γ but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ-/- mice, however, the migration to, and accumula-tion of, effector CD4+ and CD8+ T cells in the lung, liver and brain was altered in IFN-γ-/- mice. Regulation of splenic T cell numbers depended upon active IFN-γ-dependent envi-
IFN-γ promotes apoptosis of splenic T cells during P. berghei ANKA infection. WT and IFN-γ−/− mice were infected i.v. with 104 P. berghei ANKA pRBC. Representative dot plots showing the surface expression of annexin V and 7-AAD on naive and infection-derived (D7) CD4+ and CD8+ T cells.
ronmental signals, leading to T cell apoptosis. In summary, this study to reveals a novel role for IFN-γ during malaria in-fection, being required for efficient contraction of the pool of activated T cells upon resolution of the infection.
Immunology & Vaccination 29
Malaria Centre Report 2010-11
Mechanisms of impaired resistance to Salmonella in malaria patients.
LSHTM Investigators: Aubrey Cunnnington & Eleanor Riley.
External Investigators/Collaborators: Michael Walther (Medical Re-
search Council, The Gambia) & Brian de Souza (University College London,
UK).
Funding Body: Medical Research Council, UK.
In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plas-modium falciparum infection. Induction of heme oxygen-ase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis. We hypothesised that HO-1 might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We have shown that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Sal-monella typhimurium) causes acute, fatal bacteremia with
high bacterial load. Salmonella typhimurium localized pre-dominantly in granulocytes. We found that malaria infection caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. In-hibition of HO by tin protoporphyrin abrogated the impair-ment of resistance to Salmonella typhimurium. Since our data suggest that HO inhibitors might be useful adjunctive therapy for NTS infection in the context of hemolysis, studies were undertaken in The Gambia to determine whether simi-lar defects in neutrophil function occur in malaria patients.
Acute, uncomplicated malaria caused the appearance of a population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 weeks of follow-up. The degree of oxidative burst impairment correlated sig-nificantly with markers of hemolysis. HO-1 expression was increased in blood during an acute malaria episode. Together these data suggest that neutrophil dysfunction also occurs in children with Plasmodium falciparum malaria and may ex-plain the associated susceptibility to NTS infection.
30 Drug Development, Deployment & Resistance
London School of Hygiene & Tropical Medicine
Summary
During the last two years, the goal of providing ef-
fective antimalarial therapy to people with Plasmo-
dium infections throughout the endemic regions of
the globe has suffered a serious setback - the emer-
gence of parasites resistant to artemisinin on the
Thai-Cambodian border, and near Mae Sod on the
Thai-Myanmar border. In this section, we present a
range of projects by members of the LSHTM Malaria
Centre addressing the challenge posed by drug re-
sistance, from improved implementation of combi-
nation therapy, to studies mapping, describing and
seeking to elucidate markers for drug resistance, to
work in the area of drug discovery – the search for
and testing of new lead compounds as precursors of
the antimalarial drugs of the coming decades. These
projects are addressing the following questions:
■ How can Artemisinin-based Combination Thera-
py (ACT) be effectively delivered to peripheral health sys-
tems, and its impact monitored?
■ How can we assist country Malaria Control Pro-
grammes to maintain access to high quality, authentic
drugs for malaria?
■ How do the new combination malaria drugs now
being heavily used across Africa interact with drugs used
by HIV-infected individuals?
■ Can emerging artemisinin resistance in South-
east Asia be contained through coordinated monitoring
and control? How far has it spread?
■ Does the emergence of artemisinin resistance in
Southeast Asia threaten ACT efficacy in Africa?
■ Do we have genetic markers of artemisinin resis-
tance we can use for monitoring and surveillance?
■ Can parasite genomics provide new approaches
to these questions?
■ Are preventive treatment-based interventions
an important source of drug selection, exacerbating the
spread of resistant parasites?
■ Can our knowledge of important molecules such
as protein kinases, essential for survival of the Plasmo-
dium parasite, assist in finding new classes of therapeutic
drugs?
■ Do new candidate antimalarial compounds, test-
ed on lab strains, also have demonstrated activity on Plas-
modium parasites taken directly from malaria patients?
These projects thus begin with the task of ensur-
ing effective delivery of combination anti-malarial
drugs to those who need them, and then examine the
potential threat to these drugs of developing resis-
tance, in both Asia and Africa. Novel approaches to
monitoring drug efficacy are described, and we track
the spread of resistant parasites in different parts of
the malaria-endemic world, in some places assisted
by current digital mapping technologies. The im-
pact of drug-based public health interventions, par-
ticularly Intermittent Preventive Treatment (IPT),
Drug Development, Deployment & Resistance 31
Malaria Centre Report 2010-11
The ACT Consortium: a research consortium to optimize the delivery of effective anti-malarial treatment.
LSHTM Investigators: Evelyn Ansah, Daniel Chandramohan, Sian Clarke,
Catherine Goodman, Harparkash Kaur, Toby Leslie, Seth Owusu-Agyei,
Hugh Reyburn, Mark Rowland, Sarah Staedke, Jayne Webster, Virginia
Wiseman, Clare Chandler, Bonnie Cundill, Kristian Hansen, Shunmay
Yeung, Christopher Whitty & David Schellenberg.
External Investigators/Collaborators: Salim Abdullah (Ifakara Health
Research & Development Centre, Tanzania); Karen Barnes (University of
Cape Town, South Africa); Anders Bjorkman (Karolinska Institutet, Swe-
den); Emma Davies, David Lalloo, Munir Pirmohamed & Steven Ward
(Liverpool School of Tropical Medicine, UK); Facundo Fernandez (Georgia
Institute of Technology, USA); Michael Green & Patrick Kachur (Centers for
Disease Control & Prevention, USA); Martha Lemnge (National Institute
for Medical Research, Tanzania); Pascal Magnussen & Lasse Vestergaard
(University of Copenhagen, Denmark); Wilfred Mbacham (University of
Yaounde, Cameroon); Anthony Mbonye & Richard Ndyomugyenyi (Minis-
try of Health, Uganda); Paul Newton (University of Oxford, UK), Obinna
Onwujekwe (University of Nigeria, Nigeria), & Kamija Phiri (University of
Malawi, Malawi).
Funding Body: The Bill & Melinda Gates Foundation.
The ACT Consortium (www.actconsortium.org) is an inter-national research collaboration aiming to maximize the pub-lic health impact of Artemisinin-based Combination Therapy (ACT) through high-quality, policy-driven, multidisciplinary operational research. Active in 10 countries and with part-ners world-wide, we use a variety of study designs including complex evaluations to address questions about:• How to improve access to good-quality ACT for those who most need them; • How to target ACT to patients with malaria, through the deployment of Rapid Diagnostic Tests;• Drug quality, by assessing the prevalence of sub-standard and counterfeit artemisinin drugs;• The safety of ACT under operational conditions, es-pecially in high risk groups and when used in combination with other drugs.
Answering these key questions will help give policy makers and programme managers the evidence they need to ensure effective malaria control programmes can be imple-mented.
on developing parasite resistance is investigated in
southern Tanzania, where IPT for malaria in infants
was first trialled. Finally, we examine potential new
therapeutic strategies using protein kinase inhibi-
tors, and test new drugs and compounds for anti-
parasite activity on ex vivo parasite isolates taken di-
rectly from our patients at the Hospital for Tropical
Diseases in London.
In each of the studies described, Malaria Centre
staff and students are working with a variety of part-
ner institutions, including UK and endemic country
government agencies, and European and endemic
country academic institutions, hospitals and non-
government organisations.
32 Drug Development, Deployment & Resistance
London School of Hygiene & Tropical Medicine
A surveillance system and drug forensic network to monitor the quality and authenticity of artemisinin combination treatments in Africa.
LSHTM Investigators: Harparkash Kaur, Albert van Wyk, Naiela Malik,
Caroline Lynch & Shunmay Yeung.
External Investigators/Collaborators: Facundo Fernandez (Georgia
Tech. School of Chemistry and Biochemistry, USA); Michael Green (Centers
for Disease Control and Prevention, USA); Paul Newton (Centre for Clini-
cal Vaccinology and Tropical Medicine, UK, Mahosot Hospital, Lao PDR &
LSHTM, UK).
Funding Body: The Bill & Melinda Gates Foundation though the ACT Con-
sortium.
The lack of reliable estimates of suspect antimalarial drugs – particularly that of Artemisinin-based Combination Ther-apy (ACT) in malaria-endemic countries poses an enormous threat to malaria patients. To contribute to the tackling of this problem, our project aims to provide robust estimates of sub-standard, counterfeit and degraded artemisinin con-taining drugs and to develop standardised methodologies for sampling. To assist in classifying whether the drugs are
degraded due to environmental impact rather than manu-facturing practices, we are carrying out the ageing of ACT in field and laboratory based studies.
We have used a range of sampling strategies to collect drugs from public and private healthcare providers in Rwan-da, Cambodia, Ghana and Tanzania, with sampling in other locations currently underway.
All samples are logged onto a database, the packages scanned and tablets weighed and measured. Qualitative (mass spectrometry, near infrared and Raman spectroscopy) and quantitative (high performance liquid chromatography and high performance liquid chromatography-mass spec-troscopy) content analyses are conducted.
Thus far around 5,000 drugs have been analysed. Pre-liminary content analyses indicate a number of samples fall below the internationally recommended thresholds for their stated Annual Parasitic Incidence (API) with variations found to occur both between and within batches of the same brand. Following cross verification between the three col-laborating laboratories, the results will be shared with the national authorities and stored on the “Counterfeit Drug Fo-rensic Network – CODFIN” database.
Packets of ACT placed in the stability chamber and field clinic for up to four years.
Samples in dark
Samples in light
Samples placed in a store in the field
Samples in dark
Samples in light
Chamber set at 37° C & 50% HT
a) ACT placed in stability chamber at LSHTM b) ACT placed in a malaria endemic country
Drug Development, Deployment & Resistance 33
Malaria Centre Report 2010-11
Fake artesunate in Africa. A near death experience for an European tourist.
LSHTM Investigators: Harparkash Kaur, Albert van Wyk, Naiela Malik &
David Mabey.
External Investigators/Collaborators: Carlos Chaccour, Pozo Luis Del &
Jose Luis Del (Clínica Universidad de Navarra, Spain).
There is limited documented evidence directly linking ma-laria treatment failure to proven poor quality antimalarial medication. Herein we present a case of Plasmodium falci-parum malaria treated with fake Artesunate purchased in West Africa.
In 2011, a Spanish citizen who visited Equatorial Guinea (EG) on a regular basis, attended a health centre in Malabo where she was diagnosed with slide-positive falciparum ma-laria and advised to buy artesunate and sulfadoxine-pyri-
methamine (SP) from the local traders. She bought two boxes of “Artesunat®” 50 mg labeled as being manufactured by Me-kophar, Vietnam, and took four tablets a day together with SP. After three days, the patient’s symptoms persisted and on returning to Navarra (Spain) was admitted to hospital and treated with the hospital’s supply of intravenous artesunate, leading to full recovery within three days.
The patient notified her doctor regarding her illness and subsequent treatment from EG. She supplied her physi-cian with the remaining “Artesunat®”. To confirm the cause of treatment failure, he forwarded the tablets to the LSHTM analytical facility. We tested the tablets for chemical content using our qualitative Rapid Field Test and then confirmed the result using high performance liquid chromatography. The tablets were not found to contain the stated (artesunate) ac-tive pharmaceutical ingredient.
Front and back of package of artesunate tablets.
Results of the field test showing the Prussian blue colour in the presence of the artemisinin reference standard (AS std) and the quality assured tablet of artesunate. The falsified drug (Artesunat®) taken by the patient did not give the expected Prussion blue colour of an authentic artesunate.
Treatment of asymptomatic malaria in HIV- positive and HIV-negative Nigerian adults using artemether-lumefantrine.
LSHTM Investigators: Ifeyinwa Chijioke-Nwauche, Mary Oguike, Albert
van Wyck, Naiela Malik, Harparkash Kaur & Colin Sutherland.
External Investigators/Collaborators: University of Port Harcourt, Ni-
geria.
The co-infection of malaria and HIV has become a major chal-lenge to public health in developing countries. The highly ac-tive anti-retroviral therapy currently used for the treatment of HIV patients has improved the prognosis of the disease, reducing mortality due to HIV infection. However the admin-istration of these drugs poses a great challenge due to the potential drug-drug interactions as a result of multiplicity of drugs involved especially in co-morbid situations with ma-laria.
Using HPLC we assessed the bioavailability of lumefan-trine based on the concentration in the capillary blood 7 days following treatment and also the impact of concomitant ne-virapine treatment in subjects positive for Plasmodium falci-parum infection.
In HIV-positive people, with and without PCR-positive parasitaemia, artemether-lumefantrine improved CD4+ counts by day 28. Day 7 peripheral blood levels of lumefan-tine were significantly higher in nevirapine-treated people; lumefantrine levels were also higher in parasite positive peo-ple (by PCR) than PCR negative, but this effect was weaker than the ARV effect.
Nevirapine, a non-nucleoside reverse transcriptase in-hibitor, is known to stimulate live P450 enzymes and this ac-tivation may account for improved day 7 lumefantrine levels. We are investigating the impact of higher levels on parasito-logical outcomes.
HIV positive individuals receiving regular nevirapine ARV treatment were found to have significantly higher lumefantrine serum levels 7 days after receiving a full course of artemether-lumefantrine.
34 Drug Development, Deployment & Resistance
London School of Hygiene & Tropical Medicine
Tracking Resistance to Artemisinins Collaboration (TRAC)
LSHTM Investigators: Shunmay Yeung, Colin Sutherland, Phillipe Guyant
& Richard Coker.
External Investigators/Collaborators: Rick Fairhurst (National Insti-
tutes of Health, USA); Pharath Lim & Yi Poravuth (Cambodian National
Malaria Centre, Cambodia); Mayfong Mayxay (Wellcome Trust-Mahosot
Hospital-Oxford Tropical Medicine, Laos); Francois Nosten (Shoklo-Malar-
ia Research Unit, Thailand); Sasithon Pukrittanyakamee, (Mahidol Uni-
versity, Thailand); Abdul Faiz (Chittagong Medical College, Bangladesh);
Olubenga Mokuolu (University of Ilorin, Nigeria); Neena Valecha (India);
Steffan Boramman (KEMRI- Wellcome Trust Research programme Re-
search Collaboration, Kenya); Ye Htut (Department of Medical Research,
Myanmar); Tran Tinh Hien (Oxford University Clinical Research Unit, Vi-
etnam).
Funding Body: UK Department for International Development.
The Tracking Resistance to Artemisinin Collaboration is a multi-country multi-disciplinary collaboration, led by the Mahidol-Oxford Research Unit, that was formed to inform artemisinin resistance containment efforts in response to a call for proposals by the UK Government Department for In-
ternational Development. The initiative is funded for three years and has three main components:
■ Clinical. A multicentre clinical trial at 15 sites in 9 countries, predominantly in Asia, to detect evidence of spread of artemisinin resistance. This work is coordinated by the Mahidol Oxford Tropical Medicine Research Unit in Bangkok with the support of WWARN and involves molecu-lar and pharmacokinetic studies.
■ Understanding demand factors. This component ,led by LSHTM, focuses on social and economic research in-cluding the demand for, use of and quality of drugs, by at-risk populations and the implications for the development and control of drug resistance using mixed methods. It is closely linked to the clinical studies in Cambodia, Thailand, Laos, Bangladesh and Nigeria, with additional operational research being conducted in Cambodia. Vector control. Re-searchers from the Liverpool School of Tropical Medicine plan to produce and evaluate innovative vector control strat-egies developed specifically to suit the Cambodian context.
The Global Malaria Programme of the World Health Or-ganisation is another key partner and will review results generated by the 3 research arms.
Drug cocktails.
Drug Development, Deployment & Resistance 35
Malaria Centre Report 2010-11
Measuring parasite clearance after ACT treatment using a newly developed qPCR method.
LSHTM Investigators: Khalid Beshir & Colin Sutherland.
External Investigators/Collaborators: WANECAM group (West Afri-
can Network for Clinical trials of AntiMalarial drugs): Malaria Research
and Training Center; Université de Bamako, Mali; Centre National de Re-
cherche et de Formation sur le Paludisme, Burkina Faso; Institut de Re-
cherche en Science de la Santé, Burkina Fas; Centre National de formation
et de Recherche en Santé Rurale, Guinée; Medical Research Council, The
Gambia; de Recherche sur la Malaria, Université Claude Bernard, France;
The malaria research unit at the Karolinska University Hospital, Sweden;
Molecular-epidemiology of malaria group, University of Heidelberg School
of Medicine, Germany.
Funding Body: The European and Developing Countries Partnership
(EDCTP) through the WANECAM Consortium.
Parasite clearance, a measure of artemisinin response phe-notype, is usually estimated using microscopic examination of thin and thick blood-smears.
However, a frequent closely-spaced venous sampling is required in order to see a significant difference in clearance time using microscopy. This approach may not be suitable in Africa where the majority of trial participants are children. In addition, some treatment failures have been reported af-ter ACT treatments, yet no differences in parasite clearance were reported between patients who had recrudescent in-fection and those who were treated successfully.
We have developed a rapid and sensitive qPCR assay to measure parasite clearance in the first three days after treat-ment. The validation of the new qPCR method on samples derived from the venous blood of imported malaria cases in the UK has recently been published. The assay has now been tested on DNA derived from filter-paper bloodspots taken from a 2009 clinical trial of AL and DHA-PIP in western Ke-nya. The method identified a greater range of parasite clear-ance kinetics among children than did microscopy, allowing the analysis of phenotype-phenotype, phenotype-genotype and drug effect relationships with more statistical power. The new qPCR method will be used in WANECAM clinical tri-als of four ACT.
Identification and validation of candidate gene alleles associated with ACT resistant phenotypes of Plasmodium falciparum: part of the MALACTRES Consortium.
LSHTM Investigators: Colin Sutherland, Rachel Hallett, Nahla Gadalla,
Khalid Beshir, Brighid O’Neill & Teun Bousema.
External Investigators/Collaborators: Henk Schallig & Petra Mens
(Royal Tropical Institute, The Netherlands), Umberto D’Alessandro (The
Prince Leopold Institute of Tropical Medicine, Belgium), Aart van Amer-
ongen (Biomolecular Sensing and Diagnostics, Agrotechnology & Food
Innovations, The Netherlands), Chris Danks & Paul Meakin (Forsite Diag-
nostics Ltd, UK), Ehise Enato (Tropical Diseases Research Group, Nigeria),
Halidou Tinto (Centre Muraz, Burkina Faso) & Seif Shekalaghe (Kiliman-
jaro Christian Medical Centre, Tanzania).
Funding Body: The European Union Seventh Research Framework Pro-
gramme through the MALACTRES Consortium.
MALACTRES is a consortium of researchers aiming to tackle multi-drug resistance in malaria under combination therapy. With partners in Europe and Africa, the overall objective is to assess specific genetic markers in Plasmodium falciparum for associations with artemisinin combination therapy (ACT) resistance and to develop innovative, rapid and simple diag-nostics for malaria.
Since the last Malaria Centre Report we have: ■ Made progress in establishing SNP detection tests
for new candidate genes pfubp1 and pfap2-mu. ■ Produced good quality genotyping results from iso-
lates with in vitro drug susceptibility data from Burkina Faso. ■ Applied a novel molecular parasite clearance time
assay to samples from a clinical trial in Kenya. ■ Shown good evidence that slow parasite clearance
by PCR is linked to post-treatment parasite recurrence and carriage of gametocytes.
■ Generated evidence that pfmdr1 selection occurs in both dihydroartemisinin-piperaquine and artemether-lume-fantrine (AL) treatment groups by day 3 after treatment and thus is being selected by the artemisinin component.
■ Validated the pfmdr1 N86Y SNP as a useful marker of parasite response to both artemisinin and lumefantrine.
■ Expanded our large external network of collabora-tors including groups running cross-sectional surveys and clinical trials from which parasite material can be used for a detailed analysis of known and candidate drug resistance markers.
For more information see www.malactres.eu
36 Drug Development, Deployment & Resistance
London School of Hygiene & Tropical Medicine
Polymorphism in pfmdr1, pfatpase6 and pfubp1 in Plasmodium falciparum infections following treatment with artemether-lumefantrine in eastern Sudan.
LSHTM Investigators: Colin Sutherland, David Warhurst & Nahla Gadalla.
External Investigators/Collaborators: Badria El-Sayed (Tropical Medicine
Research Institute, Sudan); Ishag Adam (University of Khartoum, Sudan).
Funding Body: WHO/TDR & IAEA.
Molecular markers for surveillance of Plasmodium falciparum resistance to current artemisinins and their partner drugs are a public health priority. In Sudan, ACT have been recommended as first-line since 2004. A few reports of the clinical efficacy of artemether/lumefantrine (AL) from Sudan are available, but there is a lack of evaluation of molecular markers for AL in Su-dan and elsewhere in Africa.
A 28-day antimalarial drug efficacy trial of artemether-lumefantrine was carried out in eastern Sudan in 2006. In this study 5 (n=100) patients failed treatment with recurrent infections detected by microscopy during the follow-up. In addition, 9 further individuals were found to harbour parasites by PCR at day 14. Polymorphisms in pfmdr1, pfatpase6 and pfubp1 were detected by DNA sequencing and pfmdr1 copy number was estimated by qPCR. One individual carried parasites with a novel pfmdr1 polymorphism (F1044L). pfmdr1 copy number ranged from 0.73 to 2.33 (95% CI, 1.16 to 1.32) with an average copy number in pretreatment isolates of 1.24. Pfmdr1 copy number estimates above 1.8 in at least two independent experiments were obtained for three pretreatment isolates. Interestingly, pfmdr1-amplified isolates in this study carried the 86Y allele in-stead of the N86 consistent with other African reports and in contrast to those seen in Southeast Asia. The NFD haplotype of pfmdr1 was found to be selected by AL. There was genetic diversity in both pfatpase6 and pfubp1, but a lack of association of either gene with treatment response.
The appearance of amplified pfmdr1 warrants further investigation into the evolution and spread of this genotype in the study area despite the lack of mefloquine use.
Frequency distribution of pfmdr1 copy number estimates. Estimates of pfmdr1 locus copy numbers obtained from 55 pretreatment isolates with complete follow-up data are grouped in bins of 0.1 copy units. The values shown represent the means of at least two independent experiments; each DNA sample in each experiment was run in duplicate. Red data represent pretreatment parasite isolates from patients without subsequent recurrent parasitemia. Green data represent pretreatment parasite isolates from patients with later recurrent parasitemia by microscopy and/or PCR. Isolates with copy number estimates of 1.8 and above were considered true duplications.
Exploring the contribution of new genetic markers of drug resistance in human malaria parasites.
LSHTM Investigators: Gisela Henriques, Rachel Hallett, Colin Sutherland
& Teun Bousema.
External Investigators/Collaborators: Pedro Cravo (Universidade Fed-
eral de Goiás, Brazil); Paul Hunt (University of Edinburgh, UK); Halidou
Tinto (Centre Muraz, Burkina Faso); Umberto D’Alessandro (Medical
Research Council, The Gambia); Seif Shekalaghe (Kilimanjaro Christian
Medical College, Tanzania).
Funding Body: Portuguese Foundation for Science and Technology.
Artemisinin derivatives form the cornerstone of anti-malar-ial drug therapy for the treatment of Plasmodium falciparum infection and recent evidence suggesting the possible devel-opment of resistance to this group of drugs is a significant
public health concern. The main aim of this PhD project is to investigate the genetic basis of the malaria parasite’s resis-tance to artemisinin derivatives. Using genome-wide strat-egies in the rodent malaria parasite Plasmodium chabaudi Pedro Cravo and Paul Hunt, our collaborating research part-ners, have identified a number of novel genetic markers of antimalarial drug resistance.
Now, using field isolates that were tested in vitro for their response to artemisinin derivatives as well as pre- and post- treatment samples from in vivo ACT trials, we are inves-tigating the contribution that these new candidate genetic markers may be making to the development of artemisinin resistance in the human malaria parasite. Our preliminary results indicate that polymorphisms in a gene encoding the mu chain of the AP2 adaptor complex protein (pfap2-mu) are associated with varying degrees of in vitro and in vivo re-sponses to artemisinin.
Drug Development, Deployment & Resistance 37
Malaria Centre Report 2010-11
Analysis of copy number variation, drug-resistant genotypes, mitochondrial haplotypes and multi-clonality in Plasmodium falciparum by direct genome sequencing from patient peripheral blood.
LSHTM Investigators: Taane Clark & Colin Sutherland.
External Investigators/Collaborators: Sanger Institute, UK.
Funding Body: Wellcome Trust & UK Health Protection Agency.
We are deploying next generation sequencing to derive ge-nome data for non-propagated parasite isolates taken di-rectly from patients treated for clinical falciparum malaria
at the Hospital for Tropical Diseases. In a proof of principle study, all patients harboured at least 3 clones of Plasmodium falciparum, novel CNV were identified, mitochondrial poly-morphism detected and robust analysis of full-length drug resistance-associated loci was successfully completed. We conclude that genome sequencing of peripheral blood Plas-modium falciparum, taken directly from malaria patients provides high quality data useful for studies of drug resis-tance, genomic structure, population genetics and clonal multiplicity. We are currently investigating differences be-tween Plasmodium falciparum isolates taken from the same patient at different timepoints after initiation of antimalarial treatment.
Evidence of an apparent major deletion at the right end of chromosome 3 in Plasmodium falciparum, from a patient in HTD, London. Paired reads across the whole of chromosome 3 are presented in pile-up view for two isolates, OX005 and OX006 (upper panel). A detailed view of ~70kb around the clag3.2 and clag3.1 loci is also shown for 4 isolates (lower panel). The locus between PFC0110w and PFC0120w is a degenerate var gene lacking a full-length ORF in 3D7 and other parasite sequences in the available databases.
38 Drug Development, Deployment & Resistance
London School of Hygiene & Tropical Medicine
Drug-sensitive Plasmodium falciparum genotypes co-circulate with Plasmodium malariae, Plasmodium ovale and Plasmodium vivax in northern Angola.
LSHTM Investigators: Rachel Hallett & Colin Sutherland.
External Investigators/Collaborators: Dina Gamboa, Cláudia Videira,
Yuri Sebastião, Susana Vaz Nery (CISA – Health Research Center, Angola).
Funding Body: Portuguese Institute for Development Assistance &
Calouste Gulbenkian Foundation with the support of the Angolan Ministry
of Health and the Bengo Provincial Government.
The aims of this study were:• To determine the prevalence of the different Plas-
modium species in Northern Angola. • To measure the prevalences of drug-resistance as-
sociated mutations in Plasmodium falciparum genes.Angolan collaborators carried out a large cross sectional
survey of women and children in a rural area of Bengo Prov-
ince, north-western Angola, approximately 60 km north of the capital Luanda. Microscopy and the molecular method PCR were compared for their ability to detect 4 different Plasmodium species infecting humans. 541/3316 (16.3%) of the participants were found to carry parasites by PCR and all 4 species were identified, while in comparison, micros-copy identified only 58.23% of the parasite positive people. Plasmodium falciparum parasites were present in 97% of the infections, and we examined mutations in 2 genes (pfcrt and pfmdr1) that are known to influence parasite sensitiv-ity to the antimalarial drugs used in Angola. The haplotypes found varied significantly from those reported in a study in Luanda 4 years previously, perhaps reflecting the heteroge-neous drug pressures that can occur across a relatively small geographical area. The use of molecular methods to moni-tor antimalarial drug resistance provides key information to policy makers as decisions regarding the use of artemisinin combination therapies are made.
Collection of samples during a cross-sectional survey in Bengo Province, north-western Angola.
Drug Development, Deployment & Resistance 39
Malaria Centre Report 2010-11
Mapping the spread of drug resistance in African malaria.
LSHTM Investigators: Cally Roper & Inbarani Naidoo.
External Investigators/Collaborators: Jennifer Flegg & Philippe Guerin
(WWARN and University of Oxford, UK); Simon Hay & Anand Patil (MAP
and University of Oxford, UK).
Funding Body: The Bill & Melinda Gates Foundation through WWARN.
In this project we have developed a mathematical model of the prevalence of point mutations in the dhfr and dhps genes of Plasmodium falciparum that confer resistance to sulpha-
doxine and pyrimethamine. Resistance in dhfr and dhps genes emerged on just a few occasions, but then showed a remarkable capacity to disperse.
After collating, standardising and mapping all published surveillance data, we are using modelling to describe spatial and temporal patterns of resistance dispersal. Adopting a Bayesian model-based geostatistics approach, we converted spatio-temporal data to a continuous surface.
Models of resistance dispersal patterns in the past will help to inform policy on the management and containment of resistance in future.
Modelling the dispersal of resistance mutations at codons 437 and 540 of the dhps gene in 2000 and 2005.
40 Drug Development, Deployment & Resistance
London School of Hygiene & Tropical Medicine
Drug resistance maps to guide intermittent preventive treatment of malaria in African infants.
LSHTM Investigators: Cally Roper & Inbarani Naidoo.
Funding Body: The Bill & Melinda Gates foundation through the Gates
Malaria Partnership and IPTi Consortium.
We have created a geographical database of the prevalence of point mutations in the dhfr and dhps genes of Plasmodium falciparum that confer resistance to sulphadoxine and pyri-methamine. This was used to guide WHO policy recommen-dations on SP-IPTi.
The data is available as a publically available web-based resource (http://www.drugresistancemaps.org/).
Africa: The mapping is continent-wide.
In Focus: The evolution of malaria drug resistance.Malaria Centre members have been involved in the development of a novel genetic approach for look-
ing at the ancestry of drug resistance mutations and applied this to field populations of parasites in
East Africa. Work has shown that pyrimethamine and sulphadoxine resistance genes were derived
from only a few ancestral lineages resulting in a paradigm shift in our basic understanding of the evolu-
tion of drug resistance in Africa.
Analysis has been extended to Southeast Asian parasites in collaboration with a research groups
there and in the USA and has shown that highly pyrimethamine resistant parasites in Africa were de-
rived from an Asian mutation. This work has shown that international migration of drug resistant
malaria infections were responsible for importation of drug resistance into Africa.
In highlighting the significance of international transportation of resistant parasites in the global
spread of drug resistance this research has had a significant impact on policy and thinking on the
future management of emerging drug resistance. There is recognition of the need for containment of
emerging resistance in Asia to protect Artemisinin-based Combination Therapy in Africa. Containment
is central to policy on management of artemisinin resistance in Southeast Asia today.
The analysis has also been extended to 20 countries across Africa and has shown that regional blocks of
countries share common parasite genotypes. There is however a separation between east and west Africa
as well as between the northern and southern populations in the east and west.
Drug Development, Deployment & Resistance 41
Malaria Centre Report 2010-11
Development of an anti-malarial drug that targets the Plasmodium falciparum cGMP-dependent protein kinase.
LSHTM Investigators: David Baker, Paul Bowyer, Simon Croft & Lindsay
Stewart.
External Investigators/Collaborators: Katy Kettleborough & Andrew
Merritt (MRC Technology, UK).
Funding Body: Medical Research Council, UK.
We are aiming to develop a new antimalarial drug that cures malaria by killing the asexual erythrocytic parasites but also attacks additional life-cycle stages. We have identified a Plasmdoium falciparum protein kinase (cGMP-dependent
protein kinase, PfPKG) that is essential in multiple life-cycle stages. PfPKG is a novel target; a specific inhibitor could be used in combination with antimalarials that hit alternative targets. Selective inhibitors of PKG block Plasmodium blood-stage schizont, gamete and ookinete development. Recent data by others indicate an essential role for PKG in liver stages. Medicinal chemists at MRC Technology are synthesis-ing new inhibitors which are being tested at LSHTM for their ability to block the growth of malaria parasites at various life cycle stages. Within the duration of the project we anticipate generating lead compounds with efficacy against the Plasmo-dium berghei in vivo model.
Drug sensitivity of wild Plasmodium isolates.
LSHTM Investigators: Sharan Atwal, Rebekah Burrow, Mary Oguike
Colin Sutherland & Don van Schalkwyk.
External Investigators/Collaborators: Ric Price (Menzies School for
Health Research, Australia).
Funding Body: Medicines for Malaria Venture.
The goal of malaria eradication needs development of new antimalarial drugs that are demonstrably effective against parasites that are currently circulating in the second decade of the 21st century. Almost all laboratory-based drug devel-opment work utilises in vitro sensitivity testing against a stable of stock Plasmodium falciparum lines isolated in the seventh and eight decades of the 20th century.
New protocols developed in the laboratory of Ric Price have opened up the possibility that investigational com-pounds with demonstrated efficacy against Plasmodium fal-ciparum laboratory line cultures can now be tested against ex vivo parasites of all human-infecting parasite species. Where sufficient high quality material is available, DNA will be ex-tracted for genomic sequencing.
The proposed ex vivo approach provides two major ad-vances on current testing protocols for investigational drugs:
■ Broad spectrum activity against non-falciparum species will be evaluated.
■ Testing against 21st century Plasmodium falciparum isolates, with their varied genetic background and a contem-porary history of drug exposure, can be performed early in the drug development process.
To date, ex vivo cultures have been attempted on two isolates of Plasmodium ovale curtisi, one of Plasmodium malariae, and on five Plasmodium falciparum isolates taken directly from malaria patients in London.
A schizont and gametocyte of Plasmodium ovale curtisi after 48 hours of culture in vitro.
42 Epidemiology
London School of Hygiene & Tropical Medicine
The Malaria Centre’s Epidemiological Studies range
from the molecular diagnosis of Plasmodium ovale
sub-species to programmatic monitoring and evalu-
ation. Many of the activities in this section relate to
the science of surveillance of infection and disease,
complemented by modelling activities to inform our
understanding of the potential impact of interven-
tions. Other studies have developed molecular as-
says to discriminate between Plasmodium ovale cur-
tisi and Plasmodium ovale wallikeri, then used them
to explore the differences in latent periods between
the two sub-species.
Malaria Centre members are contributing epide-
miological expertise to a WHO-led project on the im-
pact of insecticide resistance and, through this, the
evaluation of the added benefit of Indoor Residual
Spraying on insecticide-treated mosquito nets in Su-
dan, Kenya, Cameroon, Benin and India. Statistical
analysis and data modelling have been used to in-
form an understanding of where Intermittent Pre-
ventive Treatment in Infants (IPTi) should be con-
sidered and the potential effects of broadening the
age group receiving Intermittent Preventive Treat-
ment (IPT).
Staff are working in Kenya to follow up on stud-
ies of school-based IPT to explore the potential of
Intermittent Screening and Treatment to improve
the health outcomes and educational achievement
of school children. School-based screening pro-
grammes may also have the potential to identify
transmission hotspots which could then be targeted
with malaria interventions. The impact of malaria in
West African school children is also being evaluated
in a range of epidemiological settings.
It is evident that hotspots of transmission sustain
transmission of malaria in some areas. The stability
of hotspots is not entirely clear and school staff are
exploring the potential of surveillance-based inter-
ventions to disrupt transmission in these hotspots.
As control improves still further, the importance of
reliably identifying gametocyte infections is thrown
into sharp focus, as is the need to understand how
best to collect and store filter paper samples. It has
also been confirmed that sub-microscopic gameto-
cyte infections are an important source of infections
to the mosquito population with implications for
surveillance in pre-elimination settings.
High level control in some countries also draws
attention to the importance of monitoring cross-bor-
der malaria and being able to distinguish between
Plasmodium falciparum and Plasmodium vivax infec-
tions in areas of low Plasmodium falciparum trans-
mission. Encouraging work has shown the potential
of anti-body responses to mosquito antigens to iden-
tify areas at high risk of malaria transmission.
Many of these activities will contribute to the de-
Summary
Epidemiology 43
Malaria Centre Report 2010-11
Global project on the impact of insecticide resistance.
LSHTM Investigators: Immo Kleinschmidt.
External Investigators/Collaborators: World Health Organization;
Liverpool School of Tropical Medicine, UK; Ministries of Health of Sudan,
Kenya, Cameroon, Benin & India.
Funding Body: The Bill & Melinda Gates Foundation through the World
Health Organization Global Malaria Programme.
This study will assess the impact that insecticide resistance has on the effectiveness of malaria vector control tools Long Lasting Insecticide-treated Nets (LLINs) and Indoor Residual Spraying (IRS). In two countries this is done by cluster ran-domised trials of universal coverage LLINs versus universal coverage LLINs in combination with IRS, with levels of in-secticide resistance of the main vector balanced between the two study arms.
In each cluster resistance to the insecticide used on LLINs is monitored, and malaria incidence is estimated from cluster specific cohorts of children followed up over the duration of the study. In three countries, clusters are es-tablished and malaria vector mosquitoes in each cluster as-sessed for resistance to the insecticide used. Clusters with either very high susceptibility or very high resistance to the insecticides in use are retained for the study, and cohorts of children recruited for follow-up and estimation of malaria in-cidence. Resistance impact will be assessed from the ratio of incidence rates in clusters with high compared to those with low resistance. Resistance mechanisms will be determined in subsets of study clusters. Initial findings from one country may be available by the end of 2012.
Combined use of vector control methods for malaria control.
LSHTM Investigators: Immo Kleinschmidt.
External Investigators/Collaborators: Martin Donnelly (Liverpool
School of Tropical Medicine, UK); Khalid Elmardi (Ministry of Health, Su-
dan); Josh Yukich (Tulane University, USA).
Funding Body: Global Environmental Facility/ United Nations Environ-
ment Programme through the World Health Organisation Regional Office
of the Eastern Mediterranean.
The project will assess whether there is added benefit if In-door Residual Spraying (IRS) and Long Lasting Insecticide-treated Net (LLINs) are used in combination, compared to
the use of LLINs alone, in a large cluster randomised trial in four study areas of Sudan. Malaria incidence through pas-sive case detection is estimated in cohorts of children in each study cluster for comparison between the study arms study as the primary endpoint. Clusters were randomised to study arms, balanced on a number of criteria including insecticide resistance at baseline. Vector control interventions according to the random allocation have been implemented at high cov-erage in 2011, cohorts recruited, community health workers trained and appointed, and follow-up of about 6,000 person years of observation completed during the malaria season. Interim results will be available in early 2013.
velopment of new approaches and tools for use in
rational surveillance and response systems. Howev-
er, it remains important to strengthen surveillance
with the tools available today and LSHTM staff are
working in West and East Africa to understand the
role of different strategies for monitoring and evalu-
ation of malaria control programmes.
44 Epidemiology
London School of Hygiene & Tropical Medicine
Modelling the protective efficacy of alternative delivery schedules for Intermittent Preventive Treatment (IPT) of malaria in infants and children.
LSHTM Investigators: Matt Cairns, Roly Gosling, Ilona Carneiro, Paul Mil-
ligan, Brian Greenwood & Daniel Chandramohan.
External Investigators/Collaborators: Lucy Okell & Azra Ghani (Impe-
rial College London, UK); Francis Anto & Victor Asoala (Navrongo Health
Research Centre, Ghana); Seth Owusu-Agyei (Kintampo Health Research
Centre, Ghana).
Funding Body: Medical Research Council PhD studentship; Navrongo trial
originally funded by the UK Department for International Development.
Intermittent Preventive Treatment (IPT) for African Children: where and how should IPT be applied?
LSHTM Investigators: Ilona Carneiro, Arantxa Roca-Feltrer, Lucy Smith, Joanna Arm-
strong-Schellenberg, Brian Greenwood & David Schellenberg.
External Investigators/Collaborators: Tom Smith, Marcel Tanner & Amanda Ross
(Swiss Tropical and Public Health Institute, Switzerland).
Funding Body: The Bill & Melinda Gates Foundation and the UK Department for In-
ternational Development.
Intermittent Preventive Treatment in infants (IPTi) is the administra-tion of a therapeutic dose of an antimalarial drug at the time of selected routine vaccinations through the Expanded Programme on Immuniza-tion. In 2010, IPTi with sulphadoxine-pyramethamine (SP) was rec-ommended by the WHO for use “in areas of moderate to high malaria transmission” and “where parasite resistance to SP is not high”.
Data on the age patterns of clinical cases of Plasmodium falciparum malaria, hospital admission with malaria parasites and malaria-asso-ciated death were used to estimate the percentage of cases of these outcomes that would occur in children aged < 10 years under different transmission intensity and seasonality of malaria. A similar analysis of severe malaria syndromes was also undertaken. A stochastic math-ematical model of IPTi was used to predict the number of cases likely to be averted by implementing IPTi.
These results were combined into an internet-based decision-support tool to help policy-makers assess whether IPTi would be ef-fective for local malaria control.
The web-tool has been updated to enable variation in IPTi sched-ule and coverage, health systems costs, and local levels of SP drug-re-sistance. It is freely accessible at http://ipti.lshtm.ac.uk.
Intermittent Preventive Treatment for malaria in infants (IPTi) using sulphadoxine-pyrimethamine delivered along-side routine infant vaccinations is a recommended WHO policy. However, in seasonal transmission settings, some IPTi courses will be given at a time of low malaria risk, and would not tackle the burden of malaria outside infancy.
We investigated potential alternatives to delivery along-side infant vaccinations for a range of transmission scenarios using a mathematical model. Targeting IPT at the peak in transmission rather than at vaccination contacts would sub-stantially improve efficacy, even in situations where the ma-laria burden is not highly seasonal. Extending IPT to include older children results in major additional gains in protection; this will become even more important as transmission is re-duced by other control efforts and the disease burden shifts to older children.
Children at Pokukrom primary school, Mankranso, Ashanti region, Ghana.
Epidemiology 45
Malaria Centre Report 2010-11
Seasonal malaria chemoprevention in children: where could it be implemented and what would be its impact?
LSHTM Investigators: Matt Cairns, Anne Wilson, Diadier Diallo, Paul Mil-
ligan & Brian Greenwood.
External Investigators/Collaborators: Arantxa Roca-Feltrer (Malawi-
Liverpool-Wellcome Trust Clinical Research Programme, Malawi); Tini
Garske & Azra Ghani (Imperial College London, UK).
Funding Body: The Bill & Melinda Gates Foundation & Medical Research
Council, UK.
Seasonal Malaria Chemoprevention (SMC, previously known as Intermittent Preventive Treatment in children, IPTc), is highly effective in areas with a short malaria transmission season. To assist policy decisions made by WHO on the areas
where this intervention would be appropriate, we have re-viewed malaria incidence data and defined a surrogate pre-dictor of seasonality in incidence based on rainfall. Spatial rainfall, malaria endemicity and population data were then used to estimate the population and malaria burden in areas with highly seasonal malaria. We estimate that in areas suit-able for SMC, there are 39 million children under five years of age, 33.7 million child malaria episodes and 152,000 child-hood deaths from malaria each year. The majority of this burden occurs in the Sahelian or sub-Sahelian regions of Af-rica, where regimens currently available for SMC have been shown to be highly effective, safe and acceptable to commu-nities. SMC has the potential to avert several million malaria cases and tens of thousands of childhood deaths each year if successfully delivered to the populations at risk.
46 Epidemiology
London School of Hygiene & Tropical Medicine
Population biology and epidemiology of two newly recognized human malaria parasite species.
LSHTM Investigators: Mary Oguike, Debbie Nolder & Colin Sutherland.
External Investigators/Collaborators: Mallika Imwong (Mahidol – Ox-
ford Research Unit, Thailand); Abdoulaye Djimde (Malaria Research &
Training Centre, Mali); Alyssa Barry (Walter & Eliza Hall Institute, Aus-
tralia).
Funding Body: Wellcome Trust.
Recent evidence have shown that the human malaria para-site Plasmodium ovale exists as two non-recombining spe-cies, sympatric in many countries. New nested PCR assays targeting three different gene loci (Potra, Pog3p and Porbp) and real-time quantitative PCR assays for discriminating be-
tween Plasmodium ovale curtisi and Plasmodium ovale wal-likeri have been developed and deployed in the field for spe-cies discrimination. Furthermore, we are investigating the possible barriers (biological, epidemiological and geographi-cal) which keep these two species apart, when they occur together in much of tropical Africa and Asia. Recently, we have shown from analysis of samples and data from the Ma-laria Reference Laboatory archives that there is a significant difference in the latency period between Plasmodium ovale curtisi and Plasmodium ovale wallikeri. We are currently in-vestigating the possible barriers to inter-species mating and recombination between the two species by looking at diver-gence of genes involved in fertilization. We have recently be-gun to evaluate both species by in vitro culture, and to test for sensitivity to a range of antimalarial drugs.
Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait.
LSHTM Investigators: Chris Drakeley.
External Investigators/Collaborators: Lauren Gong, Philip Rosenthal,
Alan Hubbard, Grant Dorsey & Bryan Greenhouse (University California
San Francisco, USA); Catherine Maiteki-Sebuguzi (International Develop-
ment Research Centre, Uganda).
Sickle cell trait (HbAS) is known to be protective against Plas-modium falciparum malaria, but it is unclear when during the course of infection protection occurs and whether protection is innate or acquired. To address these questions, a cohort of 601 children aged 1-10 was enrolled in Kampala, Uganda, and followed for 18 months for symptomatic malaria and asymptomatic parasitemia. Genotyping was used to detect and follow individual parasite clones longitudinally within subjects. Children with HbAS were protected against estab-lishment of parasitemia, as assessed by the molecular force of infection, at older but not younger ages (2 years old: inci-dence rate ratio [IRR] 1.16, 95%CI 0.62-2.19, p=0.6; 9 years old: IRR 0.50, 95%CI 0.28-0.87, p=0.01) suggesting an ac-quired mechanism of protection. Once parasitemic, children with HbAS were less likely to progress to symptomatic ma-laria, with protection again most pronounced at older ages (2 years old: RR 0.92, 95%CI 0.77-1.10, p=0.3; 9 years old: RR 0.68, 95%CI 0.51-0.91, p=0.008). Conversely, the youngest
children were best protected against high parasite density (2 years old: relative density = 0.24, 95% CI 0.10-0.54, p=0.001; 9 years old: relative density = 0.59, 95%CI 0.30-1.19, p=0.14) suggesting an innate mechanism of protection against this endpoint.
Epidemiology 47
Malaria Centre Report 2010-11
Evaluation of malaria diagnostic strategies using community health workers in South Central Asian where vivax is co-endemic with falciparum.
LSHTM Investigators: Toby Leslie, Amy Mikhail, Chris Whitty & Mark Rowland.
External Investigators/Collaborators: HealthNet TPO; MERLIN & Health Pro-
tection and Research Organisation.
Funding Body: The Bill & Melinda Gates Foundation through the ACT Consor-
tium.
In many low-resource settings where health services may be inac-cessible, community health workers are relied upon to provide a range of services amongst which is the diagnosis and treatment of malaria. Until very recently this diagnosis was almost always based on clinical signs and symptoms of the patient. The clinical method of diagnosis based on symptoms alone, especially in ar-eas with low malaria transmission, is notoriously inaccurate and results in up to 95% of patients being misdiagnosed with malaria when, in fact, the patient has some other cause of disease which may include severe bacterial diseases.
In partnership with three NGOs in Afghanistan, members of the Malaria Centre are undertaking a large-scale cluster ran-domised field trial to assess whether RDTs are appropriate tools for community health workers. The study is conducted amongst ~400 health workers who are administratively attached to 22 clinics in two provinces in Afghanistan. The primary outcome is the proportion of patients who are appropriately treated for their condition. The project is nearing its midpoint and results will be released in the coming year.
CONFIA: causes of Non-malarial Fever in Afghanistan.
LSHTM Investigators: Amy Mikhail, Toby Leslie, Chris Whitty, Hugh Rey-
burn & Mark Rowland.
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
In many areas of the world there has been a welcome reduc-tion in malaria transmission. The result is that fewer cases who present with a fever have malaria. This makes diagnosis of both malaria and non-malaria cases important for patient care. It is often not known what the cause of the fever is when it is not malaria but when the symptoms in the patient resemble (and are often indistinguishable from) malaria.
The CONFIA project began enrolling patients in February 2012. It aims to identify as many of the non-malarial causes
of fever as possible. These may be attributable to a range of viral, parasitic and bacterial diseases. The patients are en-rolled in the study if they do not have malaria (their malaria negative status is confirmed with a malaria rapid diagnostic test). After taking a detailed history and physical examina-tion, blood, respiratory and urine samples are taken from the patient and assessed using a range of laboratory tech-niques including culture, serological and molecular methods to screen for causative pathogens. The spectrum of diseases identified will be examined in light of their reported expo-sure factors and clinical data. Once there is a better under-standing of non-malarial causes of fever, additional research can be undertaken to assist in improving treatment for fever when a malaria parasite test is negative and for providing information for control of the alternative causes of disease.
The project will be completed in December 2012 and re-sults will be reported shortly thereafter.
Polyclinic in Afghanistan.
48 Epidemiology
London School of Hygiene & Tropical Medicine
Malaria in school-aged children in Senegal: epidemiological risk, disease burden and strategies for control.
LSHTM Investigators: Sian Clarke, Daniel Chandramohan, Badara Cisse,
Paul Milligan, Simon Brooker & Chris Drakeley.
External Investigators/Collaborators: Jean-Francois Trape, Cheikh
Sokhna & Alioune Badara Ly (Institut de recherché pour le developpement,
Senegal); Oumar Gaye, Jean-Louis Ndiaye (Université Cheikh Anta Diop,
Senegal); Malick Sembene, Aliou Dia & Khady Diallo (Ministry of Educa-
tion, Senegal); Fatou Ba Fall (National Malaria Control Programme, Sen-
egal); Matthew Jukes (Harvard Graduate School of Education, USA).
Funding Body: Wellcome Trust.
The risk of malaria is greatest in early childhood and most research and control has justifiably focussed on younger children. Less is known about the impact of malaria in older school-aged children. A recent intervention trial, in an area of intense perennial transmission in Kenya, showed that preventive treatment in schools, given once each term, can reduce malaria-related anaemia and increase sustained at-tention in class – suggesting that malaria control in school-children could yield educational, as well as health benefits.
This study aims to characterise the epidemiological im-pact of malaria in school-aged children in a setting of marked seasonal transmission in the West African Sahel. The study
compares the burden of malaria in children aged 6 months - 14 years in three different epidemiological settings within in Senegal: following three cohorts of 2400 children exposed to perennial transmission, intense seasonal transmission and low-moderate seasonal transmission over a 12-month period. The incidence of clinical attacks, prevalence of as-ymptomatic infection, anaemia and cognitive function is ex-amined in two age groups (children below school age, and children enrolled in primary school) in each transmission setting.
The study is intended to inform the development of pre-ventive interventions in schools suited to areas of seasonal transmission.
Malaria prevention in Kenyan school children.
LSHTM Investigators: Simon Brooker, Kate Halliday, Sian Clarke, Tom
Drake, Lindsay Mangham, Kara Hanson, Caroline Jones & Elizabeth Allen.
External Investigators/Collaborators: Kenya Medical Research Insti-
tute, Kenya; KEMRI-Wellcome Trust Research Programme, Kenya; Uni-
versity of Nairobi, Kenya; Kenya Ministry of Public Health and Sanitation,
Kenya; Harvard University, USA; Duke University, USA.
Funding Body: International Initiative for Impact Evaluation; World
Bank & Wellcome Trust.
Malaria can adversely affect schoolchildren, the full scale of which is yet to be investigated. An ongoing study is evaluating the impact of regular Intermittent Screening and Treatment (IST) for malaria on the health and educational achievement of schoolchildren living on the south coast of Kenya. Along-side the IST intervention, a training programme for teachers to improve literacy instruction has been introduced to inves-tigate the interactions between health and education inter-
ventions. The evaluation uses a cluster-randomized design, with a total of 101 primary government schools randomly assigned to one of four groups (IST; education intervention; IST + education intervention; neither intervention). Base-line health and education surveys were conducted between January and March 2010. The first round of follow-up assess-ments was carried out between January and April 2011 and the second round between February and April 2012. The pri-mary outcomes are educational achievement and anaemia, the hypothesised mediating variables through which educa-tion is affected. Secondary outcomes include malaria parasi-taemia, school attendance and school performance. A nested process evaluation, using semi-structured interviews, focus group discussion and a stakeholder analysis is investigating the community acceptability, feasibility and cost-effective-ness of the interventions.
Epidemiology 49
Malaria Centre Report 2010-11
Stability of hotspots after implementation of community wide vector control with indoor residual spraying.
LSHTM Investigators: Simon Hemelaar, Teun Bousema, Nahla Gadalla,
Brian Greenwood, Chris Drakeley, Daniel Chandramohan & Colin Suther-
land.
External Investigators/Collaborators: Jacklin Mosha (Kilimanjaro
Christian Medical College, Tanzania); Ramadhan Hashim (National Insti-
tute for Medical Research, Tanzania); Roly Gosling (University of Califor-
nia, USA).
Funding Body: The Bill & Melinda Gates Foundation.
Malaria tends to be clustered in hotspots of high transmis-sion intensity. The heterogeneity of malaria creates opportu-nities for targeted interventions, but it is unclear if hotspots remain stable after implementation. We aimed to establish the stability of hotspots after intervention with Indoor Re-sidual Spraying (IRS).
Two surveys were conducted in the Mwanza region, Tan-zania, before and after implementation of IRS. In total, 3031 people were included in both surveys. Parasite carriage was determined using sensitive nested PCR. Responses against malaria specific antibodies, AMA-1 and MSP-1, were used to determine the stable spatial patterns in transmission inten-sity. In the first survey, before implementation of IRS, para-site prevalence was 31.1% but varied between villages, from 24.9% to 60%. Two hotspots (p≤0.01) and two coldspots (p≤0.01) were detected. The current ongoing work aims to determine the stability of these hotspots and coldspots over time, 12 months after the initial survey and IRS implementa-tion. We describe the persistence of hotspots after communi-ty-wide implementation of vector control. The success of any intervention greatly depends on its ability to reduce malaria transmission in hotspots.
Identifying and characterising foci of malaria transmission in potential malaria elimination settings in rural Senegal.
LSHTM Investigators: Badara Cissé, Catherine Pitt, Matt Cairns, Colin
Sutherland, John Cox, Immo Kleinshmidt, Chris Drakeley, Brian Greenwood
& Paul Milligan.
External Investigators/Collaborators: Lansana Konaté, Babacar Faye,
Ousmane Faye & Oumar Gaye (University Cheikh Anta Diop, Senegal); El
hadj Ba, Jules-François Gomis, Cheikh Sokhna, Jean-François Trape (Insti-
tut de Recherche pour le Développement, Senegal).
Funding Body: Bill & Melinda Gates Foundation through the Malaria Ca-
pacity Development Consortium.
Sparse distribution of malaria morbidity has become a con-sistent feature of the disease, particularly in the new context of malaria decline. Foci of residual transmission (hot spots) are particularly relevant to malaria control programme in countries such as Senegal with low transmission intensity, since their presence makes it very difficult to eliminate the disease.
Based on the 2008 and 2009 general changes on the epi-demiological profile of the disease and in particular on the very low incidence rates observed all over the sub-region, we designed this project to identify and characterize the foci of residual transmission and to pilot methods for surveillance
that could be used as part of an elimination programme. Sci-entific research questions were therefore the following:
■ Has transmission stopped in some areas? ■ Evaluation of the validity of health facilities records ■ Use of serology to determine if transmission of ma-
laria has stopped in defined area. ■ Why is transmission persisting in some places?
Several factors could explain the patchy distribution of malaria (use of preventive measures, housing, environmen-tal or climatic factors.
Several activities were conducted to answer to the re-search questions including:
■ A collection and analyses and validity assessment of 2008-2011 health facilities records.
■ A case-control study with a community survey around all cases and controls intervention coverage in the vicinity of where the cases and the controls live.
■ Cross sectional surveys to assess level of malaria transmission from serology.
■ An environmental evaluation in and in areas with low transmission.
The entomological evaluation including nets assays in hotspots and non hotspots areas will be carried out in 2012.
50 Epidemiology
London School of Hygiene & Tropical Medicine
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
E
E
E
E
E
EE
E
E
E
E
E
E
EE
E
EE
E
E
E
E
EE
EE
EE
E
EE
E
EEE
EE
E
EEE
E
EE E
E
E
E
E
EE
E
EE
E EE
EE
E
E
EE
EE
E
E
E
EE
E
E
E
E
E
E
E
E
EE
EE
E
E
EE
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
EE
E
EE
EE
E
E
E
E
E
E
EE
E
EE
E
EE
EE
EE
E
E
E
E
EE
E
E
EEE
E
E
E
EE
E
E
EE
E
E
E
E
E
E
E
E
E
E
EE
EE
E
E
E
E
E
EE
EE
E
E EE
E
E
E
E
E
E
E
E
E
EEE
EEE
E
E
E
EE
E
EE
E E
E
E
E
EE
E
E
EE
E
E
E
EEE
E
E
E
E
E
E
E
E
EE
EE E
EE
E
E
E EEE E
E
E
E
EE
E
E EE
EE
E
E
E
E
E
EE
E
EE
E
E
E
E
E
EE
E
E
E
EE
E
E
E
E
EE
E
E
E
EE
E
E
EEE
E E
E
E
E
E
E
E
E
E
E
E E
E
E
E E
E
E
E
EE
E
E
E EEE
E
E
EE
E
EEEE
EEE
EE EE
E E
E
E
E
E
E
EEE
E
EE
E
EEEEEE E
E
E
E
EE
E
EE
EE
E
E
EE
E
EE
E
E
E
EEE E
EE
E
E
E
E
E
E E
E
E
E
E
EE
E
E
EE
E
E
EEE
E
EE
EE
E
EE
E
E
EE
E
E
E
E
E
E
EE
E
E
E
E
E
E
EE
E
E
EE
E
E
E E
E
E
E
EE
E
E
E E
E
E
EE E
EEE
E
EEE
E
E
E
E
E EEE EE
E
E
E
E E
EE
EE
E
EE
E
EE
E
E
E
E
E E
EEE
E
E
E
EEEE
E
E
E
E
E
E
EE
E
E E
E
EE
E
E
E EEEE
E
E
E
E
EE
E
E
E
E
E
E
E
EE
E
E
E
E
E
EE
EE
E
E
E
EEE
E
E
E
E
E
E
EE
E
E
E
EE
E
E
E
E
E
E
EE
E
E
E
E
E
E
E
EE
EE
E
EE
E
E
E
E
E
E
E
E
EEE
E
E
E
E
E
EE
E
EE
E EE
EE
E
E
EE
E
E
EE
E
E
E
E
E
E
E
E
EE
EE
E
E
E
E
E E
E
EE
EE
E
E
E
E
EE
E
E
E
E
E
E
EEEE
E
E
E
EE
E
E
EE
E
EE
E
E
E
E
EE
EE
E
E
E
E
E
E
E
E E
E E
E
EE
E
E
E
E
E
E
E
E
E
E
E
EE
EE
EE
E
E
E
EE
E
E
E
E E
E
E
EE
E
E
E
EE
EE
E
EE E
E
E
E
3
230311
230314
230304
230315
230301
230309230316
230306
230308
230313
230303
230319
230312
230302
230317
230310
230318
230307
BLOCK 3Households to sample! Within hotspot! Buffer zone (0-250 m)! Buffer zone (250-500 m)
Hotspot area
Evaluation area
Detail of hotspot intervention area in highland Kenya
Epidemiology 51
Malaria Centre Report 2010-11
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!!
!
!
!
!
!
E
E
E
E
E
EE
E
E
E
E
E
E
EE
E
EE
E
E
E
E
EE
EE
EE
E
EE
E
EEE
EE
E
EEE
E
EE E
E
E
E
E
EE
E
EE
E EE
EE
E
E
EE
EE
E
E
E
EE
E
E
E
E
E
E
E
E
EE
EE
E
E
EE
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
EE
E
EE
EE
E
E
E
E
E
E
EE
E
EE
E
EE
EE
EE
E
E
E
E
EE
E
E
EEE
E
E
E
EE
E
E
EE
E
E
E
E
E
E
E
E
E
E
EE
EEE
E
E
E
E
E
E
EEE
EE
E
E EE
E
E
E
E
E
E
E
E
E
EEE
EEE
E
E
E
EE
E
EE
E E
E
E
E
EE
E
E
EE
E
E
E
EEE
E
E
E
E
E
E
E
E
EE
EE E
EE
E
E
E EEE E
E
E
E
EE
E
E EE
EE
E
E
E
E
E
EE
E
EE
E
E
E
E
E
EE
E
E
E
EE
E
E
E
E
EE
E
E
E
EE
E
E
EEE
E E
EE
E
E
E
E
E
E
E E
E
E
E
E E
E
E
E
E
E
E
E EEE
E
E
EE
E
EEEE
EEE
EE EE
E E
E
E
E
E
E
EEE
E
EE
E
EEEEEE E
E
E
E
EE
E
EE
EE
E
E
EE
E
EE
E
E
E
EEE E
EE
E
E
E
E
E
E E
E
E
E
E
EE
E
E
EE
E
E
EEE
E
EEE
EE
E
EE
E
E
EE
E
E
E
E
E
E
EEE
E
E
E
EE
E
E
EE
E
E
EE
E
E
E E
E
E
E
EE
E
E
E E
E
E
EE E
EEE
E
EEE
E
E
E
E
E EEE EE
E
E
E
E E
EE
EE
E
EE
E
EE
E
E
E
E
E E
EEE
E
E
E
EEEE
E
E
E
E
E
E
EEE
EE
E E
E
EE
E
E
E
E EEEE
E
E
E
E
E
EE
E
E
E
E
E
E
E
E
EE
E
E
E
E
E
EE
EE
E
E
E
EEE
E
E
E
E
E
E
EE
E
E
E
EE
E
E
E
E
E
E
EE
E
E
E
E
E
E
E
EE
EE
E
EE
E
E
E
E
E
E
E
E
EEE
E
E
E
E
E
EE
E
EE
E EE
EE
E
E
EE
E
E
EE
E
E
E
E
E
E
E
E
EE
EE
E
E
E
E
E E
E
EE
EE
E
E
E
E
EE
E
E
E
E
E
E
EEEE
E
E
E
EE
E
E
EE
E
EE
E
E
E
E
EE
EE
E
E
E
E
E
E
E
E E
E E
E
EE
E
E
E
E
E
E
E
E
E
E
E
EE
EE
EE
E
E
E
EE
E
E
E
E E
E
E
EE
E
E
E
EE
EE
E
EE E
E
E
E
3
230311
230314
230304
230315
230305
230301
230309230316
230306
230308
230313
230303
230319
230312
230302
230317
230310
230318
230307
BLOCK 3Households to sample! Within hotspot! Buffer zone (0-250 m)! Buffer zone (250-500 m)
Hotspot area
Evaluation area
Reducing the burden of malaria by targeting hotspots of malaria transmission (REDHOT).
LSHTM Investigators: Teun Bousema, Jonathan
Cox, Jennifer Stevenson, Ulrike Fillinger & Chris
Drakeley.
External Investigators/Collaborators: Nabie
Bayoh, Meghna Desai, Simon Kariuki, Kayla Laser-
son, John Vulule (Kenya Medical Research Institute,
Kenya & Centers for Disease Control and Preven-
tion, USA); Robert Sauerwein (Radboud University
Nijmegen Medical Centre, the Netherlands); Willem
Takken (Wageningen University, the Netherlands).
Funding Body: The Bill & Melinda Gates Founda-
tion through the Malaria Transmission Consortium
and Grand Challenge.
In the Rachuonyo district in the Kenyan highlands, the burden of malaria is not equally distributed with community parasite prevalences ranging from 0% to >70%. The persistence of malaria in small geographical areas despite high coverage with Insecticide Treated Nets (ITNs) and Indoor Residual Spraying (IRS) may be partially explained by outdoor biting and resting of malaria vectors and suggests that a revision of malaria control strate-gies may be needed to successfully control and eliminate malaria.
We identified 10 hotspots of intense malaria transmission by serological mark-ers of malaria exposure. These hotspots will be randomly assigned to serve as in-tervention or control clusters. In the in-tervention clusters, four malaria interven-tions will be targeted to the hotspots: local upscaling of IRS and ITNs, larviciding and a focal screening and treatment campaign. In control clusters, IRS and ITN distribu-tion will continue as planned by the Ke-nyan division of malaria control.
The impact of the targeted interven-tions on overall transmission intensity will be assessed in the context of current-ly ongoing malaria control activities in a 2-year study.
52 Epidemiology
London School of Hygiene & Tropical Medicine
Clinical development and field evaluation of a malaria transmission blocking vaccine (REDMAL).
LSHTM Investigators: Teun Bousema, Sophie Jones, Michael Bretscher &
Chris Drakeley.
External Investigators/Collaborators: Robert Sauerwein, Will Roeffen
(Radboud University Nijmegen Medical Centre, the Netherlands); Michael
Theisen (Statens Serum Institute, Denmark); Sanjay Singh (Gennova Bi-
opharmaceuticals, India); Jaffu Chilongola (Kilimanjaro Christian Medical
Centre, Tanzania); André Lin Ouédraogo (Centre National de Recherche et
de Formation sur le Paludisme, Burkino Faso); Dawit Ejigu (African Ma-
laria network Trust, Tanzania).
Funding Body: European Committee, 7th framework programme.
REDMAL aims to develop a transmission blocking vaccine for malaria. Transmission-blocking vaccines arrest the develop-ment of the sexual stage of the malaria parasite. This inter-ruption of the life cycle of the parasite inhibits the generation of infectious mosquitoes leading to reduction of the spread of malaria. This is indispensible for sustained control, elimina-tion and eventually eradication of malaria.
The workpackage coordinated by LSHTM involves the development of field assays for trials with malaria transmis-sion blocking vaccines and the preparation of field sites. One of the first components of this work involved testing different strategies for the detection of low density gametocyte car-riage. Different filter paper matrices and different gameto-cyte detection tools were compared. In the figure below, 903 protein saver cards (a) and FTA cards (b) are compared for storage of gametocyte mRNA under tropical conditions. Cul-tured gametocytes were blotted at different concentrations (10, 1 or 0.1 gametocytes/µL); filter papers were stored for one week at 35°C and subsequently for three months at 35°C or -20°C. Filter papers were stored with dessicant or in wet conditions. Gametocyte detection by Pfs25 QT-NASBA indi-cates that RNA degradation occurs at higher temperatures and when filter papers are not properly dried but that deg-radation depends on the filter paper used. Pfs25 mRNA can be reliably extracted from 903 Protein Saver Cards several months after storage.
Submicroscopic gametocyte carriage is now determined in relation to sexual stage specific immune responses at three field sites in West and East-Africa.
Gametocyte detection using two filter paper types stored under tropical conditions.
Epidemiology 53
Malaria Centre Report 2010-11
Assessment of the Infectious Reservoir of Malaria (AFIRM).
LSHTM Investigators: Teun Bousema & Chris Drakeley.
External Investigators/Collaborators: Robert Sauerwein (Radboud Uni-
versity Nijmegen Medical Centre, the Netherlands); André Lin Ouédraogo,
Sodiomon Sirima (Centre National de Recherche et de Formation sur le
Paludisme, Burkina Faso); Kevin Marsh & Charles Mbogo (Kenya Medi-
cal Research Institute, Kenya); Richard Mukabana (ICIPE, Kenya); Tom
Churcher (Imperial College, London, UK).
Funding Body: The Bill & Melinda Gates Foundation.
The AFIRM project will establish a standardized framework for assessing population infectivity to mosquitoes and thus the infectious reservoir in different malaria endemic set-tings. This will enable identification of target populations and optimal timings for control efforts including malaria Transmission Blocking Vaccines (MTBV). Data generated by the project will fill crucial gaps in mathematical models of malaria transmission and will allow examination of corre-
lates between routinely collected clinical, parasitological and entomological metrics by quantifying the processes that link these metrics.
As a first step the project is improving and validating currently available assays in order to develop a quantitative measure of infectivity to mosquitoes that is suitable for large scale screening of naturally infected individuals. Molecular and serological approaches will be validated in laboratory settings and subsequently implemented in field trials that aim to determine the human infectious reservoir for malaria in settings in Burkina Faso and Kenya that are representa-tive of the different patterns of malaria transmission in Af-rica. Longitudinal studies will be conducted to determine the relative importance of symptomatically and asymptomati-cally infected individuals in the context of natural exposure to mosquitoes.
54 Epidemiology
London School of Hygiene & Tropical Medicine
Epidemiology of border malaria in Namibia.
LSHTM Investigators: Immo Kleinschmidt.
External Investigators/Collaborators: Roly Gosling & Hugh Sturrock
(University of California, USA), Daves Mumbengegwi (University of Na-
mibia, Namibia), Stark Katokel (National Malaria Program, Namibia).
Funding Body: The Bill & Melinda Gates Foundation.
Malaria incidence has declined to low levels in Namibia, and the country has set 2020 as the target for malaria elimina-tion. Many of the residual cases occur in the border regions with Angola. It is possible that malaria transmission is as-sociated with cross border movements of people between
Angola and Namibia. This study will document the epide-miology of malaria in northern Namibia and strengthen the malaria surveillance system in the border district of Engela, in Ohangwena region. A case control study will be carried out to determine risk factors for malaria, including cross-border travel, intervention coverage and compliance, and local fac-tors that may be linked to transmission of malaria. By map-ping cases and controls, and testing for sub-patent infections and antibody seroconversions in the neighbourhood of each case and each control, the study will investigate the existence of any hotspots of transmission. It is expected that the results of the study will considerably aid the National Malaria Con-trol Program of Namibia to target and optimise its strategies for malaria elimination.
Prev
alen
ce
Children on their way to school in The Gambia.
Epidemiology 55
Malaria Centre Report 2010-11
Molecular detection of malaria: what lies beneath the microscopy detection threshold and is it relevant for control?
LSHTM Investigators: Chris Drakeley & Teun Bousema.
External Investigators/Collaborators: Lucy Okell, Jamie Griffin & Azra
Ghani (Imperial College London, UK); André Lin Ouédraogo (CNFRP,
Burkina Faso).
Funding Body: The Bill & Melinda Gates Foundation; Medical Research
Council, UK & Wellcome Trust.
Malaria prevalence in population surveys has traditionally been assessed by microscopy however there are increasing numbers of surveys which describe estimates of parasite carriage by molecular methods. PCR estimates are almost invariably higher than those by microscopy and raise impor-tant questions for epidemiology, basic biology and control of the parasite. This study quantifies the relationship between microscopy and molecular parasite prevalence estimates and shows that overall 54.1% (95% CI 50.3-58.2%) more in-dividuals are infected when assessed by PCR compared with microscopy. We further described the prevalence of submi-
Age
Prev
alen
ce
croscopic parasite carriers and assess their contribution to onward transmission to mosquitoes according to level of en-demicity. We have shown that these low density submicro-scopic infections are common in adults and in low endemic settings where they can form as much as half of the human infectious reservoir.
56 Epidemiology
London School of Hygiene & Tropical Medicine
Rapid diagnostic test for detection of Plasmodium falciparum and Plasmodium vivax infections during a cross sectional survey in selected villages of Southern Mindanao, the Philippines.
Identifying areas of ongoing malaria transmission in Southern Mindanao, the Philippines.
LSHTM Investigators: Mary Grace Dacuma, Rachel Hallett & Colin
Sutherland.
External Investigators/Collaborators: Antonio Yasaña (Provincial
Health Office, Philippines); Federico Yadao (Malaria Control Office, Philip-
pines); Ernesto Bona (Department of Health Region XII, Philippines); Wal-
ter Notario; (Pilipinas Shell Foundation, Philippines); Judeline Dimalibot
(University of the Philippines Los Baños, Philippines).
Funding Body: The Ford Foundation; The Chadwick Trust; University of
the Philippines Los Baños; Philippine Council for Health Research and De-
velopment.
Intensive malaria control efforts have reduced parasite prevalence to very low levels in parts of the Philippines, but pockets of transmission remain. To realise the goal of malaria elimination in this region, it is important to determine where
parasites still circulate. In this ongoing PhD study, a cross sectional survey was conducted in nine villages in Sarangani, Southern Mindanao and blood samples from participants were tested by Rapid Diagnostic Test (RDT) and Polymerase Chain Reaction (PCR). RDTs significantly underestimated the prevalence of parasites, compared to PCR, particularly in in-fections with Plasmodium vivax. This indicates that sensitive molecular methods are more suited to detecting remaining low levels of parasite infection. A further use of PCR has been to show that the simian Plasmodium knowlesi parasite, re-cently shown to cause human disease in Malaysian Borneo, is not present in this study population. Remaining work will be to assess the participants’ levels of antimalaria antibodies in a bid to further understand the precise location and risk factors for ongoing malaria infection in the Southern Mind-anao region. It is hoped that results will enable local malaria control programmes to focus efforts and resources appropri-ately as they move towards elimination.
Epidemiology 57
Malaria Centre Report 2010-11
IgG responses to the recombinant Anopheles gambiae salivary antigen gSG6 detect small-scale spatial variation associated with malaria vectors and predict risk of clinical disease.
LSHTM Investigators: Will Stone, Teun Bousema, Sophie Jones, Ilona Car-
neiro, Daniel Chandramohan & Chris Drakeley.
External Investigators/Collaborators: Samwel Gesase & Ramadani
Hashim (National Institute for Medical Research, Tanzania); Roly Gosling
(University of California, USA); Thor Theander (Centre for Medical Parasi-
tology, Denmark); Bruno Arca (La Saienza, Italy).
Funding Body: Wellcome Trust & the IPTi Consortium.
Accurate assessment of exposure to malaria vectors is es-sential to our understanding of spatial and temporal varia-tions in disease risk and facilitates the reliable targeting and evaluation of control efforts. Recently, an immunogenic Anopheles gambiae salivary protein (gSG6) was identified and proposed as the basis of an immuno-assay determin-ing exposure to Afrotropical malaria vectors. In the present study, IgG responses to gSG6 and 6 malaria antigens (CSP,
AMA-1, MSP-1, MSP-3, GLURP R1, and GLURP R2) were mea-sured among children from Korogwe district, Tanzania; an area of moderate and heterogeneous malaria transmission. Anti-gSG6 responses were positively associated with geo-graphical variations in Anopheles exposure, in accordance with the distribution of anti-malarial responses previously observed in the same area. Additionally, at the individual level, IgG responses to gSG6 showed a strong positive as-sociation with mosquito exposure. IgG level for all antigens except AMA-1 was associated with the frequency of malaria episodes following sampling, and strikingly - gSG6 seroposi-tivity was a strong positive indicator of subsequent malaria incidence, comparable to malaria antigens MSP-1 and GLURP R2. Our results indicate that the gSG6 assay is sensitive to micro-epidemiological variations in exposure to Anopheles mosquitoes, and may provide a correlate of malaria risk that is unrelated to immune protection. Overall, these findings strengthen the case for the application of the gSG6 assay in epidemiologic studies and in the evaluation and planning of targeted and preventative anti-malaria interventions.
Relationship between mosquito exposure and antibody responses to gSG6 and malaria antigens.
58 Epidemiology
London School of Hygiene & Tropical Medicine
Bioko Island malaria control project, phase II.
LSHTM Investigators: Immo Kleinschmidt, Chris Drakeley, Colin Suther-
land, Andrea Rehman, John Bradley & Andrea Mann.
External Investigators/Collaborators: Christopher Schwabe (Medical
Care Development International); Michel Slotman (Texas A&M University,
USA); Janet Hemingway (Liverpool School of tropical Medicine, UK); John
Vontas (Innovative Vector Control Consortium).
Funding Body: Marathon Oil Co.
The Bioko Island Malaria Control Project, in collaboration with the government of Equatorial Guinea introduced an integrated malaria control programme in 2004 consisting of delivery of Indoor Residual Spraying (IRS) and Long last-ing Insecticidal Nets (LLIN) to all households, malaria case management consisting of Artemisinin-based Combination Therapy and definitive diagnosis, Intermittent Preventive Treatment for pregnant women, training of health workers and information and education campaigns. Major reductions in malaria transmission were documented during the first five year phase of the project (2004-2008). Progress and im-pact are being extensively monitored through a surveillance
system consisting of (1) annual household surveys collecting a number of biomarkers, and information on child mortality, illness episodes, household wealth and health seeking be-haviour; (2) patient information systems; (3) entomological surveillance; (4) serological surveys; and (5) monitoring of drug resistance associated mutations in Plasmodium falci-parum.
This project serves to gain experience in critical aspects of malaria control and surveillance in control and pre-elimi-nation phases.
In a programmatic setting, the following questions are being addressed: the causes of the heterogeneity of the im-pact of the interventions on the island; the evaluation of insecticide resistance management; evaluation of the effec-tiveness of combining interventions; developing and evalu-ating new malaria control monitoring tools (serological con-version, ITN and IRS test kits, computerised microscopy for parasitology); investigating the operational impact of the kdr gene in Anopholes gambiae on the effectiveness of pyrethroid based vector control; documentation of changes in malaria epidemiology; assessment of practical limitations of IRS and LLINs.
PRISM: Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda.
LSHTM Investigators: Sarah Staedke & Chris Drakeley.
External Investigators/Collaborators: Grant Dorsey & Philip Rosenthal,
Edwin Charlebois & Bryan Greenhouse (University of California, USA); Mo-
ses Kamya, Harriet Mayanja-Kizza, Samuel Nsobya & Fred Wabwire-Man-
gen (Makerere University, Uganda); David Smith & Andy Tatem (Universi-
ty of Florida, USA); Martin Donnell (Liverpool School of Tropical Medicine,
UK); Steve Lindsay (Durham University, UK).
Funding Body: US National Institutes of Health.
An International Centre of Excellence in Malaria Research was established in Uganda in 2010, focusing on surveillance, immunology and parasite and insecticide resistance. This programme aims to address the complexity of interactions between the mosquito vector, malaria parasite, and human host, and combine standard malaria surveillance techniques and metrics with cutting-edge methods designed to improve surveillance.
The surveillance project will identify optimal strategies for malaria surveillance, estimate the impact of key control
interventions and conduct an economic evaluation of control interventions in different epidemiological settings. The im-munology project will characterize the individual-level rela-tionships between Plasmodium falciparum exposure, the im-mune response and protection from disease and develop and validate immunologic assays for estimating the population-level dynamics of exposure to Plasmodium falciparum. The resistance project will compare the prevalence of molecular markers of antimalarial drugs and anopheline insecticide re-sistance and search for novel mediators of antimalarial and insecticide resistance using transcriptome and high through-put sequencing techniques.
Comprehensive malaria surveillance, including outpa-tient and inpatient surveillance, entomology studies, cohort studies and cross-sectional surveys of communities and pri-mary schools, was implemented in three sites in Uganda in 2011. Samples collected in the field are being utilized by the immunology and resistance projects. In 2013, the surveil-lance field activities will be streamlined and will continue through 2017.
Epidemiology 59
Malaria Centre Report 2010-11
Cross-sectional parasitemia data at enrollment
Prevalence of asymptomatic parasitemia and clinical malaria by age, in cross-sectional surveys in Uganda.
PRISM Cohort study team, Jinja, Uganda.
60 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
Members of the Malaria Centre members are in-
volved in Pharmacokinetics studies, phase II and III
efficacy & safety trials, phase IV studies and large
intervention trials involving Rapid Diagnostic Tests
(RDTs), antimalarial drugs, and vaccines in Africa
and Asia.
WHO now recommends test-based management
of malaria across all age groups and transmission
settings. The national malaria programs in sub-Sa-
haran Africa are at various stages of implementing
the revised guideline. However, there is a need for
more evidence on the effectiveness and safety of this
strategy. A study conducted by our staff in Tanzania
showed that application of malaria RDTs to deter-
mine the use of anti-malarial drugs in young children
did not result in any missed diagnoses of malaria. A
cluster randomised controlled trial to evaluate the
effect of restricting Artemisinin-based Combination
Therapy (ACT) to RDT-positive malaria in under-five
children is underway in Ghana.
Ensuring adherence to the treatment guide-
lines based on RDT result is a challenge. A trial of
a complex intervention consisting of 3 sessions of
interactive small-group training, feedback of pre-
scribing results and motivational SMS messages is
underway in Tanzania. Another cluster-randomized
controlled trial in Uganda is evaluating the effective-
ness and cost-effectiveness of training of registered
drug shop owners using participatory approach in
applying RDTs for diagnosis and rational drug use in
case management of malaria. A trial in Afghanistan
is assessing the effectiveness of different strategies
to provide accurate diagnosis and treatment for ma-
laria and non-malarial fevers, and another trial in
Uganda is evaluating the effects of a package of in-
terventions involving training of health workers and
supplementing supply of antimalarials and diagnos-
tics on health outcomes of <5 year old children.
Several studies of safety and efficacy of Intermit-
tent Preventive Treatment for malaria in children
(IPTc) have been completed or nearing completion.
WHO now recommends IPTc, renamed as Seasonal
Malaria Chemoprevention (SMC), in areas of highly
seasonal malaria transmission. Sulfadoxine-pyri-
methamine plus amodiaquine (SP+AQ) is the regi-
men recommended by WHO for SMC. However, the
pharmacokinetics data of this combination of drugs
in children are very limited. In Burkina Faso, a study
to determine the pharmacokinetic profile of SP+AQ
and a trial comparing the safety, tolerability and effi-
cacy of dihydroartemisinin+piperaquine (DHA+PQ)
with suphadoxine-pyremithamine+amodiaquine
(SP+AQ) when used for SMC in children, were re-
cently completed. A large study to confirm the safety
and feasibility of SMC using SP+AQ for children 3
months to 10 years of age is underway in Senegal.
Summary
Clinical Trials & Studies 61
Malaria Centre Report 2010-11
Although SMC has been shown to provide sub-
stantial reductions in malaria morbidity, there is
limited evidence on the additional benefit of SMC
when implemented along with prompt treatment of
malaria in their communities. Members of the Ma-
laria Centre are investigating the additional benefits
of SMC in communities using home-management of
malaria in Ghana and Senegal.
Although the risk of malaria is greatest in early
childhood, significant numbers of school-aged chil-
dren remain at risk from malaria. Previous research,
in an area of intense perennial transmission, showed
that Intermittent Preventive Treatment, given once
each term, can reduce malaria-related anaemia and
increase sustained attention in class. Members of
the Malaria Centre are now investigating the impact
of Intermittent Preventive Treatment in school chil-
dren in highly seasonal transmission area in Senegal.
Pregnant women and their unborn children are
vulnerable to malaria, increasing the risk of maternal
anaemia, low birth weight, abortion and stillbirth.
Intermittent Preventive Treatment in pregnancy
(IPTp) and Insecticide Treated Nets (ITNs) have
proven benefits. However there is little evidence on
the impact and cost-effectiveness of these approach-
es in areas of low and unstable transmission areas. A
randomised controlled trial undertaken in the high-
lands of Uganda showed that there is no difference
Man and child in the Gambia.
62 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
in the effects of IPTp using SP given in combination
with ITNs, IPTp-SP alone or ITNs alone on maternal
anaemia and low birth weight.
As the incidence of malaria is declining in some
parts of Africa and the resistance to SP is increasing,
there is a need to identify appropriate interventions
to replace IPTp-SP for control of Malaria in Pregnan-
cy (MiP). A trial of Intermittent Screening and Treat-
ment (IST) of parasitaemia at scheduled antenatal
clinic visits in the second and third trimester was
undertaken in The Gambia, Mali, Burkina Faso and
Ghana. A similar study of IST is underway in India.
Results of these studies will inform the MiP control
policies in Africa and India. Although ACT is recom-
mended to treat MiP in the second and third trimes-
ter there is a need to generate further evidence on
the safety of these drugs during pregnancy. A study
to assess the efficacy and safety of artesunate +me-
floquine or artesunate+SP for treatment of MiP is
underway in India.
In some other parts of Africa, there has recently
been a sharp decline in the incidence of malaria, co-
inciding with increased control efforts. This raises
the prospect that malaria could be eliminated, but
despite scaling up of control methods transmission
persists in foci which provide a continuing source
of infection. Members of the Malaria Centre are in-
vestigating different tools and strategies to interrupt
transmission. A study to evaluate the efficacy and
safety of lower doses of PQ to clear gametocytes is
underway in Uganda. Another study in Senegal is
evaluating the effectiveness of targeted application
of Indoor Residual Spraying and chemotherapy, de-
livered by district health staff to villages reporting
clinical cases, on transmission reduction. Members
of Malaria Centre are involved in several vaccine tri-
als. Phase 1 trials have shown that the MSP3-LSP
vaccine is safe and immunogenic in adults and chil-
dren and provided preliminary evidence of efficacy.
A phase2b efficacy trial of this vaccine is underway
in two sites in Mali. We are involved in another phase
2b trial to determine whether the GMZ2 vaccine, a
recombinant fusion protein of Plasmodium falci-
parum Glutamate Rich Protein and Merozoite Sur-
face Protein 3, adjuvanted with aluminum hydrox-
ide, can protect against clinical attacks of malaria in
children aged 1-5yrs that is conducted in Uganda,
Burkina Faso, Ghana and Gabon. Finally, as malaria
control improves, it is important to understand the
cause of non-malaria febrile illness. This has been
evaluated in an inpatient setting in Northern Tan-
zania and studies are ongoing in several additional
outpatient settings in Africa and south-east Asia.
Clinical Trials & Studies 63
Malaria Centre Report 2010-11
Effects of restricting the use of artesunate plus amodiaquine combination therapy to malaria cases confirmed by a dipstick test: a cluster randomised control trial.
LSHTM Investigators: Daniel Chandramohan, Jayne Webster & Seth
Owusu-Agyei.
External Investigators/Collaborators: Frank Baiden (Kintampo Health
Research Centre, Ghana).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The WHO now recommends test-based management of ma-laria across all age groups and transmission settings. The na-tional malaria programs in sub-Saharan Africa are at various stages of implementing the revised guideline. However, there are concerns that restricting Artemisinin-based Combination Therapy (ACT) to Rapid Diagnostic Test (RDT)-positive ma-laria could lead to increased frequency of malaria and as a result, anaemia in children who are denied ACT on account of negative RDT results. On the other hand, uncurtailed use of ACT has the potential to accelerate the development of resistance to ACT. The Kintampo-ACT study is a cluster ran-domised controlled trial to evaluate the effect of restricting ACT to RDT-positive malaria in under-five children in rural Ghana. In June 2010, a cohort of 3061 under-five children from 32 clusters was randomly allocated to RDT-based ma-laria management or to presumptive malaria management groups. The follow up of the cohort and collection of data on study endpoints (smear-confirmed malaria, anaemia, overall sick visits and cost-effectiveness) will be completed in June 2012. Study results will be disseminated in the last quarter of 2012.
Childhood Febrile Illness Treatment Study (C-FIT ).
LSHTM Investigators: Hugh Reyburn & Chris Whitty.
External Investigators/Collaborators: George Mtovu (National Insti-
tute for Medical Research, Tanzania).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
In late 2010, WHO guidelines abandoned the policy of pre-sumptive treatment of malaria in favour of treatment guid-ed by a blood slide or malaria Rapid Diagnostic Test (RDT). However, there is limited evidence of the safety of this policy in routine outpatient settings in Africa.
In a malaria endemic area of Tanzania, 965 children with a non-severe febrile illness were enrolled, and treatment for malaria was determined by the results of a clinical examina-tion and RDT result. Blood culture and serum lactate were also collected. RDT-negative children were followed up over 14 days.
Overall, 158 (16.4%) were RDT-positive and treated with artemether-lumefantrine and 807 (83.4%) were RDT-
negative and treated with non-anti-malarial medicines. Com-pared with RDT-positives, RDT-negative children were on average younger with a lower axillary temperature and more likely to have a history of cough or difficulty in breathing. Six (0.6%) children became RDT-positive after enrolment, all of whom were PCR-negative for Plasmodium falciparum DNA at enrolment. In addition, 12 (1.2%) children were admitted to hospital, one with possible malaria, none of whom died. A bacterial pathogen was identified in 9/965 (0.9%) children, eight of whom were RDT-negative and one was RDT-positive, but slide-negative. Excluding three children with Salmonella typhi, all of the children with bacteraemia were ≤12 months of age. Compared to double-read research slide results RDTs had a sensitivity of 97.8% (95%CI 96.9-98.7) and specificity of 96.3% (95%CI 96.3-98.4).
Use of RDTs to direct the use of anti-malarial drugs in young children did not result in any missed diagnoses of ma-laria although new infections soon after a consultation with a negative RDT result may undermine confidence in results. Invasive bacterial disease is uncommon in children with non-severe illness and most cases occurred in infants with a cur-rent fever.
Meeting of the study team and staff of study health centres held in Kintampo in April 2010.
64 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
Evaluation of malaria diagnostic strategies in South Central Asian health facilities where vivax is co-endemic with falciparum.
LSHTM Investigators: Toby Leslie, Amy Mikhail, Chris Whitty & Mark
Rowland.
External Investigators/Collaborators: HealthNet TPO; MERLIN &
Health Protection and Research Organisation.
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Malaria in many areas outside Africa is a consequence of two or more species; in Afghanistan and surrounding countries, the less-often fatal or serious vivax malaria predominates although falciparum is also seen. This situation complicates diagnosis and treatment of malaria and requires that malaria cases are accurately diagnosed and treatment is targeted at the specific species. In health facilities in low-income coun-
tries this is a challenge. Our study aims to assess the effec-tiveness of current strategies to provide accurate diagnosis and treatment for malaria and non-malarial fevers.
Although Rapid Diagnostic Tests (RDTs) appear more ac-curate than conventional light microscopy, the study shows that around 50% of patients who do not have malaria, based on a laboratory diagnostic result, received an antimalarial re-gardless of the negative parasite diagnosis.
The situation decreases the cost-effectiveness of RDTs and results in cases of potentially severe non-malarial febrile illness being mistreated as malaria. Improved guidelines which emphasise the importance of treatment according to laboratory diagnostic results will be part of the solution, but ensuring changes in treatment practice that are sustainable will also require additional point of care diagnostics for al-ternative, non-malarial causes of febrile illness.
Rapid Diagnostic Test being taken in Tanzania
Clinical Trials & Studies 65
Malaria Centre Report 2010-11
A cluster-randomised trial of health worker and community interventions to improve adherence to national guidelines for the use of ACT in Tanzania: The TACT trial: (Targeting ACT).
LSHTM Investigators: Hugh Reyburn, Clare Chandler, Bonnie Cundill,
Shunmay Yeung & Chris Whitty.
External Investigators/Collaborators: Florida Muro (Kilimanjaro
Christian Medical Centre, Tanzania); George Mtove (National Institute of
Medical Research, Tanzania).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
In 2010, WHO abandoned the policy of ‘presumptive treat-ment for malaria’ whereby young children with a fever and no obvious cause were treated with an antimalarial drug even if a diagnostic test for malaria was negative.
The TACT trial aims to address one of the most challeng-ing consequences of this policy shift, i.e. how to maximise the use of malaria Rapid Diagnostic Tests (RDTs) in primary care settings and how to ensure that all and only those with a positive test result are treated for malaria.
Following extensive formative research, a 3-arm clus-ter randomised trial was initiated in February 2011 and will close in March 2012. Health workers in all arms have received the Ministry of Health’s standard 3-day training on use of RDTs. In addition, health workers in two arms have received a complex intervention consisting of 3 sessions of interactive small-group training, feedback of prescribing re-sults and motivational SMS messages. In one of these arms, patient-directed messages have also been provided through leaflets and posters. Results from the 36 health facilities in the trial will be reported later in 2012 and we anticipate an important contribution towards maximising the benefit of RDTs throughout Africa.
ACT PRIME Study: evaluating the impact of enhanced health facility-based care for malaria and febrile illnesses in children in Tororo, Uganda.
LSHTM Investigators: Sarah Staedke & Clare Chandler.
External Investigators/Collaborators: Moses Kamya & Fred Wabwire-
Mangen (Makerere University, Uganda); Grant Dorsey & Philip Rosenthal
(University of California, USA); Ambrose Talisuna (WWARN East Africa
Centre); Heidi Hopkins (FIND Diagnostics, Uganda).
Funding Body: The Bill & Melinda Gates Foundation through the ACT
Consortium.
ACT PRIME is designed to evaluate whether enhancing public health facilities by training health workers and supplement-ing the supply of malaria drugs and diagnostics improves the health of children, as compared to ‘standard care’ currently available in Tororo, Uganda.
Twenty lower-level health centres were randomly as-signed to the Health Facility Intervention (HFI) or to stan-dard care using a cluster-randomised design. The HFI has three components: (1) training in-charges in health centre management, (2) training health workers in fever case man-agement and patient-centred services, and (3) ensuring ad-equate supplies of artemether-lumefantrine and Rapid Diag-nostic Tests (RDTs).
To evaluate the impact of the intervention, a cross-sec-tional survey was conducted at baseline in randomly select-
ed children from each cluster, and will be repeated annually. A cohort of children was recruited from randomly selected households, and will be followed for 2 years. Health facilities are also assessed using patient exit interviews, health work-er knowledge questionnaires, and monthly surveillance. The primary outcome of the study is prevalence of anaemia in children under five. Formative research was completed in September 2010, and the main trial began in December 2010. The intervention was rolled out in May 2011, and the study will continue until May 2013.
Cohort study team.
66 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
The role and cost-effectiveness of Rapid Diagnostic Tests (RDTs) in home-based management of malaria: a comparative study in two areas of high and low transmission in rural Uganda.
LSHTM Investigators: Sian Clarke, Kristian Hansen, Sham Lal
Clare Chandler, Bonnie Cundill & Caroline Lynch.
External Investigators/Collaborators: Richard Ndyomugyenyi (Min-
istry of Health, Uganda); Pascal Magnussen (DBL Centre for Health Re-
search and Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
A cluster-randomized controlled trial of use of Rapid Diag-nostic Tests (RDTs) for malaria by Community Medicine Dis-tributors (CMDs). The study aims to examine the role and cost-effectiveness of RDTs in home-based management of fever in two contrasting areas of high and low malaria trans-mission in rural Uganda.
CMDs in the intervention arm received training in use of RDTs, and to only give antimalarial treatment after a posi-tive test result. The training which adopted a participatory approach to build on prior knowledge and experience, also included modules on signs and symptoms of malaria, correct use of ACT, communication, and introduced the use of rectal artesunate pre-referral treatment and referral.
The trial examines the impact and cost-effectiveness of RDT use on the proportion of patients receiving appropriate antimalarial treatment (consistent with their malaria infec-tion status as determined against microscopy of a research slide), compared with CMDs following current practice (pre-sumptive clinical diagnosis and treatment of fever), in each of the two contrasting areas of high and low malaria trans-mission.
The study also investigates the positive predictive value of RDTs used by CMDs, and perceptions and acceptability of RDTs among malaria patients, CMDs and health staff, in each transmission setting. The impact of improved malaria diag-nosis on ACT adherence among patients will also be exam-ined.
Introducing Rapid Diagnostic Tests (RDTs) into the private sector. A cluster-randomised trial among registered drug shops in Mukono district, Uganda.
LSHTM Investigators: Sian Clarke, Kristian Hansen, Sham Lal, Clare
Chandler, Bonnie Cundill, Caroline Lynch & Harparkash Kaur.
External Investigators/Collaborators: Anthony Mbonye (Ministry of
Health, Uganda); Pascal Magnussen (DBL Centre for Health Research and
Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
A cluster-randomized controlled trial of Rapid Diagnostic Tests (RDTs) for malaria in registered drug shops. The study aims to examine the feasibility of introducing RDTs into reg-istered drug shops in Uganda to encourage rational drug use in case management of malaria.
Drug shop vendors in the intervention arm received training in use of RDTs for malaria, and to only recommend antimalarial treatment after a positive test result. The train-ing which adopted a participatory approach to build on prior knowledge and experience, also included modules on signs and symptoms of malaria, correct use of Artemisinin-based Combination Therapy (ACT), patient communication, and in-
troduced the use of rectal artesunate pre-referral treatment and standardised referral forms.
The trial examines the impact and cost-effectiveness of RDT use on the proportion of patients receiving appropriate antimalarial treatment (consistent with their malaria infec-tion status as determined against microscopy of a research slide), compared with prescription practices in control drug shops following current practice (presumptive clinical di-agnosis and treatment of fever). The study also investigates perceptions and acceptability of RDTs among malaria pa-tients and private providers, the impact of diagnostic testing on referral and the impact of improved malaria diagnosis on ACT adherence among patients. The socio-economic charac-teristics of patients seeking treatment for fever from regis-tered drug shops will be described.
Clinical Trials & Studies 67
Malaria Centre Report 2010-11
Pharmacokinetics of sulfadoxine-pyrimethamine plus amodiaquine when used for Seasonal Malaria Chemoprevention (SMC) in children.
LSHTM Investigators: Issaka Zongo,
Harparkash Kaur, Neal Alexander, Ba-
dara Cisse & Paul Milligan.
External Investigators/Collabora-
tors: Jean Louis NDiaye & Oumar Gaye
(Université Cheikh Anta Diop, Senegal).
Sulfadoxine-pyrimethamine plus amodiaquine (SP+AQ) is the most effective regimen for Sea-sonal Malaria Chemoprevention (SMC), but there is little informa-tion about the pharmacokinetics of these drugs in children. This information is important in or-der to check the bioavailability of the two drugs when used for SMC and to check the adequacy of the currently recommended dosage and to determine the duration of therapeutic levels. To determine the pharmacokinetic profile of sulfadoxine, pyrimethamine, and desethyl amodiaquine, 150 chil-dren 3-59 months of age were given one course of treatment with SP+AQs and were followed-up for one month. Finger prick blood samples were taken on four occasions for measurement of drug concentrations by HPLC using photo-diode array detec-tion and samples of the drugs drugs were tested to make sure of their bioavailability.
Mother and baby in Uganda.
68 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
Dihydroartemisinin-piperaquine for Seasonal Malaria Chemoprevention (SMC) in African children: efficacy, safety, tolerability and pharmacokinetics.
LSHTM Investigators: Issaka Zongo, Brian Greenwood, Daniel Chan-
dramohan, Colin Sutherland & Paul Mlligan.
External Investigators/Collaborators: Francois Nosten (Nuffield De-
partment of Clinical Medicine, UK); Jean Bosco Ouedrago (Institut de Re-
cherche en Sciences de la Santé, Burkino Faso), Philip Rosenthal (Univer-
sity of California, USA).
Funding Body: Holley Cotec.
The aim of this study is to compare the safety, tolerability and efficacy of DHA+PQ with SP+AQ when used for Seasonal Ma-laria Chemoprevention (SMC). The trial took place in Lena district near Bobo-Dioulasso. 1500 children were random-ized to receive SMC with one or other regimen and, outside the trial, a cohort of untreated children was followed to de-termine malaria incidence without SMC. Four finger prick blood samples were taken each month from a subset of chil-dren for measurement of piperaquine concentrations and ve-nous samples were taken from a second subset each month to measure the effect of SMC doses on haematological and biochemical parameters.
The clinical impact of combining Intermittent Preventive Treatment (IPT) with home management of malaria in children aged below 5 years: a cluster randomised trial.
LSHTM Investigators: Harry Tagbor, Matt Cairns & Daniel Chandramo-
han.
External Investigators/Collaborators: Emmanuel Nakwa, Edmund
Browne (Kwame Nkrumah University of Science and Technology, Ghana);
Badu Sarkodie (District Health Administration, Ghana); Helen Counihan &
Sylvia Meek (Malaria Consortium, UK).
Funding Body: Communicable Diseases Research Consortium.
Seasonal Intermittent Preventive Treatment in children (IPTc) has been shown to provide substantial reductions in
malaria morbidity but this has not been investigated where children also have access to prompt treatment of malaria in their communities. We investigated the additional impact of seasonal IPTc in Ghanaian communities using home-man-agement of malaria for presumptive treatment of fevers in a cluster-randomised trial. Bimonthly courses of seasonal IPTc with artesunate-amodiaquine reduced the incidence of fevers, particularly among children who received all three IPTc courses. Using IPTc to reducing the number of fevers that require management in the community could reduce selection pressure for resistance on the first-line treatment drug. However, high coverage will be necessary to maximise the impact of IPTc. Community-based delivery may be one approach to achieving this goal.
Ejisu-Juaben District, Ashanti, Ghana.
Clinical Trials & Studies 69
Malaria Centre Report 2010-11
Cluster randomized trial of SMC with sulfadoxine-pyrimethamine over 5 months combined with community case management, versus community case management alone, in children under 10 years of age in Southern Senegal.
LSHTM Investigators: Paul Milligan, Colin Sutherland & Rachel Hallett.
External Investigators/Collaborators: Jean Louis NDiaye, Youssoupha
NDiaye & Oumar Gaye (Université Cheikh Anta Diop, Senegal).
Funding Body: The European and Developing Countries Partnership.
Although the overall incidence of malaria has recently de-clined in Senegal as in some other countries, this hides the fact that the burden of malaria remains very high in some parts of the country, such as Saraya district, where 70% of the community lives more than 15km from the nearest health post.
Community case management for malaria is being in-troduced by volunteers (Distributeurs de soins à domicile or DSDOM) who are trained to recognize the signs and symp-toms of uncomplicated and severe malaria, to use Rapid Di-agnostic Tests (RDTs) and to treat malaria with Artemisinin-
based Combination Therapy. The DSDOM could also deliver Seasonal Malaria Chemoprevention (SMC) to children, SMC is known to be highly effective in preventing malaria illness but the relative advantage of adding SMC in villages which have access to prompt effective treatment from the village health worker has not been evaluated. In this trial, 24 vil-lages were randomized to deliver SMC with community case management, or community case management alone. In SMC villages, the DSDOM gave all children under 10 years old pre-ventive treatment with sulfadoxine-pyrimethmine plus amo-diaquine each month from July to November 2011.
Previously SMC has been delivered over three months so this study will also provide new evidence about the feasi-bility, tolerability and acceptability of delivery over a longer period. The DSDOM were trained to make blood films which were collected by the study team so that malaria cases could be confirmed by microscopy. The impact of SMC on drug re-sistance is being evaluated by analysis of used RDTs and from blood samples taken from a sample of children at the end of the transmission season.
Safety of Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine+amodiaquine when delivered on a large sacale by district health staff in Senegal.
LSHTM Investigators: Badara Cisse, Colin Sutherland, Rachel Hallett,
Matt Cairns, Catherine Pitt, Brian Greenwood & Paul Milligan.
External Investigators/Collaborators: El Hadj Ba, Oumar Gaye, Jean
Louis NDiaye, Babacar Faye, Cheikh Sokhna, Jean Francois Trape, Yank-
ouba Dial, Oumar Faye, Ousmane Faye; Lesong Conteh.
Funding Body: The Bill & Melinda Gates Foundation.
The WHO now recommends Seasonal Malaria Chemopreven-tion (SMC) for prevention of malaria in children in areas of highly seasonal malaria transmission.
This study provided key evidence establishing the safety of the intervention and feasibility of delivery. In three rural districts SMC with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) was delivered to children aged 3 months to 10 years by community health workers supervised by heath post nurses. A surveillance system was established to record all deaths, malaria cases diagnosed at health facili-ties and to detect adverse drug reactions. Community health
workers visited each child one month after the first and sec-ond round of treatment to check that there had been no se-vere reactions to the previous treatment and to give the next round of treatment and surveillance for adverse events was maintained at 54 health posts and 6 hospitals serving the population.
Training workshops were held to explain how to recog-nize, manage and document adverse drug reactions, leaflets illustrating the most common features of adverse reactions to SP or AQ were distributed and a reminder system was implemented using text messages sent to nurses just before the start of SMC delivery and sending them a phone credit as an incentive.
Coverage was independently assessed after each trans-mission season using cluster sample surveys. Nearly 800,000 documented courses of SMC were administered, high cover-age was achieved and though a number of cases of liver fail-ure and Steven Johnson syndrome were detected in study hospitals none had received SMC medication and no serious adverse events attributable to the intervention were detect-ed despite a high level of surveillance.
70 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
Intermittent parasite clearance in schools: a randomised double-blind placebo-controlled trial of the impact of IPC on malaria, anaemia and cognition amongst schoolchildren in Kedougou, Senegal.
LSHTM Investigators: Sian Clarke, Daniel Chandramohan, Badara Cisse,
Paul Milligan & Simon Brooker.
External Investigators/Collaborators: Jean-Francois Trape, Cheikh
Sokhna & Alioune Badara Ly (Institut de Recherché pour le Developpe-
ment, Senegal); Oumar Gaye & Jean-Louis Ndiaye (Université Cheikh Anta
Diop, Senegal); Malick Sembene, Aliou Dia, Khady Diallo & AlHousseynou
Sy (Ministry of Education, Senegal); Fatou Ba Fall (National Malaria Con-
trol Programme, Senegal); Matthew Jukes (Harvard Graduate School of
Education, USA).
Funding Body: Wellcome Trust.
Although the risk of malaria is greatest in early childhood, significant numbers of school-aged children remain at risk from malaria. Previous research, in an area of intense pe-rennial transmission, showed that Intermittent Preventive Treatment, given once each term, can reduce malaria-related anaemia and increase sustained attention in class – suggest-
ing that malaria control in schoolchildren could yield educa-tional, as well as health, benefits.
This study investigates the impact of malaria control in schools in a different epidemiological setting - highly season-al transmission - in Senegal, West Africa. Here, despite a new policy of universal coverage of ITNs with mass distribution of long-lasting nets to all age groups and almost 100% reported utilisation of ITNs, over a third of schoolchildren were found, at the end of the transmission season, to harbour asymptom-atic malaria infections.
The study thus examines whether a single round of cu-rative treatment, using sulphadoxine-pyrimethamine and amodiaquine, to clear asymptomatic parasitaemia at the end of the rains would confer any additional benefit in school-children sleeping under insecticide-treated nets. Study de-sign: An individually-randomized placebo-controlled trial of intermittent parasite clearance given in primary schools, with 845 children recruited into the study in Oct 2011. Trial outcomes include malaria, anaemia, cognitive function and school performance.
School staff are also providing scientific advice on inter-vention design and analysis for a similar cluster-randomised trial being conducted in Sikasso, Mali by Save the Children.
A randomised trial to compare the safety, tolerability and efficacy of artesunate plus mefloquine, amodiaquine plus sulfadoxine-pyrimethamine and proguanil in prevention of malaria and related complications in patients with sickle cell anaemia.
LSHTM Investigators: Paul Milligan & Brian Greenwood.
External Investigators/Collaborators: Rasaq Olaosebikan, Ernest
Kolade, Kalifa Bojang & Olugbenga Mokuolu.
Funding Body: Wellcome Trust.
Effective prophylaxis should be provided for people with sickle cell disease in malaria endemic areas. In Nigeria daily proguanil or weekly pyrimethamine are the most commonly prescribed regimens, but the effectiveness of this policy is limited by poor compliance and drug resistance. Sickle-cell patients who are stable are recommended to visit the clin-ic once every two months. A long-acting drug regimen that could provide prophylaxis for two months could be admin-istered under supervision at each clinic visit, this might be
more effective than the current practice that relies on pa-tients remembering to take their prophylaxis regularly.
The aim of this trial is to compare the tolerability and acceptability of supervised bimonthly treatment with either sulfadoxine-pyrimethamine plus amodiaquine or meflo-quine plus artesunate, with unsupervised daily proguanil. Two hundred and seventy patients with sickle cell disease at-tending the paediatric sickle cell disease clinic in Ilorin hos-pital were randomized to one of the three prophylactic regi-mens and were asked to return to clinic every two months and whenever they are sick. Participants will be followed for one year. If the bimonthly regimens are well tolerated and the preliminary data from this study are promising, a larger multicentre trial will be required to determine efficacy.
Clinical Trials & Studies 71
Malaria Centre Report 2010-11
A Phase II/III randomised clinical trial of the efficacy & safety of artesunate + suplhadoxine-pyrimethamine and artesunate + mefloquine to treat uncomplicated falciparum malaria in pregnancy .
LSHTM Investigators: Daniel Chandramohan, Irene Kuepfer, Jane Bruce, Jayne
Webster & Brian Greenwood.
External Investigators/Collaborators: Neena Valecha, Anupkumar Anvikar
& Bhartendu Shahi (National Malaria Research Institute, India); Feiko ter Kuile
(Liverpool School of Tropical Medicine, UK).
Funding Body: The Bill & Melinda Gates Foundation through the MiP Consor-
tium.
The current first line treatment for Malaria in Pegnancy (MiP) during second and third trimester in India is artesunate + sulph-adoxine-pyremethamine (AS+SP). The emergence of malaria parasites resistant to SP from some parts of India is a concern. The primary objective of this study is to assess the efficacy and safety of artesunate +mefloquine (AS+MQ) as an alternative to AS+SP for treatment of MiP. This is an open label randomised superiority trial the required sample size is 500 women. The primary endpoint is adequate clinical and parasitological response by day 63. The secondary endpoints include adverse events (clinical, haematological & biochemical), re-infection rates by day 63, birth outcomes, and pharmacokinetic profile of AS+MQ. By January 2012, 4341 pregnant women had been screened for malaria, 158 women were found to have either symptomatic or asymptom-atic malaria and 136 women have been enrolled in the study. The study is expected to be completed in 2013.
Comparison of three interventions to prevent malaria in pregnancy in a highland area of low transmission in Southwest Uganda.
LSHTM Investigators: Sian Clarke, Kristian Hansen & Daniel Chandramo-
han.
External Investigators/Collaborators: Richard Ndyomugyenyi (Min-
istry of Health, Uganda); Pascal Magnussen (DBL Centre for Health Re-
search and Development, Denmark).
Funding Body: The Bill & Melinda Gate Foundation through the Gates
Malaria Partnership.
Pregnant women and their unborn children are vulnerable to malaria, increasing the risk of maternal anaemia, low birthweight, abortion and stillbirth. Intermittent Preventive Treatment in pregnancy (IPTp) and Insecticide-Treated Nets (ITNs) have proven benefits, yet the impact and cost-effec-tiveness of these approaches in areas of low and unstable transmission remains unknown.
An individually-randomised placebo-controlled trial was undertaken in the highlands of Uganda to compare the impact and cost-effectiveness of IPTp using sulfadoxine-py-
Investigators meeting, Delhi February 2012.
rimethamine given in combination with ITNs, IPTp-SP alone and ITNs alone on maternal anaemia and low birthweight. Data was recorded on stillbirth, abortion, neonatal and ma-ternal mortality. No differences were observed between the three alternative interventions in any of the maternal and infant health outcomes examined. The cost-effectiveness and sensitivity analyses performed did not provide convinc-ing evidence for replacing IPTp-SP (current policy) by ITNs alone or the combined intervention, on economic grounds.
Other factors may be of greater relevance for policy set-ting in areas of low transmission, including risks of each ap-proach and extended benefits beyond the period of pregnan-cy. The relative cost-effectiveness of antenatal distribution of ITNs might improve if the cost savings accruing from contin-ued use of a long-lasting insecticidal net after pregnancy and other positive externalities are also taken into account.
72 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
Intermittent Preventive Treatment (IPT) with sulfadoxine-pyrimethamine versus intermittent screening and treatment of malaria in pregnancy.
LSHTM Investigators: Harry Tagbor, Paul Milligan, Daniel Chandramo-
han & Brian Greenwood.
External Investigators/Collaborators: Sheick Oumar Coulibaly (Univer-
sité de Ouagadougou, Burkino Faso); John Williams & Abraham Hodgson
(Ghana Health Research Centre, Ghana); Kalifa Bojang (Medical Research
Council, UK); Kassoum Kayentao (Medical Research and Training Centre,
Mali); Feiko Ter Kuile (Liverpool School of Tropical Medicine, UK); Pascal
Magnussen (DBL Centre for Health Research and Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the MiP Con-
sortium & European Union.
The incidence of malaria, including the incidence in pregnant women is declining in many African countries. Thus, there is a need to re-examine the efficacy and cost effectiveness of giving Intermittent Preventive Treatment in pregnancy
(IPTp) on several occasions during pregnancy. A randomised, multi-centre controlled trial in 5000
pregnant women who sleep under an insecticide treated bed net to compare the standard SP - IPTp regimen (3 doses of SP in second and third trimester) and intermittent screen-ing using a Rapid Diagnostic Test and treatment of parasi-taemia at scheduled antenatal clinic visits in the second and third trimester undertaken in four west African countries. The primary end points of the trial are birth weight; anae-mia at 36 – 38 weeks of gestation and at the time of delivery or shortly afterwards and placenta malaria. Mothers and in-fants are seen again six weeks after delivery. The study was powered to show that intermittent screening and treatment of parasitaemia is not inferior to standard SP - IPTp regimen. The costs and cost effectiveness of each intervention will be evaluated.
Recruitment of study participants is over now. Progress is currently being monitored closely to ensure that follow up is completed successfully. We anticipate study completion and final reporting in the fourth quarter of 2013.
Effective and save interventions for prevention of malaria in pregnancy in India: an assessment of burden of malaria in pregnancy, implementability of a screening strategy and barriers to scaling up interventions.
LSHTM Investigators: Daniel Chandramohan, Jayne Webster, Irene Kuep-
fer, Jane Bruce, Chris Drakeley & Brian Greenwood.
Funding Body: The Bill & Melinda Gates Foundation through the MiP Con-
sortium.
The current strategy for control of Malaria in Pregnancy (MiP) in India is to test for malaria during antenatal care (ANC) visits only in a woman has any sign or symptom sug-gestive for malaria. This strategy is probably inadequate to reduce the burden of MiP because a substantial proportion of MiP cases remain asymptomatic. The aim of this study is to evaluate Intermittent Screening and Treatment (IST) as a new control strategy delivered through routine ANC. In the phase one of this study starting in April 2012, a total of 8000 pregnant women will be enrolled into a cluster randomized controlled trial with two arms. Women in the IST arm will be screened for malaria using a Rapid Diagnostic Test (RDT)
at each routine ANC visit. If positive, they will be treated ac-cording to the national policy (AS+SP). The women in the control will be tested for malaria only if they have any sign or symptom of malaria. The primary outcome is placental ma-laria. In the second phase of the study starting in September 2012, RDT based IST will be implemented at pilot scale in a sub-district. A series of studies (household & health facility surveys, structured observations, focus group discussions) will be conducted to assess the implementability of IST, in-cluding costs for provider and users.
Clinical Trials & Studies 73
Malaria Centre Report 2010-11
Evaluation of the efficacy and safety of primaquine for clearance of gametocytes in uncomplicated falciparum malaria in Uganda.
LSHTM Investigators: Chi Eziefula, Chris Drakeley, Shunmay Yeung & Sa-
rah Staedke.
External Investigators/Collaborators: Infectious Diseases Research Col-
laboration, Uganda; Mahidol Oxford Research Unit, Thailand.
Funding Body: Wellcome Trust.
The study is a randomized placebo-controlled trial of the anti-malarial drug primaquine. For Plasmodium falciparum primaquine has specific gametocytocidal properties, mean-ing it destroys the form of the parasite in human blood that is infectious to mosquitoes. It is recommended for reduction of malaria transmission by the WHO. However, treatment with primaquine is associated with haemolysis in individuals with G6PD deficiency. This effect is dose-related. This study aims to evaluate whether lower doses of primaquine have equally potent gametocytocidal effects but result in reduced levels of haemolysis. This would potentially allow more widespread
use of the drug as part of malaria control and elimination strategies.
The study is conducted at Walukuba Health Centre, Jin-ja, Uganda in children with uncomplicated (mild) malaria. Children with G6PD deficiency are excluded. Participants receive the local standard malaria treatment artemether-lumefantrine on days 0-2 and are randomized to one of four treatment arms (placebo and three different doses of prima-quine) on day 2. They are followed up for 28 days.
The general objective is to evaluate the efficacy and safety of different doses of primaquine administered with AL for the purpose of reducing Plasmodium falciparum gameto-cytes in the infected human host to prevent transmission of falciparum malaria to the anopheles mosquito vector. Efficacy endpoints are assessed by measuring gametocyte prevalence and density on days 3, 7 and 14 after treatment. Safety is evaluated by measuring haemoglobin, prevalence of severe anaemia and active detection of serious adverse events on days 3, 7, 10, 14, 21 and 28 and passively throughout the trial.
Child from the primaquine study, Uganda.
74 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
Randomized trial of spatially targeted malaria control to virtually eliminate malaria in areas of low and patchy transmission in Senegal.
LSHTM Investigators: Badara Cisse, Catherine Pitt, Mark Rowland, Immo
Kleinschmidt, Matt Cairns, Colin Sutherland, Chris Drakeley & Paul Mil-
ligan.
External Investigators/Collaborators: Oumar Gaye, Ousmane Faye,
El Hadj Ba, Babacar Faye, Yemou Dieng, Fatou Ba Fall, Bakary Sambou,
Cheikh Sokhna, Jean Francois Trape & Jean Louis NDiaye.
Funding Body: Medical Research Council, UK, Wellcome Trust & UK De-
partment for International Development,.
In Senegal, as in some other parts of Africa, there has recent-ly been a sharp decline in the incidence of malaria, coincid-ing with increased control efforts, primarily the large-scale distribution of free and highly subsidized insecticide-treated nets. This raises the prospect that malaria could be elimi-nated, but despite scaling up of control methods, transmis-sion persists in foci which provide a continuing source of infection. Additional strategies are needed to eliminate these foci. Strategies to target communities with high incidence of malaria in order to achieve community-wide malaria control have a sound basis in population theory but have not been evaluated in randomized trials. Such strategies become in-creasingly relevant as malaria incidence declines and the geographical distribution becomes very patchy. The purpose of this trial is to evaluate the extent to which a targeted ma-laria control strategy combining vector control with Indoor Residual Spraying and chemotherapy, delivered by district health staff to villages reporting clinical cases, can virtually eliminate malaria, in an area in central Senegal where malar-ia incidence is very low and patchy. Secondly we will deter-mine whether, as part of this strategy, chemotherapy should be delivered to all members of targeted communities or only those who have been tested and are known to be infected.
A phase 2b double blind, randomized, controlled trial to evaluate the safety, immunogenicity and protective efficacy of merozoite surface protein-3 (MSP3-LSP) vaccine candidate adjuvanted in aluminium hydroxide against Plasmodium falciparum clinical malaria in healthy children aged 12-36 months in Mali.
LSHTM Investigators: Paul Milligan
External Investigators/Collaborators: Pierre Druihle, Mahamadou Sis-
soko, Issaka Sagara, Zarifah Reed & Ogobara Doumbo.
MSP3-LSP is a synthetic peptide of 95 amino acids, derived from the highly conserved MSP3 C-terminal region of Mero-zoite Surface Protein 3. The vaccine is based on an immune mechanism associated with reduction in parasite density ob-served when antibodies were transferred from immune sub-jects to non-immunes infected with Plasmodium falciparum. Phase 1 trials have shown the vaccine is safe and immuno-genic in adults and children and provided preliminary evi-dence of efficacy. This phase2b efficacy trial is being conduct-ed in two sites in Mali, Doneguebougou, which has a short transmission season, and Bougoula, with a longer season with rainfall from May to October. In 2011 400 children aged 12-48 months were enrolled in each site and randomized to receive three doses one month apart of 30 µg of MSP3-LSP adjuvanted in Aluminium hydroxide, or rabies vaccine, fol-lowed by a fourth dose three months after the third dose. Follow-up will be for 2 years from dose 1. Dispensaries were set up so that all children are within 1km of a study nurse, and each household is visited weekly to ask if the child is well and to remind the family to take the child to the nearest clinic if they are unwell. The primary endpoint of the trial is the number of malaria episodes with an auxiliary temperature of at least 37.5oC and parasite density ≥5000/µL, assessed initially after three months and the trial is designed to have at least 90% power to detect a vaccine efficacy of 30% over this period.
Street scene in Senegal.
Clinical Trials & Studies 75
Malaria Centre Report 2010-11
A Phase II, randomized, controlled, double-blind, multi-centre study to evaluate the efficacy, safety, and immunogenicity of the GMZ2 candidate malaria vaccine in Ugandan, Ghanaian, Burkinabe and Gabonese children aged 12 – 60 Months.
LSHTM Investigators: Samuel Bosomprah & Paul Milligan.
External Investigators/Collaborators: Sodiomon Sirima, Saadou Is-
sifou, Kalifa Bojang, Fred Kironde, Tiono Alfred, Ateba Ngoa, Kaddu Mu-
kasa, Frank Atuguba, Roma Chilengi, Brenda Okech, Dawit Ejigu, Michael
Thiesen, Benjamin Mordmuller, Soren Jepsen, Ismaela Abubakar.
Funding Body: The European and Developing Countries Partnership.
The aim of this phase 2b trial is to determine whether the GMZ2 vaccine, a recombinant fusion protein of Plasmodium falciparum Glutamate Rich Protein and Merozoite Surface Protein 3, adjuvanted with aluminium hydroxide, can protect against clinical attacks of malaria in children aged 1-5yrs.
Baseline studies were conducted to determine the inci-dence of malaria in potential trial sites. 1840 children have been enrolled in five sites, in Uganda, Burkina Faso, Ghana and Gabon. The primary endpoint is the incidence of clinical malaria defined as fever or history of fever in the previous 24 hours with parasite density of 5000 asexual parasites per ul or more, detected by passive surveillance over a 6 month period from the third vaccination. Immune responses to the vaccine antigens GMZ2, GLURP and MSP3 will be assessed by measuring antigen specific IgG by ELISA, and antigen specific memory B-cell responses by ELISA spot.
Functionality of the immune response will be assessed by growth inhibition of Plasmodium falciparum in the pres-ence or absence of monocytes. Cell mediated immunogenic-ity will be assessed by cytokine profiling and intracellular cell staining following stimulation with the vaccine antigen, and the quality of the antibody response by type and sub-class-specific ELISA. Children will be followed for a total of 22 months from the third vaccination.
In Focus: Intermittent Preventive Treatment for malaria.In the late 1990’s and early 2000’s a set of new strategies were evaluated – the Intermittent Preven-
tive Treatments (IPT). IPT is the delivery of a treatment dose of an anti-malarial drug at pre-specified
times, regardless of the presence of malaria parasites at the time of treatment. IPT in pregnancy (IPTp),
IPT in infants (IPTi) and IPT in children (IPTc) are now all recommended by WHO for malaria control
in parts of Africa. LSHTM staff led the first major randomised controlled trials of each of the three IPT
strategies and have generated additional evidence to inform policy and implementation.
In 2010, IPTp was part of the malaria control strategy for 33 of the 43 malaria-endemic countries
in Africa. Good coverage data is illusive but surveys in 8 countries (total population 270 million) have
shown that 2.4-62% of women in pregnancy received at least 2 doses of IPTp in pregnancy.
WHO recommended IPTi as a malaria control tool for implementation in areas of moderate to
high transmission in 2010. Although IPTi has not yet been adopted by any national malaria control
programmes, if it were rolled out in those countries where studies have been conducted, unpublished
estimates suggest that up to 1 million clinical episodes could be prevented every year.
The WHO Technical Expert Group recommended IPTc (Seasonal Malaria Chemoprevention) for
malaria control in May 2011. SMC has now been recommended by WHO for areas of the Sahel and
sub-Sahel where malaria transmission is highly seasonal. Geospatial models show that SMC has the
potential to prevent about 100,000 deaths per year.
76 Clinical Trials & Studies
London School of Hygiene & Tropical Medicine
The severe febrile illness study.
LSHTM Investigators: Behzad Nadjm, Christopher Whitty & Hugh Rey-
burn.
External Investigators/Collaborators: George Mtove (National Insti-
tute of Medical Research, Tanzania).
Funding Body: European Commission.
The aims of the study were to establish the treatable causes of febrile illness among children admitted to hospital in a high malaria transmission region of Tanzania and the clinical features that accompanied them. Children were enrolled at admission. Over 1 year 3,708 children were enrolled and re-sults were available for 3,639. Blood slides for malaria were positive in 2195 (60.3%), 341 (9.4%) had invasive bacte-rial disease and 142 (3.4%) were seropositive for HIV. Non-typhi Salmonella were the most common bacterial isolate (160/341, 46.9%). Mortality in children with invasive bacte-rial disease was significantly higher (58/341, 17%) than in those without (126/3298, 3.8%, p<0.001) and this was true regardless of the presence of Plasmodium falciparum para-sitaemia.
The sensitivity and specificity of WHO criteria in iden-tifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative chil-dren. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were sus-ceptible to the first recommended antimicrobial agent. The site went on to be involved in 2 large randomised controlled trials (AQUAMAT & FEAST) and typhoid surveillance studies.
Numbers and deaths of children infected with Plasmodium falciparum by blood slide, invasive bacterial disease (IBD), or HIV. Areas in Venn diagram approximately to scale. *IBD consisted of 336 children with a positive blood culture, of whom 20 also had a positive cerebrospinal fluid (CSF) culture, and an additional five with a pathogenic organism isolated from CSF and a nega-tive or contaminated blood culture. †Blood cultures classified as negative included 251 (6.9%) from which contaminant organisms were cultured. ‡Three negative HIV results were based in Capillus testing only (negative predictive value 99.5%, details not shown); all other HIV results were based on at least two concordant test results.
Point-of-care measurement of blood lactate in children admitted with febrile illness to an African district hospital.
LSHTM Investigators: Behzad Nadjm & Hugh Reyburn.
External Investigators/Collaborators: George Mtove (National Insti-
tute for Medical Research, Tanzania).
Funding Body: European Commission.
Lactic acidosis is a consistent predictor of mortality due to severe infectious disease but its detection in low-income set-tings is limited to the clinical sign of ‘deep breathing’ due to lack of accessible technology for its measurement. We eval-uated the use of a point-of-care diagnostic device for blood lactate to assess the severity of illness in children admitted to a district hospital in Tanzania.
Children between the age of 2 months and 13 years with a history of fever were enrolled in the study over 1 year. A full clinical history and examination were undertaken and
blood drawn for culture, microscopy, complete blood count and POC measurement of blood lactate and sugar.
3,248 children were included in the study of whom 164 (5.0%) died; 45 (27.4%) of these had raised blood lactate (>5mmol/L) but no deep breathing. Compared to mortal-ity in children with lactate of >=3mmol/L, the unadjusted odds of dying were 1.6 (95%CI 0.8-3.0), 3.4 (95%CI 1.5-7.5) and 8.9 (95%CI 4.7-16.8) in children with blood lactates of 3.1-5.0mmol/L, 5.1-8.0 mmol/L and >8.0mmol/L respective-ly. The prevalence of raised lactate (>5mmol/L) was greater in children with malaria than in children with non malarial febrile illness (P<0.001) although the associated mortality was greater in slide-negative children.
POC lactate measurement can contribute to the assess-ment of children admitted to hospital with febrile illness and can also create an opportunity for more hospitals in resource-poor settings to participate in clinical trials of interventions to reduce mortality associated with hyperlactataemia.
Clinical Trials & Studies 77
Malaria Centre Report 2010-11
The use of a HRP2 based Rapid Diagnostic Test (RDT) to guide treatment of children admitted to hospital in a malaria endemic area of Northeast Tanzania.
LSHTM Investigators: Behzad Nadjm & Hugh Reyburn.
External Investigators/Collaborators: George Mtove (National Insti-
tute for Medical Research, Tanzania); Ilse Hendriksen (The Mahidol Oxford
Tropical Medicine Research Unit, Thailand).
Funding Body: European Commission.
In a busy paediatric ward in Tanzania children with a febrile illness were enrolled over 1 year. A standard clinical history and examination were recorded and blood drawn for cul-ture, complete blood count, Paracheck RDT and double-read blood slide.
Of 3,639 children in the study 2,195 (60.3%) were slide-positive. The sensitivity and specificity of Paracheck results were 97.5% (95% CI 96.9-98.0) and 65.3% (95% CI 63.8-66.9) respectively. There was an inverse relationship between age-specific prevalence of parasitaemia and the
specificity of Paracheck. In a logistic regression model, false-positive Paracheck results were significantly associated with pre-admission use of an antimalarial drug (OR 1.44, 95% CI 1.16-1.78), absence of current fever (OR 0.64, 95% CI 0.52-0.79) and a positive blood culture for non-typhi Salmonella (OR 3.89. 95% CI 2.27-6.63). In spite of high sensitivity, only 56/2,195 (2.6%) of true infections were Paracheck-negative and 8(14.3%) of these were in patients with >50,000 para-sites/µl.
Paracheck had poor specificity in diagnosing malaria in severely ill children and this was likely to be due to persis-tence of HRP2 following recent clearance of parasites. The combination of a positive Paracheck and negative blood slide result identified a group of children at high risk of non-typhi Salmonella infection. While Paracheck was highly sensitive, some high-density infections were missed. For children with severe febrile illness at least 2 reliable negative parasitologi-cal test results should be available to justify withholding an-timalarial treatment.
78 Vector Studies
London School of Hygiene & Tropical Medicine
The malaria vector landscape across Africa is under-
going rapid change and entomologists in the LSHTM
Malaria Centre are rising to meet the challenge. In
East Africa, Anopheles arabiensis has become more
prevalent relative to its sibling species Anopheles
gambiae. Along coastal Tanzania Anopheles gambiae
has declined in density, and this coincides with a fall
in clinical malaria recorded in local hospitals. Mean-
while there is growth of pyrethroid resistance in
Anopheles gambiae which is no longer restricted to
West Africa but is detectable in several East African
countries and growing in frequency with each pass-
ing year. An important driver of change – besides
environmental factors - is the scaling up of vector
control and the increasing coverage of Long Lasting
Insecticide-treated Nets (LLINs) and Indoor Residu-
al Spraying (IRS). These interventions are having a
major impact on malaria burden but perhaps inevi-
tably are also affecting the dynamics and evolution
of mosquito vectors. There is tantalising evidence
that Anopheles arabiensis is less readily killed by an
LLIN than Anopheles gambiae, owing to behavioural
differences between the species, and is perhaps one
reason why Anopheles arabiensis seems more evi-
dent while Anopheles gambiae declines.
In Benin in West Africa, it is shown that in pockets
of high pyrethroid resistance that Insecticide Treat-
ed Nets (ITNs) provide less protection to families as
demonstrated by reduced mosquito mortality rates
and higher blood feeding rates higher compared to
areas with little or no resistance. Is this a problem
now occurring in East Africa? In Northwest Tanzania
there is a surprisingly high prevalence of malaria in
some areas despite several rounds of IRS.
There is interest in the potential of combina-
tion interventions to reduce transmission over and
above what IRS or LLIN can achieve individually.
Community randomised trials of LLIN and IRS with
carbamate insecticides are being sponsored by US-
AID to control pyrethroid resistant populations in
Northwest Tanzania. The Innovative Vector Control
Consortium, supported by The Bill & Melinda Gates
Foundation, has funded small scale funding trials of
LLIN plus IRS with novel insecticides such as chlorf-
enapyr and these combination interventions seem to
restore vector control where previously pyrethroid
resistance was undermining recent gains. The race is
on to identify alternative insecticides to pyrethroids
and to make these long lasting through reformula-
tion. Two organophosphate insecticides have been
given a new lease of life through reformulation, and
one of these, pirimiphos methyl, offers the prospect
of several months of vector control with a single ap-
plication. Aside from improving formulations, mem-
bers of the Malaria Centre are also investigating al-
ternative substrates for applying insecticide in the
Summary
Vector Studies 79
Malaria Centre Report 2010-11
home. Durable wall lining, a form of polyethyelene
sheeting that was first developed for use as refugee
shelter in displacement camps, can be impregnated
with insecticide during manufacture and used to
line the interior walls of habitations to serve as both
decoration and long lasting IRS. Impregnated with
pyrethroid, durable wall lining works like any pyre-
throid IRS, but for longer periods. But treated with
a non-pyrethroid insecticide it offers the prospect
of controlling pyrethoid resistant mosquitoes. An-
other simple but promising alternative substrate for
applying chemical control agents are wall hangings
made from curtains or netting material. Appropriate
technology is not limited to chemical control. Work
with spatial repellents, once again sponsored by The
Bill & Melinda Gates Foundation, may circumvent
the need for discipline in applying topical repellent
and drive mosquitoes away from domestic interiors.
Some repellents come from natural sources. Lanta-
na camara is a mosquito repelling plant which can
be arranged around houses to reduce house entry
by vector mosquitoes by 56-83% depending on the
species. Repellent treated sheets and blankets to
provide additional control over that achievable with
LLINs are being investigated in cluster randomised
trials.
While the malaria vector landscape continues to
evolve and produce new challenges, members of the
Malaria Centre are working to address these, though
a mixture of ingenuity and pragmatism, working
with southern partners through field sites in Tan-
zania, Kenya, Benin and the Gambia and though alli-
ances such as the Malaria Transmission Consortium,
Pan African Malaria Vector Research Consortium,
the President’s Malaria Initiative, WHO Pesticide
Evaluation Scheme and Medical Research Council.
Mosquito net.
80 Vector Studies
London School of Hygiene & Tropical Medicine
Malaria Transmission Consortium (MTC) in the Western Kenyan Highlands.
LSHTM Investigators: Jonathan Cox, Chris Drakeley, Jennifer Stevenson,
Mary Cooke
External Investigators/Collaborators: Mary Hamel, John Gimnig, Kayla
Laserson, John Vulule & Nabie Bayoh (KEMRI/CDC, Kenya); Neil Lobo,
Brandy St. Laurent, Frank Collins (University of Notre Dame, USA); Ralph
Harbech (Natural History Museum, UK).
Funding Body: The Bill & Melinda Gates Foundation through the Malaria
Transmission Consortium.
MTC activities in Western Kenya encompass a range of sub-projects that together address the need to develop standard-ized measures of malaria transmission as a means of assess-ing the effectiveness of programmatic interventions in unsta-ble transmission settings. This has included studies compar-ing a range of evaluation approaches (community and school cross-sectional surveys, community cohort studies, health facility monitoring and entomological monitoring).
As part of this work a Latin-square design experiment was carried out in 2010 to compare the suitability of differ-ent vector trapping methods in a highland fringe setting. In the event a large proportion of the mosquitoes caught could not be identified definitively using available morphological keys or by using diagnostic PCR for Anopheles gambiae. Sub-
sequent genetic sequencing of ribosomal ITS2 and mitochon-drial CO1 regions revealed that the majority of the mosqui-toes, including those with malaria sporozoites, had unique unpublished sequences dissimilar to all known malaria vec-tors in the area. Significantly, the most abundant clade of un-identified mosquitoes (42% of the specimens sampled) was trapped outdoors and before 22:30 hours. We are continuing to work with our collaborators at Notre Dame University to sequence mosquitoes caught by pyrethrum spray catch from across the district.
In late 2011 collaborators from the Natural History Museum collected and reared over 500 Anopheles larvae through to adult stages from the study sites. Sequencing of the ITS2 and CO1 region by Notre Dame collaborators will be linked to full morphological descriptions of the samples to fully describe any unusual species from the area.
A longitudinal survey is now ongoing to determine the relative importance of specific species (including newly-identified species) in terms of malaria transmission and to investigate species-specific host-seeking behaviours. Initial data support observations that a substantial proportion of host seeking mosquitoes are sampled outdoors in the eve-ning . This has potentially important implications in an area where vector control (in the form of IRS and LLINs) is predi-cated on the expectation of indoor, night-time biting.
Phylogenetic tree of sequence group consensuses with NCBI reference sequences. Samples caught arbitrarily named species ‘A’ to ‘I’, ranked by abundance.
Vector Studies 81
Malaria Centre Report 2010-11
Pan African Malaria Vector Research Consortium (PAMVERC).
LSHTM Investigators: Richard Oxborough & Mark Rowland.
External Investigators/Collaborators: Franklin Mosha (Kilimanjaro
Christian Medical University College, Tanzania).
Funding Body: The Bill & Melinda Gates Foundation through the Innova-
tive Vector Control Consortium.
The London School of Hygiene and Tropical Medicine in partnership with Kilimanjaro Christian Medical University College conducted a series of insecticide evaluations of new products for malaria vector control.
Pyrethroids are the only group of insecticides approved by World Health Organization for treating mosquito nets (ITN) and have also been preferred for Indoor Residual Spraying (IRS) in Africa in recent years. Consequently, pyre-throid resistance has become widespread in malaria vectors across Africa. For continued effectiveness of malaria control programmes it is imperative to develop new formulations of insecticides for ITN and IRS.
A series of trials were done in collaboration with several major chemical manufacturers including BASF, Bayer, Du-
Summary table of genetic and morpho-logical identification of female Anopheles caught in Kisii, Kenya.
Pont, Sumitomo and Syngenta. Trials have focused on Phase 1 laboratory and Phase 2 experimental hut evaluation of nov-el products for the control of pyrethroid resistant mosquito populations.
Several novel long-lasting or wash resistant formula-tions have produced promising results and data has been submitted to the World Health Organization Pesticide Evalu-ation Scheme as part of product registration.
There is still a major dearth of public health insecticides and in future we will continue evaluating promising new products at all stages from laboratory to community testing, as well as investigating resistance management strategies.
We expect that some of the products we have evaluated will be used for widespread malaria vector control in Africa within the next few years.
82 Vector Studies
London School of Hygiene & Tropical Medicine
Species shifts in the Anopheles gambiae complex: do LLINs successfully control Anopheles arabiensis?
LSHTM Investigators: Richard Oxborough, Jane Bruce & Mark Rowland.
External Investigators/Collaborators: Franklin Mosha & Jovin Kitua
(Kilimanjaro Christian Medical University College, Tanzania); Stephen
Magesa, Robert Malima & Patrick Tungu (National Institute for Medical
Research, Tanzania).
Funding Body: The Bill & Melinda Gates Foundation through the Gates
Malaria Partnership.
Coverage of conventional and Long-Lasting Insecticide treat-ed Nets (ITNs and LLINs) in parts of East Africa are associ-ated with reductions in local malaria burdens.
Between 2005-2006 six experimental hut trials of ITNs and LLINs were conducted in parallel at two field stations in northeastern Tanzania; the first was in Lower Moshi Rice Irrigation Zone, an area where Anopholes arabiensis predom-
inates, and the second was in coastal Muheza where Ano-pholes gambiae and Anopholes funestus predominate. Five pyrethroid and one carbamate insecticide were evaluated on nets in terms of insecticide-induced mortality, blood-feeding inhibition and exiting rates.
Mortality of Anopholes arabiensis was consistently lower than that of Anopholes gambiae and Anopholes funestus. Mor-tality rates in trials with pyrethroid treated nets ranged from 25-52% for Anopholes arabiensis, 63-88% for Anopholes gambiae and 53-78% for Anopholes funestus.
LLINs and ITNs treated with pyrethroids were more ef-fective at killing Anopholes gambiae and Anopholes funestus than Anopholes arabiensis. This could be a major contribut-ing factor to the species shifts observed in East Africa follow-ing the scale up of LLINs.
With continued expansion of LLIN coverage in Africa Anopholes arabiensis is likely to remain responsible for re-sidual malaria transmission, and species shifts might be re-ported over larger areas.
Experimental hut, Tanzania.
Combined use of Indoor Residual Spraying (IRS) and Long-Lasting Insecticidal Nets (LLINs) for malaria reduction in endemic rural Tanzania.
LSHTM Investigators: Natacha Protopopoff, Philippa West, Alexandra
Wright, Immo Kleinschmidt & Mark Rowland.
External Investigators/Collaborators: Frank Mosha & Reginald Kavishe
(Kilimanjaro Christian Medical Colleges, Tanzania), Robert Malima & Wil-
liam Kisinza (National Institute for Medical Research, Tanzania).
Funding Body: President’s Malaria Initiative.
Numerous studies have shown that Long Lasting Insecticidal Nets (LLINs) and Indoor Residual Spraying (IRS) are effec-tive in preventing malaria. What is less certain is the added value of combining both. The present study aims to evaluate the impact of combining IRS and LLINs compared to LLINs alone on malaria prevalence through a two-arm cluster
randomized trial. The study is being carried out in Muleba district to the west of Lake Victoria in Tanzania. During this baseline year both arms of the study area received IRS with pyrethroid and universal LLIN coverage. IRS coverage reach-es 95% of households and net usage increased from 41% to 56% after the LLIN mass distribution campaign. Result from two household and malaria prevalence cross-sectional surveys among children under 15 years showed an overall prevalence of 9.3% (5000 children) in February and 22.8% in July (4315 children). Seven monthly rounds of cross sec-tional mosquito collection using CDC light traps were con-ducted between April and December. A total of 12819 mos-quitoes were collected of which 46% were Anopheles. A high frequency of resistance to pyrethroid and DDT was observed among Anopheles gambiae with mortality to these insecti-cides in WHO tests less than 40%. During the intervention year (2012), two more cross sectional malaria prevalence surveys are planned and 12 rounds of light trap collection.
Vector Studies 83
Malaria Centre Report 2010-11
Indoor Residual Spraying (IRS) and Long-lasting Insecticide Treated Nets (LLIN): Integration of methods and insecticide mode of actions for control of African malaria vector mosquitoes.
LSHTM Investigators: Fredros Okumu & Sarah Moore.
External Investigators/Collaborators: John Grieco & Nicole Achee.
Funding Body: USAID.
Insecticide Treated Nets (ITNs) and Indoor Residual Spray-ing (IRS) are the preferred techniques for malaria vector con-trol in Africa, where their application has already contrib-uted to significant reductions in the burden of the disease. Even though both methods are commonly used together in the same households, evidence of greater health benefits due to these combinations as opposed to use of either ITNs or IRS alone has been minimal and inconclusive.
The main aim of this research was therefore to contribute to this essential evidence, by way of experimental hut stud-ies and mathematical simulations. We investigated whether there would be any added protective advantages when any
of three selected Long Lasting Insecticidal Nets (LLINs) are combined with any of three selected IRS chemicals, as op-posed to using any of the treatments alone. Data generated from the experimental hut studies was then inputed into an optimised deterministic mathematical model, simulating a typical malaria endemic village.
Both the field studies and the simulations showed that any synergies or redundancies resulting from LLIN/IRS com-binations are primarily a function of modes of action of ac-tive ingredients used in the two interventions. Where LLINs are already present, addition of IRS would be redundant un-less the IRS chemical is highly toxic, but where IRS is the pre-existing intervention, these combinations always confer im-proved protection. Therefore, IRS households should always be supplemented with nets, preferably LLINs, which not only protect house occupants against mosquito bites, but also kill additional mosquitoes. Finally, where resources are limited, priority should be given to providing everybody with LLINs and ensuring that these nets are consistently and appropri-ately used, rather than trying to implement both LLINs and IRS in the same community at the same time.
Combining Indoor Residual Spraying (IRS) with chlorfenapyr and Long-Lasting Insecticide Nets (LLINs) for improved control of pyrethroid-resistant Anopheles gambiae: an experimental hut trial in Benin.
LSHTM Investigators: Corine Ngufor, Raphael N’Guessan & Mark Row-
land.
External Investigators/Collaborators: Pelagie Boko, Abibatou Odjo, Es-
telle Vigninou, Alex Asidi & Martin Akogbeto (Centre de Recherches Ento-
mologiques de Cotonou, Benin).
Funding Body: The Bill & Melinda Gates Foundation through the Innova-
tive Vector Control Consortium.
Neither Indoor Residual Spraying (IRS) nor Long-Lasting Insecticidal Nets (LLINs) are able to fully interrupt trans-mission in holoendemic Africa as single interventions. The combining of IRS and LLINs presents an opportunity for im-proved control and management of pyrethroid resistance through the simultaneous presentation of unrelated insec-ticides. Chlorfenapyr IRS and a pyrethroid-impregnated polyester LLIN (WHO approved) were tested separately and together in experimental huts in southern Benin against py-rethroid resistant Anopheles gambiae and Culex quinquefas-ciatus. Anopheles gambiae were genotyped for the kdr gene
to assess the combination’s potential to prevent the selection of pyrethroid resistance.
The frequency of kdr was 84%. The overall mortality rates of Anopholes gambiae were 37% and 49% with the six- hole and 80-hole LLINs, respectively, and reached 57% with chlorfenapyr IRS. Overall mortality rates were significantly higher with the combination treatments (82-83%) than with the LLIN or IRS individual treatments. Blood feeding (biting) rates and repellency of mosquitoes with the combination of LLIN and chlorfenapyr IRS showed significant improvement compared to the IRS treatment but did not differ from the LLIN treatments indicating that the LLINs were the primary agents of personal protection. The combination killed signif-icantly higher proportions of Culex quinquefasciatus (51%, 41%) than the LLIN (15%, 13%) or IRS (32%) treatments.
The chlorfenapyr IRS component was largely responsible for controlling pyrethroid-resistant mosquitoes and the LLIN component was largely responsible for blood feeding inhi-bition and personal protection. Together, the combination shows potential to provide additional levels of transmission control and personal protection against pyrethroid-resistant mosquitoes, thereby justifying the additional resources re-quired. Chlorfenapyr has potential to manage pyrethroid resistance in the context of an expanding LLIN/IRS strategy.
84 Vector Studies
London School of Hygiene & Tropical Medicine
Investigating novel indoor delivery systems for insecticides against malaria vectors.
LSHTM Investigators: Corine Ngufor, Raphael N’Guessan & Mark Row-
land.External Investigators/Collaborators: Patrick Tungu (National In-
stitute for Medical Research, Tanzania); Benjamin Koudou (Centre Suisse
de Recherche Scientifique, Cote D’Ivoire); Sagnon N’Fale (Centre National
de Recherche et de Formation sur le Paludisme, Burkina Faso).
Funding Body: The European Union Seventh Research Framework Pro-
gramme through the AvecNet Consortium.
Despite the considerable increase in donor funding to sup-port the global drive towards malaria elimination, it is un-likely that Indoor Residual Spraying (IRS) due to its associ-ated operational and logistic constraints would be scaled-up to satisfactory levels to effectively interrupt transmission in holoendemic areas in sub-Saharan Africa. Alternative effec-tive tools for delivering insecticides in doors which can be deployed either as single interventions or to complement Long Lasting Insecticidal Nets (LLINs). LLINs need to be ur-gently investigated and developed.
Evaluation of the long-lasting organophosphate pirimifos methyl CS for Indoor Residual Spraying (IRS) against pyrethroid-resistant Anopheles gambiae Giles and Culex quinquefasciatus: an experimental hut trial in Southern Benin.
LSHTM Investigators: Raphael N’Guessan & Mark Rowland.
External Investigators/Collaborators: Pelagie Boko, Abibatou Odjo, Es-
telle Vignonou, Hermione Adje, Alex Asidi & Martin Akogbeto (Centre de
Recherche Entomologique de Cotonou, Benin).
Funding Body: The Bill & Melinda Gates Foundation through the Innova-
tive Vector Control Consortium.
There is an urgent need to develop safe, long- lasting alterna-tives to DDT and pyrethroids to sustain malaria vector con-trol and reduce selection pressure for pyrethroid resistance.
Two formulations of pirimiphos methyl (CS) applied as an IRS treatment were evaluated in experimental huts in an area of southern Benin where Anopheles gambiae and Culex quinquefasiactus are resistant to pyrethroids but suscep-tible to organophosphates. Dosages tested were 1g/m2 and 0.5g/m2 against standard pirimiphos methyl EC for up to 12 months on mud and cement walled substrates.
The aim of this study is to evaluate plastic wall linings and net wall hangings treated with the organophosphate pirimiphos methyl as novel malaria vector control tools. In-secticide treated plastic sheeting and net wall hangings can be likened to a long-lasting IRS treatment and also have the advantage of providing a more uniform covering of the wall with insecticide compared to IRS and of improving interior appearance of traditional dwellings. Their potential to pro-vide improved vector control and/or manage insecticide re-sistance when deployed to complement LLINs in a combina-tion approach will also be investigated.
Experimental hut trials are being carried out in 3 ma-laria endemic areas in Sub-Saharan Africa including Muheza-Tanzania where the vectors are largely susceptible to insecti-cides, Valley du Kou-Burkina Faso where the vectors are very resistant to pyrethroids but susceptible to organophospates and Tiassales-Cote D’Ivoire where pyrethroid and organo-phosphate resistance co-exist.
In mud huts 1 g/m2 was clearly superior to 0.5 g/m2 and induced >50% mortality of Anopheles gambiae for more than 10 months. In cement walled huts 0.5 g/m2 induced high levels of control for almost one year. Overall, the BM formulation seemed superior to B formulation. The EC for-mulation of pirimiphos methyl sprayed at 1 g/m2 was giving inadequate control of Anopheles gambiae within 2 months of spraying. A microencapsulated formulation of lambdacy-halothrin (Icon CS) was sprayed as a positive control and al-though it showed prolonged residual activity in cone tests on walls using a susceptible reference strain, it was unable to control freely entering pyrethroid resistant Anopheles gam-biae. Pirimiphos methyl CS was also found to be highly effec-tive against Culex quinquefasciatus, giving between 90-50% control for up to 10 months at 1 g/m2 on cement surfaces and for 6 months on mud surfaces.
Pirimiphos methyl CS showed great promise for control of pyrethroid-resistant Anopheles gambiae in West Africa and for delaying development of pyrethroid resistance where LLINs are already widely used. A cost effective alternative to DDT, giving year-round transmission control in endemic ru-ral settings in Africa is now a realistic prospect.
Vector Studies 85
Malaria Centre Report 2010-11
Control of pyrethroid and DDT-resistant Anopheles gambiae by application of Indoor Residual Spraying (IRS) or mosquito nets treated with a long-lasting organophosphate insecticide, chlorpyrifos-methyl.
LSHTM Investigators: Raphael N’Guessan & Mark Rowland.
External Investigators/Collaborators: P Boko, A Odjo, J Chabi, M Akog-
beto (Centre de Recherche Entomologique de Cotonou, Benin).
Funding Body: The Bill & Melinda Gates Foundation through the Innova-
tive Vector Control Consortium.
Dow Agrosciences have developed a microencapsulated for-mulation (CS) of the organophosphate chlorpyrifos methyl as a cost-effective, long-lasting alternative to DDT.
We tested this product as an IRS or ITN treatment in ex-perimental huts in an area of Benin where Anopheles gam-biae and Culex quinquefasiactus are resistant to pyrethroids, but susceptible to organophosphates. Efficacy and residual activity was compared to that of DDT and the pyrethroid
An experimental hut evaluation of PermaNet® 3.0, a deltamethrin–piperonyl butoxide combination net, against pyrethroid-resistant Anopheles gambiae and Culex quinquefasciatus mosquitoes in southern Benin.
LSHTM Investigators: Raphael N’Guessan, Alex Asidi & Mark Rowland.
External Investigators/Collaborators: P Boko, A Odjo, M Akogbeto, O
Pigeon.
Funding Body: Vestergaard Frandsen.
PermaNet 3.0 is a long-lasting combination net with delta-methrin present on the sides and a mixture of deltamethrin and piperonyl butoxide (PBO), an oxidase synergist, on the top panel.
An experimental hut trial comparing unwashed and 20 times washed PermaNet 3.0 and PermaNet 2.0, Olyset Net and a conventional deltamethrin-treated net washed three times was conducted in southern Benin. Anopheles gambiae
lambdacyalothrin.IRS with chlorpyrifos methyl killed 95% of Anopheles
gambiae that entered the hut as compared to 31% with lambdacyhalothrin and 50% with DDT. Control of Culex quin-quefasciatus showed a similar trend; although the level of mortality with chlorpyrifos methyl was lower (66%) it was still much higher than for DDT (14%) or pyrethroid (15%) treatments. Nets impregnated with lambdacyhalothrin were compromised by resistance, killing only 30% of Anopheles gambiae and 8% of Culex quinquefasciatus. Nets impregnat-ed with chlorpyrifos methyl killed more (45% of Anopheles gambiae and 15% of Culex quinquefasciatus, but its activity on netting was of short duration. Contact bioassays on the sprayed cement-sand walls over the nine months of moni-toring showed no loss of activity of chlorpyrifos methyl, whereas lambdacyhalothrin and DDT lost activity within a few months of spraying.
The remarkable residual activity indicates that cost-effective alternatives to DDT are feasible through modern formulation technology.
and Culex quinquefasciatus from this area are highly resistant to pyrethroids through kdr and cytochrome P450 mecha-nisms. The unwashed PermaNet 3.0 killed slightly more A. gambiae (52%) than the unwashed PermaNet 2.0 (44%) (P=0.036), indicating only partial synergism of resistance. After washing there was significant loss of activity to a simi-lar level, with PermaNet 3.0 killing 31%, PermaNet 2.0 kill-ing 29% and the conventional net killing 26%. Blood-feeding rates were partially inhibited for unwashed PermaNet 3.0 and Olyset Net (27% inhibition). Personal protection against Anopholes gambiae derived from PermaNet 3.0 was similar to that from PermaNet 2.0 before washing (50% vs. 47%), and after 20 washes it decreased to 30%. Against Culex quin-quefasciatus, no treatment killed >24% entering the huts. The synergism from unwashed PermaNet 3.0 was lower than expected, probably due to an unidentified resistance mecha-nism unaffected by PBO.
Mosquito net, Tanzania Mount Kilimanjaro, Tanzania.
86 Vector Studies
London School of Hygiene & Tropical Medicine
Vector Studies 87
Malaria Centre Report 2010-11
Health promotion for impoverished rural and refugee populations in Tanzania focusing on malaria control, sanitation and water supply.
LSHTM Investigators: Frank Mng’ong’o, Jeroen Ensink & Sarah Moore.
External Investigators/Collaborators: Joseph Sambali (Ifakara Health
Institute, Tanzania); Jaka Magonga (Concern Worldwide, Tanzania); Ann
Le Mare (University of Durham, UK).
Funding Body: Concern Worldwide Tanzania.
In line with Concern’s goal to “help people living in extreme poverty achieve major improvements in their lives which last and spread without ongoing support from Concern”, we aim to develop and institutionalize research support for Con-cern’s activities at the Ifakara Health Institute through an ac-tive operational research programme focusing on preventing malaria and water-borne diseases.
Sustained malaria control is underway using a combina-tion of vector control, prompt diagnosis and treatment of ma-laria cases. Progress is excellent, but for long-term control, low-cost, sustainable tools that supplement existing control programs are needed. Conventional vector control tools such as Indoor Residual Spraying and house screening are highly effective, but difficult to deliver in rural areas. Therefore, an additional means of reducing mosquito house entry was evaluated: the screening of mosquito house entry points by planting the tall and densely foliated repellent plant Lantana camara L. around houses.
A pilot efficacy study was performed in Kagera Region, Tanzania in an area of high seasonal malaria transmission, where consenting families within the study village planted L. camara (Lantana) around their homes and were responsible for maintaining the plants. Questionnaire data on house de-sign, socioeconomic status, malaria prevention knowledge, attitude and practices was collected from 231 houses with Lantana planted around them 90 houses without repellent plants. Mosquitoes were collected using CDC Light Traps be-tween September 2008 and July 2009. Data were analysed with generalised negative binomial regression, controlling for the effect of sampling period.
Indoor catches of mosquitoes in houses with Lantana were compared using the Incidence Rate Ratio (IRR) relative to houses without plants in an adjusted analysis. There were 56% fewer Anopheles gambiae s (IRR 0.44, 95% CI 0.28–0.68, p,0.0001); 83% fewer Anopheles funestus (IRR 0.17, 95% CI 0.09–0.32, p,0.0001), and 50% fewer mosquitoes of any kind (IRR 0.50, 95% CI 0.38–0.67, p,0.0001) in houses with Lan-tana relative to controls.
House screening using Lantana reduced indoor densities of malaria vectors and nuisance mosquitoes with broad com-munity acceptance. Providing sufficient plants for one home costs USD 1.50 including maintenance and labour costs, (30 cents per person).
Study site, Tanzania.
88 Vector Studies
London School of Hygiene & Tropical Medicine
Field efficacy of pyrethroid treated plastic sheeting (durable lining) in combination with Long Lasting Insecticidal Nets (LLINs) against malaria vectors.
LSHTM Investigators: Raphael N’Guessan, Seth Irish & Mark Rowland.
External Investigators/Collaborators: F Chandre, J.M Hougard & L
Djogbenou (Institut de Recher pour le development); R.K Dabire (Centre
Muraz, Burkina faso).
Funding Body: Sumitomo Chemical.
Insecticide Treated Plastic Sheeting (ITPS), sometimes known as durable lining, has potential as a long-lasting in-secticidal surface for malaria vector control indoor. We ex-amined the effect of combining ITPS with LNs in experimen-tal huts in Burkina Faso. Two molecular forms of Anopheles gambiae (S and M) coexist, with kdr resistance more preva-lent in S. The treatment arms included ITPS, Olyset, ITPS plus
Olyset, ITPS plus untreated net (with or without holes), and untreated control.
ITPS was significantly inferior to Olyset LN in terms of mortality (37% vs 63%), blood feeding inhibition (20% vs 81%) and deterrence (0 vs 42%) effects, and hence alto-gether inferior as a means of personal protection (16% vs 89%). The addition of ITPS to Olyset did not improve mortal-ity (62%), blood feeding inhibition (75%), deterrence (50%) or personal protection (88%) over that of Olyset used alone. Use of untreated nets - both holed and intact - with ITPS pro-vided greater protection from blood-feeding. The intact net/ITPS combination killed more mosquitoes than ITPS on its own.
The combination of pyrethroid IRS and pyrethroid LN - as practiced in some countries - is unlikely to be additive or synergistic. A combination of LN and ITPS treated with an alternative insecticide is likely to be more effective, particu-larly in areas of pyrethroid resistance.
Multiple Phase III Trials.
LSHTM Investigators: Matt Kirby, Mark Rowland & Patrick Tungu.
External Investigators/Collaborators: William Kisinza, Robert Malima
& Stephen Magesa (National Institute for Medical Research, Tanzania).
Funding Body: Sumitomo Corporation (PRISM) & WHO Pesticide Evalua-
tion Scheme (all other trials).
The PRISM, Icon®Maxx and InterceptorTM trials are ongo-ing household or cluster randomized controlled trials of in-secticide treated materials (bed nets and bed sheets) in rural hamlets and villages close to Muheza. There are considerable similarities in the protocols of these trials; namely, the prod-ucts are being evaluated in terms of entomological efficacy, durability and acceptability, during use in the communities by participants blinded to the type of net/sheet received, for a period between 6 months and 3 years. Sheets and nets are retrieved from the field periodically and tested in cone and tunnel bioassays against susceptible Anopheles gambiae Ki-sumu. The frequency of washing is also determined and sam-ples are subjected to HPLC to determine AI residue.
Pyrethroid and Repellent Insecticidal Sheets against Malaria (PRISM).
Bed sheets treated with Scoron® (Cyphenothrin) were giv-en to 1205 households (universal coverage) whilst another 1246 households received otherwise identical untreated
sheets prior to the main transmission season of 2011. Pre-and post-intervention surveys recorded malaria and anae-mia prevalence from 2450 children aged 6 months - 13 years, whilst light trap catches from 240 sentinel houses measured vector densities in both arms of the trial. Focus group dis-cussions, bioassays and chemical analyses of sample surveys determined durability and acceptability. Though some bioas-says and analyses are still ongoing, it is clear that there are problems with the product. Laboratory tests show that new sheets are both repellent and insecticidal, but that these ef-fects are lost over several rounds of washing. In the field no difference in Anopheles gambiae density was observed be-tween intervention and control clusters though relative to the dry season the increase in total mosquitoes in the rainy season was less marked in the intervention clusters com-pared to the control. Fewer children in Scoron® clusters were anaemic and the haemoglobin density was higher com-pared to the control clusters, though differences were slight 4.6% and 11.03g/dL v 5.5% and 10.97g/dL) & there was no significant difference in parasite prevalence (24% v 28%, p >0.05). On average sheets in the community were washed once every two weeks and it is thought that inadequacy of the insecticide binder to prevent loss of insecticide during washing, plus inconsistent/incorrect use of the sheets, limit the performance of the product.
Vector Studies 89
Malaria Centre Report 2010-11
Insecticidal efficacy and household acceptability of Icon® Maxx long-lasting treatment for nets.
This re-treatment kit consists of a slow-release lambda-cyh-alothrin capsule suspension. Nets treated with Icon®Maxx and conventional nets with the same insecticide (IconNet) have been distributed randomly to 818 households within two villages, for which baseline data was collected in 2011. Participants were blinded to which type of net they received.
Net pieces from Icon Maxx and Icon Net treated but not distributed (i.e. baseline AI) have been prepared for HPLC analysis and tested in cone bioassays. The IconMaxx nets at baseline have 99.9% killing efficacy and 100% knockdown efficacy. The trial is ongoing: nets of both types are now be-ing retrieved from the field every 6 months.
Insecticidal efficacy and household acceptability of InterceptorTM long-lasting treated nets.
This long lasting insecticidal net contains a finishing prod-uct that binds the alphacypermethrin insecticide in a special
coating to the fibres of the nets. Interceptor LN received a WHO interim recommendation for use in malaria control in 2007. It then entered a 3 year community trial carried out by LSHTM and NIMR during 2009-2011 to determine whether the product can receive a full recommendation. Interceptor nets and conventional insecticide treated nets (the control) were distributed at random to households in rural 3 villages in Muheza Tanzania. Every 6 months nets were sampled for bioassay and assessment of net durability and insecticide content ,and householders were surveyed for washing prac-tices, net usage and adverse effects. Nets years that failed the cone bioassay criteria were assessed in tunnel bioassays. Nets were regularly used and washed, and no adverse effects were reported after the first month of use. After 3 years only 13% of the Interceptor TM nets were failing the bioassay criteria whereas after just one year of use 37% of the con-ventional treated net were failing. After review by the WHO expert committee InterceptorTM was granted full recom-mendation as a long lasting insecticidal net.
Mosquito nets and sheets.
90 Vector Studies
London School of Hygiene & Tropical Medicine
Multiple Phase II Trials.
LSHTM Investigators: Matt Kirby, Mark Rowland & Patrick Tungu.
External Investigators/Collaborators: William Kisinza, Robert Malima
& Stephen Magesa (National Institute for Medical Research, Tanzania).
Funding Body: Sumitomo Corporation (PRISM) & WHO Pesticide Evalua-
tion Scheme (all other trials).
All trials follow the WHO guidelines for laboratory and field testing of LNs (WHO/CDS/WHOPES/GCDPP/2005.11). Six dentical experimental huts specially designed for recording the entering and exiting behaviour of mosquitoes and for measuring responses to insecticide-treated materials (nets and sheets) were used for all trials. The standard procedure in these trials was to test the insecticide-treated material un-der evaluation, unwashed and washed 20x, against conven-tional treated material (+ve control) and untreated material (-ve control). These materials were rotated weekly between huts. The outcome measures were deterrence, repellence, immediate and delayed mortality, and induced bloodfeeding inhibition. Pieces are cut from all materials before and after the trial to measure the concentration of active ingredients.
DawaPlus 2.0 LN.
Long-lasting deltamethrin-coated polyester bed net. DawaP-lus outperformed conventional insecticide-treated nets in laboratory assays of mosquito mortality, but these differenc-
es were less marked in experimental huts. However, Dawa Plus nets (unwashed and 20x washed) did give better per-sonal protection than 3x washed conventional nets. Blood-feeding inhibition was 63% for DawaPlus nets and there was no difference between washes implying that the deltame-thrin coating had a high degree of wash resistance.
Efficacy of Cyphenothrin (Scoron®) and DEET-MC treated bed sheets.
Bed sheets treated with Cyphenothrin (250mg/m2) or 1 of 2 concentrations (4 & 8g/m2) of micro-encapsulated DEET. For Anopheles mosquitoes, deterrence (11-33% increase), mortality (33-47% increase) and repellency were higher for all treated materials compared to the untreated control. The 8g/m2 DEET sheet induced significantly higher mortality than all other treated sheets. Feeding inhibition was moder-ate to high (25-88%) for all treated materials against Anoph-eles and Culex mosquitoes
Evaluation of Olyset Plus LN against Anopheles gambiae arabiensis and Culex quinquefasciatus in experimental huts.
Permethrin & Oxidase synergist Piperonyl butoxide. Trial is assessing whether bed nets treated with this combina-tion show enhanced activity against insecticide-susceptible Anopheles and resistant Culex quinquefasciatus. Trial is on-going.
Vector Studies 91
Malaria Centre Report 2010-11
Replacing DDT: Rigorous evaluation of spatial repellents for the control of vector borne diseases.
LSHTM Investigators: Sheila Ogoma, Peter Sangoro, Marta Maia, Lena
Lorenz, Ann Kelly, Raphael N’Guessan & Sarah Moore.
Funding Body: The Bill & Melinda Gates Foundation.
Insecticide Treated Nets (ITNs) and Indoor Residual Spray-ing (IRS) are the preferred techniques for malaria vector con-trol in Africa, where their application has already contrib-uted to significant reductions in the burden of the disease. However, there remains a proportion of malaria transmis-sion that is transmitted by early evening feeding mosquitoes that bite and rest outdoors. One solution to this problem is spatial repellents that continuously protect people within a
space from mosquito bites without the need for people to re-member to apply repellents.
The main aim of this research is to devise effective means of quantifying the effects of spatial repellents, as they are a new paradigm in the field of vector control. The research will provide industry with a target product profile (TPP) for spatial repellents to advise on the development of new and effective vector control products.
Both field and laboratory assays have been developed to characterise the mode of action of spatial repellents. This will be used to inform new WHO spatial repellent guidelines that are currently being developed. Data on the TPP will be available later in the year.
Update on resistance status of Anopheles gambiae to conventional insecticides at a previous WHOPES field site, “Yaokoffikro”, 6 years after the political crisis in Côte. d’Ivoire.
LSHTM Investigators: Raphael N’Guessan.
External Investigators/Collaborators: Alphonsine Koffi, Ludovic Alou,
Maurice Adja, Moussa Koné (Institut Pierre Richet, Bouake, Côte d’Ivoire)
; Fabrice Chandre (Institut de Recherche pour le Development, France).
Funding Body: Ministere Cooperation Française.
At Yaokoffikro field site near Bouaké, in central Côte d’Ivoire, group of experimental huts built in 1996 served over many years for the evaluation of insecticides against highly resis-tant mosquitoes. Breeding sites of mosquitoes and selection pressure in the area were maintained by local farming prac-tices until a war broke out in September 2002. Six years after the crisis, we conducted bioassays and biochemical analysis to update the resistance status of Anopheles gambiae s.s. population and detect other potential mechanisms of resis-tance that might have evolved.
High pyrethroids, DDT and carbamate resistance was confirmed in An. gambiae s.s. population from Yaokoffikro. Mortality rates were less than 70% with pyrethroids and etofenprox, 12% with DDT, and less than 22% with the car-bamates. Tolerance to fenitrothion was observed, with 95% mortality after 24h.
PCR analysis of samples from the site showed high allelic frequency of the L1014F kdr (0.94) and the ace-1R (0.50) as before the crisis. In addition, increased activity of NSE, GST and to a lesser extent MFO was found relative to the reference strain Kisumu. This was the first report detecting enhanced activity of these enzymes in An. gambiae s.s from Yaokoffi-kro, which could have serious implication in detoxification of insecticides. Their specific roles in resistance should be investigated using additional tools.
The insecticide resistance profile at Yaokoffikro appears multifactorial. The site presents a unique opportunity to evaluate its impact on the protective efficacy of insecticid-al products as well as new tools to manage these complex mechanisms. It calls for innovative research on the behav-iour of the local vector, its biology and genetics that drive resistance.
92 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Social and economic studies continue to play an im-
portant role in the Malaria Centre’s profile of work.
In 2010-11, many of these studies were evaluatory
in nature, considering the social and/or economic
process and impacts of malaria-related interven-
tions and programmes. Researchers also continued
to undertake descriptive social and economic stud-
ies, highlighting the social and economic realities of
the lives of those affected by malaria, those involved
in delivering malaria programmes and those partici-
pating in clinical research.
Topics of social and economic research under-
taken in 2010-11 reflect a range of areas consid-
ered critical to strengthening the implementation of
malaria control methods, particularly access to Ar-
temisinin-based Combination Therapies (ACT) and
targeting of drugs through malaria Rapid Diagnostic
Tests (RDTs). Improving access to effective drugs has
been a long-standing recommendation of the WHO,
and Malaria Centre members have undertaken a va-
riety of studies to understand the ways people ac-
cess health care for malaria. Research has also con-
tributed to the design and evaluation of strategies to
improve access to antimalarial drugs through public
health services, private facilities, retail outlets and
community based programmes. This includes evalu-
ation of large-scale interventions, such as the Afford-
able Medicines Facility – malaria, which is being pi-
loted at the national level in eight countries. Smaller
scale studies have contributed to the design and
evaluation of supporting interventions being imple-
mented on a smaller scale within malaria endemic
countries in order to inform programmes for future
scale-up, particularly in terms of feasibility and cost-
effectiveness. Improving targeting of precious ACT
has become a priority in malaria control, and the
WHO’s 2010 recommendation for universal parasi-
tological diagnosis before treatment where possible
has stimulated interest in how RDTs can be used in
low-resource settings. Social and economic studies
within the Malaria Centre have designed ways to
support the introduction of RDTs in different set-
tings, including at public and private facilities, retail
outlets and by community volunteers, incorporating
novel social and incentive approaches to encourag-
ing changes in provider and patient behaviour. Large
and smaller-scale studies have evaluated the pro-
cesses and outcomes of such interventions. Under-
standings of the social and economic realities of pa-
tients and the different types of providers operating
in pluralistic health systems have been valuable to
the design and interpretation of trials addressing ac-
cess to and targeting of antimalarial drugs for treat-
ment and chemoprophylaxis.
Other key topics that have engaged social and
economic researchers in the Malaria Centre revolve
Summary
Social & Economic Studies 93
Malaria Centre Report 2010-11
around malaria control strategies for vulnerable
groups, particularly pregnant women and children,
and methods for assessing safety of ACT. The scale-
up of malaria control initiatives in vulnerable groups
is central to the WHO’s strategy to reduce deaths
due to malaria to zero. Pregnant women are a par-
ticularly vulnerable group for whom malaria con-
trol efforts continue to be poorly delivered. A better
understanding of the use and delivery of these ser-
vices is required, and Malaria Centre members are
undertaking a number of studies to assess existing
systems and to develop approaches to strengthen
malaria control efforts for this group across differ-
ent country contexts. Children, the most vulnerable
group to malaria morbidity and mortality, are the
focus of multiple malaria control efforts. Findings
of social and economic research carried out by Ma-
laria Centre members have contributed to important
policy recommendations for Seasonal Malaria Che-
moprevention which has the potential to prevent
childhood malaria across areas of the Sahel and Sub-
Sahel regions of Africa where 25 million children are
at risk. With the wide-scale roll out of ACT across
different population groups, including those with
comorbidities who are taking other medications,
concerns have been raised about the safety of drugs
used in real life scenarios. Members of the Malaria
Centre have been involved in studies to understand
social aspects of ACT safety. These include contrib-
uting to novel methods for population level phar-
macovigilance involving reporting from non-clinical
workers, and understanding the experiences of pa-
tients taking ACT together with other drugs, par-
ticularly anti-retroviral drugs by those affected by
both malaria and HIV. Research has also examined
the way safety data are produced within clinical tri-
als, focusing on the process of elicitation of adverse
events, which has been found to be mediated by the
social circumstances of reporting within a drug trial.
More broadly, social research continues to reflect on
the experiences of research participants involved in
a variety of malaria-related research, contributing to
discussions of best practice methods for conducting
research in resource-limited settings.
94 Social & Economic Studies
London School of Hygiene & Tropical Medicine
ACTwatch: evidence for malaria medicines policy.
LSHTM Investigators: Kara Hanson, Catherine Goodman, Benjamin Pala-
fox, Edith Patouillard, Sarah Tougher, Sergio Torres Rueda & Immo Klein-
schmidt
External Investigators/Collaborators: Population Services Interna-
tional.
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The goal of ACTwatch is to provide a complete picture of the antimalarial markets in Benin, Cambodia, DRC, Madagascar, Nigeria, Uganda and Zambia to enable policymakers and oth-er actors to design interventions to increase availability and decrease the consumer price of quality assured Artemisinin-based Combination Therapy (ACT). Along with conducting nationally representative surveys of pharmaceutical outlets and households, ACTwatch also includes a component that investigates the structure and operation of the distribution chain for antimalarials and Rapid Diagnostic Tests (RDTs) for malaria in each country.
Using a number of different data collection methods, in-cluding document review, structured surveys of antimalarial wholesalers, and in-depth interviews with a wide range of stakeholders and businesses at all levels of the distribution chain, this study has developed schematic representations of the antimalarial distribution chains; estimated antimalar-ial availability among wholesalers; investigated regulatory compliance and enforcement in the private sector; estimated
Mobilize Against Malaria (MAM).
LSHTM Investigators: Jayne Webster, Caroline Jones, Jane Bruce & Lucy
Paintain.
External Investigators/Collaborators: Population Services Interna-
tional, Kenya; KEMRI-Wellcome Trust, Kenya; Family Health Internation-
al, Ghana; Ghana Social Marketing Foundation, Ghana; Health Partners,
Ghana; IntraHealth International, Senegal.
Funding Body: Pfizer Investment in Health.
Mobilize Against Malaria was implemented between 2007 and 2011 by partners in Ghana, Kenya and Senegal. As Pfizer’s signature philanthropic program to reduce malaria morbidity and mortality, the program supported promising models for the effective delivery of Artemisinin-based Com-bination Therapy (ACT) through private, public and commu-
nity sectors. The pilot project demonstrated the viability of improv-
ing access to ACT by training Licensed Chemical Sellers in Ashanti Region, Ghana. It demonstrated sustainable ap-proaches to building and maintaining the capacity of com-munity-run health huts in Senegal, and tested the efficacy of healthworker training in Kenya.
Throughout 2012-13, a multidisciplinary team at LSHTM will continue to work with local evaluation partners to fa-cilitate the synthesis of cross-cutting issues emerging from the research, of strategic importance in the development of regional and global policy agendas on the delivery of health services. Cross-cutting evaluation research will focus on contextual evaluation, implementation fidelity, methodologi-cal approaches, training efficacy and the development of an evaluation model across the three country settings.
retail- and wholesale-level mark-ups for antimalarials and RDTs; investigated factors affecting drug selection, sales vol-umes and prices; and compared distribution chains within and between each of the 7 ACTwatch countries.
Data collection for the distribution chain component has been completed in all countries, and a number of country-specific reports are available from the ACTwatch website, www.actwatch.info. Reports of the ACTwatch Outlet and Household Surveys, conducted by Population Services Inter-national, are also available from this site.
Benin market.
Social & Economic Studies 95
Malaria Centre Report 2010-11
The impact of retail sector delivery of artemether-lumefantrine on effective malaria treatment of children under five in Kenya .
LSHTM Investigators: Catherine Goodman, Simon Brooker & Greg Fegan.
External Investigators/Collaborators: Beth Kangwana, Sarah Kedenge,
Abdisalan Noor & Bob Snow (KEMRI-Wellcome Trust Research Pro-
gramme, Kenya); Andrew Nyandigisi (Division of Malaria Control, Kenya);
Jayesh Pandit (Pharmacy and Poisons Board, Kenya).
Funding Body: Wellcome Trust & UK Department for International De-
velopment.
In 2006, Kenya introduced Artemisinin-based Combination Therapy (ACT) through the public sector free of charge, but access remains low. The aim of this study was to evaluate to what extent the provision of pre-packed, subsidised ACT, de-livered through private sector retailers, will increase the pro-portion of children under five, with fever, receiving appro-
IMPACT2: monitoring interventions to improve ACT access and targeting.
LSHTM Investigators: Catherine Goodman, Katia Bruxvoort, Rebecca
Thomson, Harparkash Kaur & Matt Cairns
External Investigators/Collaborators: Salim Abdulla, Admirabilis Ka-
lolella, Emmy Metta, Charles Festo, Boniface Johannes, Happy Nchimbi &
Clarence Mkoba (Ifakara Health Institute, Tanzania); Patrick Kachur, Julie
Thwing, Denise Roth Allen & Melissa Briggs (Centers for Disease Control
and Prevention, USA).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
While a general consensus over the choice of Artemisinin-based Combination Therapy (ACT) as the future malaria therapy has developed, a solid evidence-base for choosing the best ACT deployment strategies to gain optimal impact on malaria morbidity and mortality does not exist. Countries are now beginning to adopt policies to enhance ACT deploy-ment but face tension between the twin goals of: (i) making ACT more readily and speedily accessible to patients, or (ii) targeting ACT to patients shown to have malaria parasitae-mia.
The Tanzanian Government has secured funding to ad-dress ACT access and targeting on a national scale. Access is being improved through the distribution of subsidised
priate anti-malarial treatment. The intervention was imple-mented by the Division of Malaria Control in collaboration with Population Services International. The study sites were in three districts in Western Kenya: Teso, Butere-Mumias and Busia. Intervention effectiveness was evaluated through a pre-post cluster randomised controlled trial. Baseline data were collected before the intervention and follow up data 9 months after the start of the intervention from both house-holds and retail outlets. The data were collected using six data collection activities: 1) Retail census 2) Household sur-vey 3) Provider survey 4) Mystery shopper 5) Focus group discussions and 6) Documentation of context.
The intervention led to a substantial increase in ACT ac-cess, and in ACT coverage for childhood fevers. The vast ma-jority of sales at the target price and correct dose. However, advice given to caretakers by shopkeepers was often inad-equate and ACT adherence remained sub-optimal.
ACT through private facilities and Accredited Drug Dispens-ing Outlets under the Affordable Medicines Facility-malaria (AMFm). Targeting is being addressed through enhancing microscopy and expanding Rapid Diagnostic Tests (RDTs) to health facilities at every level of the system. This study aims to evaluate these interventions through a pre-post plausibil-ity evaluation in selected regions (Mwanza, Mtwara, Mbeya). The study forms part of the programme of work of the ACT Consortium.
The key objective is to assess the effectiveness of the introduction of RDTs in health facilities, and subsidized ACT in the private sector in terms of coverage, equity, qual-ity, adherence and public health impact, and to explore the socio-cultural context and other factors that influence the implementation and outcome of the interventions. Data col-lection methods include surveys of households, health facili-ties and drug shops, studies of adherence and parasitaemia prevalence at health facilities and drug shops and qualitative methods.
96 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Evaluation of a pilot ACT subsidy programme in two rural districts in Tanzania.
LSHTM Investigators: Catherine Goodman.
External Investigators/Collaborators: Oliver Sabot, Lorrayne Ward,
Justin Cohen, Yahya Ipuge & Megumi Gordon (Clinton Foundation, USA);
David Bishop (HLSP, UK); Alex Mwita (National Malaria Control Pro-
gramme, Tanzania); Moses Odhiambo (Steadman Group).
Funding Body: Clinton Health Access Initiative.
WHO estimates that only 3% of fever patients use recom-mended Artemisinin-based Combination Therapy (ACT), partly reflecting their high prices in the retail sector from where many patients seek treatment. To overcome this chal-lenge, a global ACT subsidy has been proposed. We tested this proposal through a pilot program in rural Tanzania.
Three districts were assigned to serve as a control or re-ceive the subsidy plus a package of supporting interventions. From October 2007, ACT were sold at a 90% subsidy through the normal private supply chain to intervention district drug shops. Data were collected at baseline and during interven-
Conducting a household survey interview in rural Mwanza, Tanzania.
tion using interviews with drug shop customers, retail audits, mystery shoppers, and audits of public and NGO facilities.
The proportion of consumers in the intervention dis-tricts purchasing ACT rose from 1% at baseline to 44.2% one year later (p<0.001), and was significantly higher among consumers purchasing for children under 5 than for adults (p=0.005). No change in ACT usage was observed in the control district. Consumers paid a mean price of $0.58 for ACT, which did not differ significantly from the price paid for sulphadoxine-pyramethamine, the most common alter-native. Drug shops in population centers were significantly more likely to stock ACT than those in more remote areas (p<0.001).
A subsidy introduced at the top of the private sector sup-ply chain can significantly increase usage of ACT and reduce their retail price to the level of common monotherapies. Ad-ditional interventions may be needed to ensure access to ACT in remote areas and for poorer individuals who appear to seek treatment at drug shops less frequently.
Social & Economic Studies 97
Malaria Centre Report 2010-11
ACT PROCESS: evaluating the process, context, and impact of interventions to enhance health facilities in Tororo, Uganda.
LSHTM Investigators: Clare Chandler, Sarah Staedke & Deborah DiLib-
erto.
External Investigators/Collaborators: Moses Kamya, Susan Nayiga, Lil-
ian Taaka, Christine Nabirye, Miriam Kayendeke (Infectious Diseases Re-
search Collaboration, Uganda).
Funding Body: The Bill & Melinda Gates Foundation through the ACT
Consortium.
The ACT PROCESS study is a mixed methods evaluation that is running alongside a cluster randomised trial (ACT PRIME) that aims to assess the effect of a health facility intervention on population health indicators.
The ACT PROCESS study aims to provide an in-depth un-derstanding of the way this intervention was delivered, its mechanisms of effect, and how context shapes the outcomes observed.
The project objectives are: ■ To develop a comprehensive logic model of the
health facility intervention with intervention components
mapped through to their intended effects and outcomes. ■ To evaluate the process of the health facility inter-
vention implementation including health worker training, health centre management tools, supply of AL and RDTs for malaria, and interactions with local and district stakehold-ers.
■ To develop a rich contextual record of factors that may have affected the health facility intervention outcomes such as other interventions or programmes implemented in the area, changes to malaria case management guidelines, and other environmental, economic, political or individual factors.
■ To carry out a limited assessment of the wider ex-pected and unexpected impacts of the HFI at the household, community, private sector, and public health system levels.
Methods for collecting data for the ACT PROCESS study include tape-recorded health worker communication assess-ments, patient exit interviews, self-filled questionnaires, in-depth interviews, focus group discussions, and a structured contextual record. Data collection started in early April 2011 and is on-going until July 2012.
Independent Evaluation of the Affordable Medicines Facility – Malaria (AMFm).
LSHTM Investigators: Kara Hanson, Catherine Goodman, Sarah Tougher,
Barbara Willey, Andrea Mann & Becky Thomson.
External Investigators/Collaborators: ICF International; Population
Services International; Centre de Recherche pour le Développement Hu-
main, Senegal; Centre International d’Études et de Recherches sur les
Populations Africaines, Niger; Komfo Anokye Teaching Hospital, Ghana;
Drugs for Neglected Diseases Initiative; Ifakara Health Institute, Tanzania.
Funding Body: The Global Fund to Fight AIDS, Tuberculosis and Malaria.
The aim of the independent evaluation of Phase 1 of the Affordable Medicines Facility – malaria (AMFm) is to as-sess whether, and to what extent, the first phase of AMFm achieves its objectives, which are: (i) to increase Artemis-inin-based Combination Therapy (ACT) affordability, (ii) to increase ACT availability, (iii) to increase ACT use, including among vulnerable groups, and (iv) to “crowd out” other oral
antimalarials by gaining market share. The evaluation re-sults will be summarized in a report to be considered by the Global Fund Board at the end of Phase 1, in November 2012.
The evaluation is being carried out in all 8 operational Phase 1 pilots (Ghana, Kenya, Madagascar, Niger, Nigeria, Tanzania mainland, Uganda, and Zanzibar). It is based on a non-experimental design with a pre- and post-test inter-vention assessment in which each participating country is treated independently as a case study. In each country, a nationally representative survey of outlets stocking antima-larial medicines was conducted at baseline and endline. In addition to measuring the changes in key indicators pre- and post-intervention, the evaluation includes an assessment of the implementation process and a comprehensive documen-tation of the context both to inform assessments about cau-sality and to aid in generalizability to other settings. Analysis of secondary household survey data is used to assess the ef-fects of the programme on ACT use.
98 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Research on the cconomics of ACT (REACT): Provider and patient surveys to inform the design of interventions to support improved use of ACT in Nigeria.
LSHTM Investigators: Virginia Wiseman, Lindsay Mangham & Bonnie
Cundill.
External Investigators/Collaborators: Obinna Onwujekwe, Benjamin
Uzochukwu, Ogochukwu Ezeoke & Emma Nwala (University of Nigeria,
Nigeria).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
In Nigeria, treatment guidelines state that malaria should be symptomatically diagnosed and treated with Artemisinin-based Combination Therapy (ACT) at primary health facili-ties. Research was undertaken to determine the extent to which patients seeking treatment at primary care facilities and medicine retailers receive the recommended treatment and what factors influence the choice of treatment. A cross-sectional cluster survey of 2,039 respondents exiting public
Research on the economics of ACT (REACT): qualitative situation analysis to inform the design of interventions to support improved use of ACT in Nigeria.
LSHTM Investigators: Virginia Wiseman, Lindsay Mangham & Clare
Chandler.
External Investigators/Collaborators: Obinna Onwujekwe, Ogo Exeoke
Nkoli Ezumah & Benjamin Uzochukwu (University of Nigeria, Nigeria).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The adoption of ACT as the first line treatment for uncompli-cated malaria in Nigeria has concentrated attention on the role of testing for appropriate diagnosis for malaria. There are calls at both national and global level for malaria treat-ment to be based on a test result, but it is still unclear how these tests can be incorporated into treatment seeking and practices of health providers. This study explored both com-munity and providers’ perceptions and experiences with ma-laria tests in south east Nigeria.
The study was conducted in an urban (Enugu) and a rural (Udi) area of Nigeria. A total of 18 focus group discus-sions were conducted with 179 community members and 26 in-depth interviews were conducted with public and private
health centres, pharmacies and patent medicine dealers was undertaken in 2009 in urban and rural settings in Enugu State, south-eastern Nigeria.
The results of these surveys showed that although 79% of febrile patients received an anti-malarial, only 23% re-ceived an ACT. Many patients (38%) received sulphadoxine-pyrimethamine. A further 13% of patients received an arte-misinin-derivative as a monotherapy. An estimated 66% of ACT dispensed was in the correct dose. The odds of a patient receiving an ACT was highly associated with consumer de-mand (OR: 55.5, p < 0.001).
The results identified major problems in the choice of treatment for malaria, and the need for interventions that target consumer preferences as well as seek to improve health service provision. The REACT study is working with the Malaria Control Programme in Enugu State to develop and evaluate innovative demand and supply-side interven-tions that aim to improve access to a confirmed malaria diag-nosis, raise awareness about the recommended antimalari-als and promote appropriate treatment for malaria.
health providers involved in prescribing medicines in the study area.
Most people had experienced malaria tests and both providers and community members identified this as an im-portant step to distinguish malaria from other illnesses with similar symptoms and to give appropriate treatment. How-ever, in practice antimalarial treatment was often used pre-sumptively, without a positive test result. The logic of test-directed treatment was undermined by cost of testing and a lack of facilities but above all concerns over the reliability of negative test results, with community members and pro-viders observing inconsistencies between results and symp-toms, and providers attributing inaccurate results to incom-petencies of technicians. Recognition of malaria symptoms was deemed most important in determining the use of anti-malarial drugs.
To tackle these issues, the REACT project designed in-tervention packages targeted at providers and community members. The core message of test-directed Artemisinin Combination Treatment is supported by provision of Rapid Diagnostic Tests, interactive learning and integration with other components of care for providers, and a school-based peer education programme with community-oriented ma-laria event to increase awareness and demand amongst care seekers. These interventions are being evaluated with a 3-arm cluster randomised trial.
Social & Economic Studies 99
Malaria Centre Report 2010-11
Research on the economics of ACT (REACT): qualitative situation analysis to inform the design of interventions to support improved use of ACT in Cameroon.
LSHTM Investigators: Virginia Wiseman, Lindsay Mangham & Clare
Chandler.
External Investigators/Collaborators: Wilfred Mbacham, Abanda Ngu
Njei & Olivia Achonduh (University of Yaoundé, Cameroon).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
In response to widespread overuse of antimalarial drugs, the World Health Organisation changed guidelines in 2010 to restrict the use of antimalarials to parasitologically con-firmed malaria cases. Malaria Rapid Diagnostic ests (RDTs) have been presented as a means to realize the new guide-lines, and National Malaria Control Programmes, including that of Cameroon, are developing plans to introduce the tests to replace microscopy or clinical diagnosis at public health facilities across the country.
We aimed to understand how malaria tests and antima-
Research on the economics of ACT (REACT): patient and provider surveys to inform the design of interventions to support improved use of ACT in Cameroon.
LSHTM Investigators: Virginia Wiseman, Lindsay Mangham & Bonnie
Cundill.
External Investigators/Collaborators: Wilfred Mbacham, Olivia Achon-
duh, Joel Ambebila, Albertine Lele, Theresia Metoh, Sarah Ndive, Ignatius
Ndong, Rachel Nguela, Akindeh Nji, Barnabas Orang-Ojong & Joelle Pa-
men-Ngako (University of Yaoundé I, Cameroon).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The objective of the provider and patient surveys was to in-vestigate the quality of malaria case management in Camer-oon 5 years after Artemisinin-based Combination Therapy (ACT) was adopted as the first-line antimalarial. Patterns of treatment were examined in different types of facility, and the factors associated with being prescribed or receiving an ACT were investigated.
A cross-sectional cluster survey was conducted among individuals of all ages who reported seeking treatment for a fever as they exit public and private health facilities and
medicine retailers. Prevalence of malaria was determined using Rapid Diagnostic Tests (RDTs) in consenting patients.
Among the patients, 73% were prescribed or received an antimalarial, and 51% were prescribed or received an ACT. Treatment provided to patients significantly differed by facil-ity type: 65% of patients at public facilities, 55% of patients at private facilities and 45% of patients at medicine retailers were prescribed or received an ACT. The odds of a febrile pa-tient being prescribed or receiving an ACT were significantly higher for patients who asked for an ACT, were physically ex-amined by the health worker, had not previously sought an antimalarial for the illness and sought treatment at a public or private facility. Malaria was confirmed in 29% of patients, and 70% of patients with a negative malaria test were pre-scribed or received an antimalarial.
The results of these surveys showed that malaria case management could be improved, and symptomatic diagno-sis is inefficient because two-thirds of febrile patients do not have malaria. As the Cameroon Government plans to extend malaria testing it will be important to promote the rational use of ACT. The REACT study is working with the National Malaria Control Programme to develop and evaluate pro-vider training interventions that can support the roll out of RDTs.
larial drugs are currently used as part of social interactions between health workers and patients at public and mission health facilities in Yaoundé and Bamenda and surrounding districts in the Northwest region of Cameroon. In May to June 2010, we held 17 focus group discussions with 146 health workers involved in clinical care from 49 health facilities.
Clinicians enacted malaria as a ‘juggling’ exercise, in-volving attention to pathophysiology of the patient as well as their desires and medical reputations, utilising tests and medicines for their therapeutic effects as symbols in the pro-cess of care. Parasites were rarely mentioned in describing diagnostic decisions.
These enactments of malaria contrast with evidence-based guidelines emanating from WHO, which assume the parasite is the central driver of practice. If RDTs are to be taken up in practice, public health practitioners need to pay careful attention to the values and priorities of health work-ers and patients if they are to work with them to improve di-agnosis and treatment of febrile illnesses. The REACT project has designed an interactive intervention with health workers to support the uptake of RDTs, being tested in a cluster ran-domised trial.
100 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Implementing the inSCALE project in Uganda: Innovations at scale for community access and lasting effects.
LSHTM Investigators: Betty Kirkwood, Raghu Lingham, Anna Vassall,
Frida Kasteng & Seyi Soremekun.
External Investigators/Collaborators: Sylvia Meek, James Tibenderana
& Karin Kallander (Malaria Consortium, UK); Zelee Hill & Daniel Strachan
(Institute of Child Health – University College London, UK).
Funding Body: The Bill & Melinda Gates Foundation.
As a way of improving access to treatment for sick children, several African countries are investing in Community Health Workers (CHWs) to deliver the integrated Community Case Management (iCCM) package. Here CHWs are trained to iden-tify, refer and/or treat children with malaria, diarrhoea, and pneumonia, which together contribute to more than 50% of the childhood illnesses in sub-Saharan Africa. However, CHW programs have been faced with challenges of scale up while maintaining effectiveness, largely due to problems of rup-tures in medicine supplies, lack of community involvement, shortfalls in training materials, lack of refresher training and supervision, high attrition and low performance of CHWs.
The inSCALE project (“Innovations at scale for commu-nity access and lasting effects”) is a Malaria Consortium-led
Discussing the inSCALE project with community stakeholders in a village in mid-Western Uganda.
project in collaboration with the LSHTM aiming to evaluate innovative technology and community-based engagement solutions to improve motivation and retention of CHWs, and thus improve the appropriate treatment of children under five years of age.
At the Uganda site we plan two approaches:Community: The community approach will use a village
health ‘club’ setting, where CHWs and club members can work together to identify and address child health and CHW challenges – and by doing so increase the local visibility and standing of the CHW and the community support of the iCCM programme.
Technology: The technology approach aims to improve the CHW experience through increased supervisory and peer support, using affordable mobile phones. CHWs and their supervisors will receive phones with built-in applica-tions allowing data submission, feedback, motivational mes-saging and job aides, whilst allowing unlimited calls and SMS amongst CHWs and their supervisors.
These two innovations will be evaluated in a 3-arm cRCT in mid-western Uganda, the results of which will contribute to advocacy efforts aiming to demonstrate the feasibility of increasing and sustaining coverage of the iCCM programme nationally.
Website: http://www.malariaconsortium.org/inscale/
Social & Economic Studies 101
Malaria Centre Report 2010-11
The amount and value of work time of community medicine distributors in community case management of malaria among children under five years in the Ejisu-Juaben District of Ghana.
LSHTM Investigators: Kristian Hansen.
External Investigators/Collaborators: Peter Agyei-Baffour & Edmund
Browne (Kwame Nkrumah University of Science and Technology, Ghana);
Pascal Magnussen (DBL Centre for Health Research and Development,
Denmark).
Funding Body: Kwame Nkrumah University of Science and Technology &
University of Copenhagen.
The contribution of Community Medicine Distributors (CMD) to prompt health service delivery in areas described as ‘hard-to-reach’ is important but the value of their work time remains unknown. This study attempted to estimate the
value (opportunity costs) of 54 CMDs work time involved in Community Case Management of malaria (CCMm) in a rural district in Ghana. Time spent by CMDs on CCMm activities was recorded for a period of 12 months to determine their work time. Opportunity costs of time were valued using dif-ferent proxy measures such as national minimum wage and average labourer wage from common economic activities in the area. The CMDs spent an average of 4.8 hours (95% CI: 3.9; 5.3) on all CCMm related activities per day. The value of time related to CMD work ranged from GHS4.8 (US$5.3) to GHS21.6 US$23.7] per week depending on time valuation approach. The estimated opportunity cost of time using any method was much higher than the money incentives actually paid by the CCMm programme to CMDs. The value of work time and the forgone income of CMD in CCMm are high and yet there are no regular and sustainable incentives provided for them.
Qualitative evaluation of the introduction of malaria RDTs and a new referral system at registered drug shops in Mukono district, Uganda.
LSHTM Investigators: Clare Chandler, Eleanor Hutchinson, Kristian
Hansen, Sham Lal & Sian Clarke.
External Investigators/Collaborators: Anthony Mbonye (Ministry of
Health, Uganda); Pascal Magnussen (DBL Centre for Health Research and
Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT
Consortium.
This qualitative study is running alongside a cluster ran-domised trial that has introduced malaria RDTs, subsidised Artemisinin-based Combination Therapy (ACT) and a new referral system to registered drug shops in Mukono district, Uganda. We aim to understand more about the processes in-volved with the introduction of RDTs at drug shops, specifi-
cally (1) to evaluate how RDTs and subsidized ACT are per-ceived and incorporated into practice by drug shop vendors and their clients, (2) to document and describe the referral process from drug shops to health facilities in Mukono from the perspective of patients, drug shop sellers and health workers and (3) to contribute to the current policy and re-search debates of involving the private sector in health ser-vice delivery. We have carried out 21 focus group discussions with drug shop vendors, clients and health facility staff and questionnaire interviews with patients on day 10-14 after visiting drug shops are ongoing. We are also carrying out a discourse analysis to describe the cultural context in which drug shops operate by analysing the ways in which words, phrases and narratives (discourse) are used to name, repre-sent and create particular concepts and images of drug shops and drug shops vendors in Uganda. We will focus on media and government discourses, locating them within the wider context of the relationship between public and private sector health providers in Uganda.
This advertisement, which reads ‘This drug shop has a fast/quick way of testing for malaria’, was assem-bled by a drug shop vendor who was given RDTs to sell by the ACT Consortium Project in Mukono, Uganda.
102 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Research on the economics of ACT (REACT): an evaluation of the effectiveness and cost-effectiveness of two interventions designed to support the roll-out of malaria Rapid Diagnostic Tests (RDTs) and improve the rational use of Artemisinin-based Combination Therapy (ACT) in Enugu State, Nigeria.
LSHTM Investigators: Virginia Wiseman & Lindsay Mangham.
External Investigators/Collaborators: Obinna Onwujekwe, Ogochukwu
Ezeoke, Emmanuel Nwala, Jane Enemuo, Eloka Uchegbu & Benjamin Uzo-
chukwu (University of Nigeria, Nigeria).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The Government of Nigeria recommends that patients pre-senting with malaria symptoms should be tested using mi-croscopy or RDTs prior to treatment, and that confirmed cases of malaria should be treated with ACT. With limited ac-cess to testing, symptomatic treatment of malaria has been the mainstay, though the Government of Nigeria plans to introduce RDTs. It is feared that without supporting inter-ventions, many patients will not receive care in line with the national malaria policy.
Research on the economics of ACT (REACT): an evaluation of the effectiveness and cost-effectiveness of provider interventions improve the rational use of Artemisinin-based Combination Therapy (ACT) in Cameroon.
LSHTM Investigators: Virginia Wiseman, Lindsay Mangham, Bonnie Cun-
dill & Clare Chandler.
External Investigators/Collaborators: Wilfred Mbacham, Olivia A
Achonduh, Akindeh Mbuh Nji & Abanda Ngu Njei (University of Yaoundé
I, Cameroon).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Governments and donors all over Africa are searching for sustainable, affordable and cost-effective ways to improve the quality of malaria case management. Widespread de-ficiencies have been reported in the prescribing and coun-selling practices of health care providers treating febrile pa-tients in both public and private health facilities. Cameroon is no exception with poor adherence to national guidelines, the frequent selection of non-recommended antimalarials and
This study aims to design, implement and evaluate two interventions to improve the care of patients presenting with malaria symptoms at primary health facilities in the public sector and at pharmacies and patent medicine dealers.
A 3-arm cluster randomized trial is ongoing and will as-sess the effectiveness and cost effectiveness of: (i) a provider intervention versus expected standard practice in malaria di-agnosis and treatment; (ii) combined provider plus school-based intervention versus expected standard practice; and (iii) the combined provider plus school-based intervention versus provider intervention alone. RDTs will be introduced in all arms of the trial. The primary outcome is the propor-tion of patients attending facilities that report a fever or sus-pected malaria and receive treatment according to malaria guidelines. This will be measured by surveying patients (or caregivers) as they exit primary health centres, pharmacies and patent medicine dealers. Costs will be estimated from both a societal and provider perspective using standard economic evaluation methodologies. Cost-effectiveness will be presented in terms of the primary outcome and a range of secondary outcomes, including changes in provider and community knowledge.
the use of incorrect dosages. This study aims to design, implement and evaluate in-
terventions to improve the care of patients presenting with malaria symptoms at public and mission health facilities. The evaluation will determine the effectiveness and cost-ef-fectiveness of introducing provider training alongside Rapid Diagnostic Tests. Two training courses have been designed. Both courses will equip providers with the basic knowledge and practical skills needed to effectively diagnose and treat malaria, while the enhanced course also uses interactive methods and additional activities to promote changes in pre-scribing practices.
A 3-arm cluster randomized trial is ongoing. The prima-ry outcome is the proportion of patients attending facilities that report a fever or suspected malaria and receive treat-ment according to malaria guidelines. This will be measured by surveying patients (or caregivers) as they exit public and mission health facilities. Costs will be estimated from a soci-etal and provider perspective using standard economic eval-uation methodologies. Cost-effectiveness will be presented in terms of the primary outcome and a range of secondary outcomes, including changes in provider knowledge.
Social & Economic Studies 103
Malaria Centre Report 2010-11
The Good Use of ACT and Rapid Diagnostic Tests (RDTs) - (GUARD) study.
LSHTM Investigators: Shunmay Yeung, Clare Chandler, Patricia Tab-
ernero & Mikhael De Souza.
External Investigators/Collaborators: Chea Nguon, Ouk Rada & Mam
Boravann (National Malaria Control Programme, Cambodia); Henrietta
Allen (Population Services International).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The role of malaria Rapid Diagnostic Tests (RDTs) in the pri-vate sector has recently become a hot topic for expansion of appropriate diagnosis and treatment of malaria. However programmatic experience is very limited. In Cambodia RDTs have been socially marketed alongside Artemisinin-based Combination Therapy (ACT) since 2004. However little was known about how they were being used in practice. We undertook the Good Use of ACT and Rapid Diagnostic tests (GUARD) study in collaboration with the National Ma-laria Control programme and other partners in Cambodia in 2010-2011. We used a mixed methods approach including a private provider census survey, RDT user assessment, RDT
quality assessment; mystery client study, chemical analysis of drugs and focus group discussions. In all, 217 providers in 12 health centre catchment areas were included. The census survey showed that only 59% of the 203 providers who sold antimalarials, also sold RDTs. Qualitative findings suggested that providers distinguish their roles as selling drugs (“lout tnam”) or diagnosing and treating (“pinit pchier bal”), and that RDTs seem to be at the margins rather than central to these practices. The mystery client findings suggested that providers were often reluctant to sell antimalarials without a prior blood test, and that the sale of “drug cocktails” is still very popular. Challenges were identified in the manual use of RDTs, including difficulties with the blood pipette, insuf-ficient waiting time and unsafe disposal of the used lancets. Providers also reported some problems in interpreting re-sults. When asked about alternative diagnoses for patients with negative RDTs, the most common diagnosis reported by providers was “typhoid”, and a third said that they would provide antibiotics. The results of the study are being used to modify aspects of the programme in Cambodia, and will hopefully be useful for other malaria-endemic countries that are considering the roll-out of RDTs in their private sectors.
Packets of drugs.
104 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Village Malaria Worker Access to Treatment (VIMWAT) study.
LSHTM Investigators: Shunmay Yeung & Edith Patouillard.
External Investigators/Collaborators: Chea Nguon & Poly Teng (Na-
tional Malaria Control programme, Cambodia).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Community health workers have been identified as a means to increase prompt access to appropriate management of malaria, through parasitological diagnosis using Rapid Di-agnostic Tests (RDTs) and Artemisinin-based Combination Therapy (ACT). There has also been interest in expanding their role to the management of childhood illnesses. How-ever, evaluations of these programmes are lacking.
In Cambodia, the national malaria control programme introduced a network of Village Malaria Workers (VMWs) in 2004. VMWs are community volunteers who perform RDTs and treat confirmed malaria cases with ACT, with some hav-
Willingness-to-pay for Rapid Diagnostic Tests (RDTs) and ACT medicines into the private sector. Costumer survey in registered drug shops in Mukono district, Uganda.
LSHTM Investigators: Kristian Hansen, Bonnie Cundill, Shunmay Yeung
& Sian Clarke.
External Investigators/Collaborators: Deborah Pedrazzoli (Health Pro-
tection Agency, UK); Anthony Mbonye (Ministry of Health, Uganda); Pascal
Magnussen (DBL Centre for Health Research and Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Many people seek treatment for malaria in drug shops as their first point of care, and the role of the private sector in providing access to prompt effective antimalarial treatment is increasingly recognised by malaria control programmes.
However, parasitological diagnosis to guide malaria treatment is not usually offered in these outlets. Rapid Diag-nostic Tests (RDTs) are easy to perform with minimal train-ing, and could feasibly be performed in drug shops, but it is not known how much customers would be willing to pay for an RDT.
The bidding game technique was used to elicit the will-ingness-to-pay (WTP) for an RDT and a course of Artemis-
ing an “expanded role” to treat children under 5 years pre-senting with diarrhoea and/or acute respiratory infections using Oral Rehydration Solution (ORS) and/or antibiotics.
The VIMWAT study is a pragmatic evaluation of the VMW programme. It aims to evaluate their effectiveness at deliver-ing prompt access to appropriate diagnosis and treatment of malaria to the most vulnerable populations and feasibility and impact of expanding their role. It employs mixed meth-ods, including:
■ A three-arm cohort study of 1,152 households (~ 5,000 individuals) to document treatment seeking behav-iours and associated costs over time for populations living in villages with VMWs offering RDT and ACT only, populations in villages with VMWs offering RDT, ACT, ORS and antibiotics and populations without access to VMWs.
■ Epidemiological and economic cost study of the VMW programme from a provider perspective.
Fieldwork started in August 2011 and is expected to be completed mid-2012.
inin-based Combination Therapy (ACT), with and without RDT confirmation, during exit interviews with drug shop customers seeking treatment for fever in Mukono District, Uganda. The geometric mean WTP for an RDT was US$0.53, and US$1.82 for a course of ACT. Customers indicated WTP for an ACT would increase to US$2.05 should the RDT have proved positive. In conclusion, the WTP for RDTs and ACT-were considerably lower than prevailing and estimated end-user prices under AMFm. Additional measures may be need-ed to increase uptake of ACT in drug shops and to restrict sale of ACT to parasitologically confirmed malaria.
Social & Economic Studies 105
Malaria Centre Report 2010-11
“Bringing treatment to the people” - emerging geographies of care and the role of rapid diagnostic tests in access to malaria treatment in Bo District, Sierra Leone.
LSHTM Investigators: Uli Beisel & Wenzel Geissler.
External Investigators/Collaborators: Jorgen Stassijns (Médecins Sans
Frontières, Belgium).
Funding Body: Leverhulme Trust.
In collaboration with Médecins Sans Frontières (MSF) in Belgium this project conducted one month of qualitative re-search in Bo District, Sierra Leone. From 2007-11 MSF ran an outreach malaria control project in rural, hard-to-reach communities; 50 medically untrained community malaria volunteers (mainly local farmers) were trained to use rapid diagnostic tests to diagnose falciparum malaria and admin-ister Artemisinin-based Combination Therapies. MSF’s proj-ect aimed to increase access to malaria care for population
Cost-effectiveness analysis of introducing RDTs for malaria diagnosis as compared to microscopy and presumptive diagnosis in public health centres in Ghana.
LSHTM Investigators: Kristian Hansen, Chris Whitty & Shunmay Yeung.
External Investigators/Collaborators: Evelyn Ansah (Ghana Health
Service, Ghana).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Overprescription of antimalarials occurs in public health centres in Ghana both where microscopes are available and where diagnosis is done presumptively due to lack of para-sitological testing facilities. The present research project as-sessed the cost-effectiveness of introducing malaria Rapid Diagnostic Tests (RDTs) in three public health centres in Dangme West district, Ghana. Suspected malaria patients attending a health centre with a microscope were randomly assigned to a diagnosis by either RDT or microscopyand sub-sequent treatment by health centre staff whereas patients visiting two health centres without a microscope were ran-domly assigned to diagnosis by an RDT or based on clinical signs. Costs of offering diagnostic services and outpatient services were collected through visits to the health centres. An exit survey among suspected malaria patients and follow-
groups that had thus far not been able to seek biomedical care due to their distance to health care facilities. This re-search project aimed to assess the community responses, so-cial implications and changed geographies of care and access to malaria treatment in the project area. MSF’s project was highly successful in increasing access to malaria diagnosis and treatment for vulnerable populations, and the results of the qualitative interviews and observations underlined that on-going medical training and regular supervision of the vol-unteers was crucial. Furthermore, the results emphasise the importance of establishing long-term and local institutional support for such capacity building projects with medically untrained and unpaid volunteers. The application of Rapid Diagnostic Tests in non-medical settings through health vol-unteers is only sustainable and effective in improving ma-laria diagnosis and treatment if projects are conceived from the beginning as medical education and capacity building projects.
up visits in their homes captured household cost of treat-ment-seeking. The measure of effect was the number of cor-rectly treated patients as determined by a double read blood slide. The cost per correctly treated patient in the health cen-tre with a microscope was at a similar level among patients diagnosed by an RDT and by a microscopy. In the health cen-tres without a microscope, the cost per correctly treated pa-tient was considerably lower among patients diagnosed by an RDT arm as compared to those diagnosed by clinical signs.
106 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Introducing Rapid Diagnostic Tests (RDTs) into the private health sector: a cost-effectiveness analysis among registered drug shops in Mukono district, Uganda.
LSHTM Investigators: Kristian Hansen, Sian Clarke & Sham Lal.
External Investigators/Collaborators: Anthony Mbonye (Ministry of
Health, Uganda); Pascal Magnussen (DBL Centre for Health Research and
Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
It is common in Uganda for people to seek treatment for ma-laria in drug shops as their first point of care. Parasitological diagnosis to guide malaria treatment is not usually offered in drug shops. Since Rapid Diagnostic Tests (RDTs) are easy to perform and have high accuracy in many settings, these tests could feasibly be offered in drug shops. The present research is designed as a cost-effectiveness study alongside a cluster-
randomised trial in Mukono district, Uganda, where drug shops will either offer RDT diagnosis or presumptive diag-nosis. Societal cost of interventions will be collected incor-porating the cost related to deployment of the interventions and the provider cost of treatment in public health facilities if patients proceed to seek care. In addition, interviews with a sample of drug shop customers will be done to capture the household cost of treatment-seeking for fever including the direct costs of transport, diagnosis and drugs and opportu-nity cost of lost time. The effectiveness measure is ‘correctly treated patient’ defined as a research blood slide positive pa-tient receiving an Artemisinin-based Combination Therapy (ACT) or a blood slide negative patient not receiving an ACT. The collected data will be used to estimate the incremental cost and effects of introducing RDTs in private, registered drug shops as well as to perform various decision tree and sensitivity analyses incorporating factors like adherence, provider compliance and accuracy of the test.
Mother and child in The Gambia.
Social & Economic Studies 107
Malaria Centre Report 2010-11
Development of programme friendly rapid assessment tools to identify and quantify the major barriers to the scale up and use of interventions for the control of malaria in pregnancy.
LSHTM Investigators: Jayne Webster, Jane Bruce & Lucy Paintain.
External Investigators/Collaborators: Jenny Hill, Rukhsana Ahmed,
Feiko ter Kuile (Liverpool School of Tropical Medicine, UK); Kassoum Kay-
entao, Sory Diawara, Samba Diarra (Malaria Research and Training Cen-
tre, Mali); Stephanie Dellicour, Meghna Desai & Peter Ouma, (KEMRI-CDC,
Kenya); Din Syafruddin (Eijkman Institute of Molecular Biology, Indone-
sia).
Funding Body: The Bill & Melinda Gates Foundation through the Malaria
in Pregnancy Consortium.
In order to support global efforts to scale up malaria control interventions, greater attention must be given to implemen-tation research in order to understand the obstacles to prog-ress at the level of local decision makers. Innovative rapid assessment approaches that explore the link between health care utilisation patterns and specific elements of the delivery
Introducing rapid diagnostic tests into community-based management of malaria: a cost-effectiveness analysis among community medicine distributors in two areas of high and low transmission in Uganda.
LSHTM Investigators: Kristian Hansen, Sian Clarke & Sham Lal.
External Investigators/Collaborators: Richard Ndyomugyenyi (Min-
istry of Health, Uganda); Pascal Magnussen (DBL Centre for Health Re-
search and Development, Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Universal access to diagnostic testing for malaria is recom-mended by the World Health Organisation. Rapid Diagnos-tic Tests (RDTs) provide a simple means of confirming ma-laria diagnosis in remote locations where community health workers after limited training may be able to perform RDTs and treat accordingly. Alongside a cluster-randomised trial, data have been collected for a cost-effectiveness analysis of introducing RDTs to improve malaria diagnosis and treat-
ment by Community Medicine Distributors (CMDs) in two sub-counties with contrasting transmission in Rukungiri Dis-trict, Uganda. Societal cost of two interventions will be col-lected: (1) having CMDs perform an RDT followed by treat-ment with artemisinin-based combination therapy (ACT) or referral and (2) CMDs treating presumptively with ACT or referral. The cost to be collected include the cost related to deployment of the interventions and the provider cost of treatment in public health facilities if patients proceed to seek care or are referred there by the CMDs. In addition, in-terviews with a sample of patients treated by CMDs will be done to capture the household cost of treatment-seeking for fever including the direct costs of transport, diagnosis and drugs and opportunity cost of lost time. The effectiveness measure was ‘correctly treated patient’ defined as a research blood slide positive patient receiving an ACT or a blood slide negative patient not receiving an ACT. The collected data will be used to estimate the incremental cost and effects of in-troducing RDTs among CMDs as well as to perform various decision tree and sensitivity analyses incorporating factors like adherence, compliance to RDT result by CMDs and ac-curacy of the RDT.
system are needed in order to support programme managers maximise the outputs of current investment levels.
We are using a combination of integrated survey tech-niques to assess barriers at the levels of ‘access’, ‘delivery’ and ‘use’. Strengths and weaknesses of the study methods will be examined and used to illustrate how they provide complementary information to improve programme perfor-mance. These comprehensive methods will be scaled down to provide essential rapid assessment tools. Findings have highlighted blockages in delivery of preventative interven-tions, methodological anomalies in the way in which we are currently assessing coverage of interventions, and the strengths and weakness of survey techniques in providing information for programme improvement.
In a second phase of the study findings of the above will be used to 1) develop streamlined second generation survey tools, 2) routine data collection for delivery of MiP interven-tions through ANC will be examined and described, 3) en-hanced data collection indicators, and tools will be imple-mented and the completeness, accuracy, validity and utility of the data evaluated.
108 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Intermittent Screening and Treatment (IST) or Intermittent Preventive Therapy (IPT) for control of Malaria in Pregnancy (MiP) in Indonesia.
LSHTM Investigators: Jayne Webster & Jane Bruce.
External Investigators/Collaborators: Jenny Hill, Rukhsana Ahmed, Eve
Worral & Feiko ter Kuile (Liverpool School of Tropical Medicine, UK); Din
Syafruddin, Jeanne Poespoprodjo & Puji Budi Asih (Eijkman Institute of
Molecular Biology, Indonesia).
Funding Body: UK Department for International Development; Medical
Research Council, UK; Wellcome Trust Joint Global Health Trial Scheme.
A range of implementation research sub studies will be used to investigate the current status of the programme for pre-vention of malaria in pregnancy, and the feasibility, accept-ability and cost effectiveness of possible new strategies. The
Scale-up of Malaria in Pregnancy (MiP)interventions.
LSHTM Investigators: Jayne Webster.
External Investigators/Collaborators: Jenny Hill & AnneMieke van Ei-
jke (Liverpool School of Tropical Medicine, UK); Rick Steketee (MACEPA);
PATH, USA.
Funding Body: The Bill & Melinda Gates Foundation through the MiP con-
sortium.
Despite clear documented evidence on the burden of ma-laria in pregnant women and proven effective interventions,
study will run alongside a randomised control trial and will involve structured observations, in-depth interviews and fo-cus group discussions.
Currently in Indonesia women are tested for malaria on their first visit to antenatal clinics, and if positive are treated with dihydroartemisinin-piperaquine (DHA-PQ) in 2nd and 3rd trimester and quinine in 1st trimester. During subse-quent visits they are only tested if they present with symp-toms. This strategy for Single Screening and Treatment (SST) will be compared with Intermittent Screening and Treatment (IST) where women are tested on every scheduled visit to ANC, and with Intermittent Preventive Treatment (IPTp), where women receive a preventive treatment on scheduled visits to ANC but no testing. The implementation research will focus on these 3 strategies of SST, IST and IPT.
as adopted/recommended in African Regional and country policies, coverage of malaria prevention in pregnant women in many malaria-endemic African countries remains unac-ceptably low.
We have adopted a 2 stage approach to address this problem. In stage 1 we are conducting reviews and second-ary data analyses to clarify the issues and problems experi-enced across countries, including variations by sub-regions. In the second stage we plan to systematically identify and ac-tively address the coverage barriers at country level. In order to facilitate the second stage we are developing an assess-ment and decision making tool.
Economic analysis for the Malaria in Pregnancy (MiP) Consortium.
LSHTM Investigators: Kara Hanson, Silke Lutzelschwab & Jayne Webster.
External Investigators/Collaborators: Elisa Sicuri (CRESIB, Barcelona);
Azra Ghani & Patrick Walker (Imperial College, UK); Feiko ter Kuile & Jen-
ny Hill (Liverpool School of Tropical Medicine, UK).
Funding Body: The Bill & Melinda Gates Foundation.
Sitting within the Public Health Impact activity of the Ma-laria in Pregnancy Consortium (MiPc), the objectives of the economics contributions are: a) to estimate the economic burden of MiP; b) to assess the cost and cost-effectiveness of new prevention and case management interventions; c) to estimate the cost of scaling up new MiP interventions.
The economic burden of malaria in pregnancy will be es-
timated using a variety of methods, including cross-sectional household and facility surveys, exit surveys, and modelling approaches. Cost-and cost-effectiveness analyses will be con-ducted alongside both prevention and case management tri-als. Information to support decision making will be provided by modelling the costs and affordability to national govern-ments of implementing MIP interventions, and exploring the costs of alternative approaches to their targeting and deliv-ery.
In collaboration with Azra Ghani, the project has sup-ported the development of a model of malaria in pregnancy which will be used to explore the applicability of potential prevention strategies to various settings with different un-derlying epidemiological and economic characteristics.
Work is being carried out alongside trials in 12 countries from 4 continents and fieldwork will commence during 2010.
Social & Economic Studies 109
Malaria Centre Report 2010-11
Cost-effectiveness of malaria microscopy and rapid diagnostic tests versus presumptive diagnosis: implications for malaria control in Uganda.
LSHTM Investigators: Kristian Hansen.
External Investigators/Collaborators: Vincent Batwala (University of
Science & Technology, Uganda); Pascal Magnussen (DBL Centre for Health
Research and Development, Denmark); Fred Nuwaha (Makerere Univer-
sity Uganda).
Funding Body: Makarere University School of Public Health; UK Depart-
ment for International Development; Centre for Health Research and De-
velopment.
Current Ugandan National Malaria treatment guidelines rec-ommend parasitological confirmation either by microscopy or Rapid Diagnostic Test (RDT) before treatment with arte-mether-lumefantrine (AL). The cost-effectiveness of these strategies has not been assessed at rural primary care cen-tres. Three health centres were randomized to three diagnos-
tic arms (microscopy, RDT and presumptive diagnosis) each in a district of low and high malaria transmission intensi-ties in Uganda. Patients presenting with fever at outpatients departments were enrolled from March 2010 to February 2011. Costing was performed from the societal perspective and following the standard step-down costing method and the ingredients approach. Effectiveness was measured as the number and proportion of patients correctly diagnosed and treated. The Incremental Cost-Effectiveness Ratio (ICER) of introducing RDT diagnosis instead of presumptive diagnosis was US$5.0 while the ICER of microscopy versus presump-tive diagnosis was US$9.61. The ICERs of RDT and micros-copy diagnosis varied by transmission setting, but RDT diag-nosis remained the most cost-effective option of the two in both settings. With a global campaign to reduce the costs of AL and RDT, the Malaria Control Programme and stakehold-ers need a strategy for malaria diagnosis because as the cost of AL decreases, presumptive treatment is likely to become more attractive.
Eliciting harms data from trial participants: how perceptions of illness and treatment mediate recognition of relevant information to report.
LSHTM Investigators: Clare Chandler & Sarah Staedke.
External Investigators/Collaborators: Karen Barnes & Elizabeth Allen
(University of Cape Town, South Africa); Adiel Mushi, Isolide Massawe &
Martha Lemnge (National Institute of Medical Research, Tanzania); Ush-
ma Mehta (South Africa); Lasse Vestergaard (University of Copenhagen,
Denmark).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
There is no consensus on ideal methodology for eliciting participant-reported harms in clinical trials, but the extent and nature of data detected depend on the types of questions asked. This gives potential for measurement error and un-dermines meta-analyses of adverse effects.
Participants in two (South African and Tanzanian) antiretroviral/antimalarial interaction trials were asked about their health and treatments by general enquiries fol-lowed by checklists. Those reporting differently between
these methods were invited to an in-depth interview and fo-cus group discussion. Health narratives were analysed to in-vestigate accuracy and completeness of the case record form data and to understand reasons for differential reporting.
Using checklists generally increased the sensitivity of detection of medical histories, concomitant medications and adverse events compared to open enquiries, though trial participants deliberately withheld some further infor-mation, revealed through the interviews. We identified the following barriers to reporting: poor memory, perception of the significance of the event or treatment to the participant, perceived relevance of the event or treatment to the trial or medical consultation, perceived consequences of reporting, and problems with naming concomitant treatments. These barriers were underpinned by psycho-social constructs con-cerned with being a trial subject and perceived responsibility for reporting. Differing perceptions between South Africans and Tanzanians about whether it is the participant or investi-gator who takes responsibility for reporting were influenced by the distinct trial contexts.
Our current aim is to work towards consensus about the design of appropriate and feasible harms data elicitation methods within the malaria clinical research community.
110 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Designing adverse event forms for real-world reporting: participatory research in Uganda.
LSHTM Investigators: Clare Chandler & Sarah Staedke.
External Investigators/Collaborators: Emma Davies, David Lalloo &
Dianne Terlouw (Liverpool School of Tropical Medicine, UK); Simeon H
Innocent (Cambridge University, UK); Charles Kalumuna (Malaria Sur-
veillance Programme, Uganda); Ane Haaland (University of Oslo/Haaland
Communication).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
The wide-scale roll-out of Artemisinin-based Combination Therapy (ACT) for the treatment of malaria should be ac-companied by continued surveillance of their safety, as stan-dard good practice. Post-marketing pharmacovigilance relies on passive and active adverse event reporting by clinicians, but as a large proportion of treatments are provided by non-clinicians in many low-resource settings, the effectiveness of such PV systems is limited. To facilitate reporting, adverse event report forms should be easily completed; however, most commonly used forms are challenging for lower-level health workers and non-clinicians to complete. Through par-ticipatory research, we sought to develop user-friendly ad-verse event report forms designed to capture information on events associated with ACT.
Following situation analysis, we undertook workshops with community medicine distributors and health workers in Jinja, Uganda, to develop a reporting form based on ex-periences and needs of users as well as communication and visual perception principles. Participants practised with the forms and gave feedback for revisions of subsequent ver-sions. We then conducted a series of 8 pretesting sessions with 77 potential end users using scenarios to test and refine passive and active versions of the form.
The development process resulted in a form that in-cluded a pictorial storyboard to communicate the rationale for the information needed, and a diary format to record the drug administration and event details in chronological relation to each other. Successive rounds of pretesting used qualitative and quantitative feedback to refine the form, with the final round showing over 80% of the form completed cor-rectly by potential end users.
We developed novel adverse event report forms that can be used by non-clinicians to capture pharmacovigilance data for anti-malarial drugs. The participatory approach was ef-fective for developing forms that are intuitive for reporters, and motivating for respondents. The forms or their key com-ponents could be adapted for use in other low-literacy set-tings to improve quality and quantity of drug safety reports as new medicines are scaled-up.
Social & Economic Studies 111
Malaria Centre Report 2010-11
Above: Community medicine distributors working to design an adverse event reporting form that encourages their respondents to give the full story of the ‘event’.
Below: Final version of a story board developed through participatory research, to communicate to low-level health workers and respondents the purpose of the adverse event reporting form.
112 Social & Economic Studies
London School of Hygiene & Tropical Medicine
Understanding perceptions of malaria and malaria treatment amongst HIV-positive individuals in Muheza, Tanzania: a qualitative study.
LSHTM Investigators: Clare Chandler & Joanna Reynolds.
External Investigators/Collaborators: Lasse Vestergaard (University
of Copenhagen, Denmark); Peter Mangesho & Martha Lemnge (National
Institute for Medical Research, Tanzania).
Funding Body: The Bill & Melinda Gates Foundation through the ACT Con-
sortium.
Acknowledging the double burden of malaria and HIV co-infection faced by many in sub-Saharan Africa, we designed a qualitative study to explore perceptions of taking antima-larial medication concomitantly with Anti-Retroviral Thera-py (ART) amongst HIV-positive people, in Muheza, Tanzania. We sought to understand these perceptions, and how they influence attitudes towards malaria prevention and treat-ment seeking, and conducted the study alongside a clinical observation trial of the efficacy and safety of taking ART con-
The costs of large-scale administration of Seasonal Malaria Chemoprevention (SMC) in Central Senegal.
LSHTM Investigators: Catherine Pitt, Badara Cisse & Paul Milligan.
External Investigators/Collaborators: Mouhamed N’Diaye & Oumar
Gaye (Université Cheikh Anta Diop, Senegal); El Hadj Ba (Institut de Re-
cherche pour le Developpement, Dakar, Senegal); Lesong Conteh (Imperial
College London, UK).
Funding Body: The Bill & Melinda Gates Foundation.
In March 2012, the World Health Organization recommend-ed Seasonal Malaria Chemoprevention (SMC) as an addi-tional malaria control tool. This is the first study to assess the costs of SMC on a large scale; preliminary results on the financial costs of SMC were presented to WHO in 2011. We evaluated the financial and economic costs of delivering SMC
comitantly with Artemisinin-based Combination Therapy (ACT) for malaria. As a secondary research question, we also sought to explore with participants their experiences of par-ticipating in the clinical observation trial and the meaning attached to it.
We conducted 13 Focus Group Discussions (FGDs) and 10 In-Depth Interviews (IDIs) between July and November 2011, with HIV-positive and negative participants of the clinical observation trial, trial staff and health workers from the surrounding health service in Muheza. The FGD and IDI transcripts are being analysed in relation to each research question, and analysis will be completed by mid-March, 2012. It is hoped the findings will help address gaps in ex-isting knowledge around perceptions of taking ART and an-timalarial medication concomitantly, informing practice in how to minimise the risks related to co-infection of HIV and malaria. Furthermore, we hope to contribute to understand-ing of the ethical dimensions of conducting trials in develop-ing country settings and how to better align participants’ and researchers’ expectations and experiences of the research process.
in a population of approximately 175,000 children aged 3 to 120 months in 45 health posts across four districts of central Senegal in 2010. Implementation was led by the Ministry of Health. At each health post, Community Health Workers (CHWs) travelled door-to-door in pairs to administer sulph-adoxine-pyramethamine and amodiaquine tablets over the course of several days in each of the three main months of the malaria season. The financial and economic costs were found to be lower than in previous studies, which is likely attributable to economies of scale, as this was a much larger study, but also to the leading role of the Ministry of Health in implementation, and the economies of scope achieved in extending the usual age range of SMC from children under five to children under ten. The SMC tablets themselves and the incentive payments to CHWs were the key cost drivers. Analyses are ongoing and will also include an assessment of the cost-effectiveness of SMC.
Boys playing in The Gambia.
Social & Economic Studies 113
Malaria Centre Report 2010-11
The burden of imported malaria among Nigerians and Ghanaians living in London: Understanding the influences of the social, cultural, environmental, economic and structural context.
LSHTM Investigators: Penny Neave, Ron Behrens & Caroline Jones.
External Investigators/Collaborators: Malaria Reference Laboratory,
UK; Hospital for Tropical Diseases, UK.
Funding Body: Health Protection Agency/self-funded.
The aim was to understand factors which influence malaria control practices in Nigerians and Ghanaians Visiting Friends and Relatives (VFRs).
An analysis of over 13 000 malaria reports showed that 58% of cases lived in London, with 83% of these caused by Plasmodium falciparum. The infection rate per 100 000 in those of “Black African” ethnicity was 152. 9 (CI 137.66-168.09) compared to 0.32 (0.2-0.45) amongst “White Brit-ish”.
Street level health workers: producing public health in the African city.
LSHTM Investigators: Ann Kelly, Wenzel Geissler, Noemi Tousignant &
John Manton.
External Investigators/Collaborators: Prosper Chaki, Gerry Killeen
(Ifakara Health Institute, Dar es Salaam, Tanzania); Ruth Prince (Cam-
bridge University, UK); Martha Chinouya (Newcastle University, UK).
Funding Body: Wellcome Trust.
This project studied routine practices and experiences of the lower levels of the urban public health infrastructure in six African cities. This arm of the study took recent efforts to implement a community-based larval control programme in Dar es Salaam as an entry point to examine the geography of civic engagement in a contemporary African city.
Semi-structured interviews were undertaken with VFRs visiting Nigeria and Ghana, malaria patients, nurses, GPs, pharmacists and hospital consultants.
Vector control behaviours were influenced by local envi-ronmental knowledge, a perceived inevitability of contract-ing malaria, and a desire to conform to established methods. Chemoprophylaxis use was influenced by perceptions of susceptibility, previous experiences of malaria, and chang-ing ideas of its seriousness. Peer pressure was also relevant. Structural factors included chemoprophylaxis cost, particu-larly compared with cheaper drugs available in Africa. There was some mistrust of non-African clinicians and beliefs they exaggerated the risk of malaria.
In managing malaria, migrants choose pragmatically be-tween two parallel social and environmental contexts and the structural constraints of each.
Future work includes a quantitative study, health pro-motion messages emphasising the risk amongst VFRs, and enhancing malaria services in the UK.
Drawing from interviews, focus-group discussions, and ethnographic ‘walks’, this project examined the political history and social identity of Community-Owned Resource Persons (CORPs) – local volunteers responsible for the sur-veillance and management of vector habitats. Our research points to the significance of Tanzania’s political history in shaping the CORPs’ understanding of their volunteer role in the project as at once informal workers, community rep-resentatives, and civil servants. The CORPs’ experiences reveal the challenges involved in negotiating these diverse positions; in Dar es Salaam, ‘participation’ is a complex and highly resonant term signifying both self-governance and the provision of free labour. We conclude by considering the im-plications of these understandings for scaling-up larval con-trol to a city-wide programme.
The primaquine study, Uganda.
114 Publications 2010-11
London School of Hygiene & Tropical Medicine
Abilio, A. P., Kleinschmidt, I., Rehman, A.
M., Cuamba, N., Ramdeen, V., Mthembu, D.
S., Coetzer, S., Maharaj, R., Wilding, C. S.,
Steven, A., Coleman, M. & Hemingway, J.
(2011). The emergence of insecticide resis-
tance in central Mozambique and potential
threat to the successful indoor residual spray-
ing malaria control programme. Malar J, 10,
110.
Agnandji, S. T., Asante, K. P., Lyimo, J., Veke-
mans, J., Soulanoudjingar, S. S., Owusu, R.,
Shomari, M., Leach, A., Fernandes, J., Dosoo,
D., Chikawe, M., Issifou, S., Osei-Kwakye, K.,
Lievens, M., Paricek, M., Apanga, S., Mwan-
goka, G., Okissi, B., Kwara, E., Minja, R.,
Lange, J., Boahen, O., Kayan, K., Adjei, G.,
Chandramohan, D., Jongert, E., Demoitie,
M. A., Dubois, M. C., Carter, T., Vansadia, P.,
Villafana, T., Sillman, M., Savarese, B., Lapi-
erre, D., Ballou, W. R., Greenwood, B., Tan-
ner, M., Cohen, J., Kremsner, P. G., Lell, B.,
Owusu-Agyei, S. & Abdulla, S. (2010). Evalu-
ation of the Safety and Immunogenicity of the
RTS,S/AS01(E) Malaria Candidate Vaccine
When Integrated in the Expanded Program of
Immunization. Journal of Infectious Diseases,
202, 1076-1087.
Agnandji, S. T., Lell, B., Soulanoudjingar, S.
S., Fernandes, J. F., Abossolo, B. P., Conzel-
mann, C., Methogo, B. G., Doucka, Y., Fla-
men, A., Mordm?Ller, B., Issifou, S., Krem-
sner, P. G., Sacarlal, J., Aide, P., Lanaspa,
M., Aponte, J. J., Nhamuave, A., Quelhas, D.,
Bassat, Q., Mandjate, S., Macete, E., Alonso,
P., Abdulla, S., Salim, N., Juma, O., Shomari,
M., Shubis, K., Machera, F., Hamad, A. S.,
Minja, R., Mtoro, A., Sykes, A., Ahmed, S.,
Urassa, A. M., Ali, A. M., Mwangoka, G.,
Tanner, M., Tinto, H., D’alessandro, U.,
Sorgho, H., Valea, I., Tahita, M. C., Kabor?,
W., Ou?Draogo, S., Sandrine, Y., Guiguemd?,
R. T., Ou?Draogo, J. B., Hamel, M. J., Kariuki,
S., Odero, C., Oneko, M., Otieno, K., Awino,
N., Omoto, J., Williamson, J., Muturi-Kioi,
V., Laserson, K. F., Slutsker, L., Otieno, W.,
Otieno, L., Nekoye, O., Gondi, S., Otieno,
A., Ogutu, B., Wasuna, R., Owira, V., Jones,
D., Onyango, A. A., Njuguna, P., Chilengi, R.,
Akoo, P., Kerubo, C., Gitaka, J., Maingi, C.,
Lang, T., Olotu, A., Tsofa, B., Bejon, P., Pe-
shu, N., Marsh, K., Owusu-Agyei, S., Asante,
K. P., Osei-Kwakye, K., Boahen, O., Ayamba,
S., Kayan, K., Owusu-Ofori, R., Dosoo, D.,
Asante, I., Adjei, G., Chandramohan, D.,
Greenwood, B., Lusingu, J., Gesase, S., Ma-
labeja, A., Abdul, O., Kilavo, H., Mahende,
C., Liheluka, E., Lemnge, M., Theander, T.,
Drakeley, C., Ansong, D., Agbenyega, T., Ad-
jei, S., Boateng, H. O., Rettig, T., Bawa, J., Syl-
verken, J., Sambian, D., Agyekum, A., Owu-
su, L., Martinson, F., Hoffman, I., Mvalo, T.,
Kamthunzi, P., Nkomo, R., Msika, A., Jumbe,
A., Chome, N., Nyakuipa, D., Chintedza, J.,
Ballou, W. R., Bruls, M., Cohen, J., Guerra, Y.,
Jongert, E., Lapierre, D., Leach, A., Lievens,
M., Ofori-Anyinam, O., Vekemans, J., Carter,
T., Leboulleux, D., Loucq, C., Radford, A.,
Savarese, B., Schellenberg, D., Sillman, M.,
Vansadia, P. & Rts, S. C. T. P., . (2011). First
results of phase 3 trial of RTS,S/AS01 malaria
vaccine in African children. N Engl J Med, 365,
1863-75.
Akpogheneta, O. J., Dunyo, S., Pinder, M. &
Conway, D. J. (2010). Boosting antibody re-
sponses to Plasmodium falciparum merozoite
antigens in children with highly seasonal ex-
posure to infection. Parasite Immunology, 32,
296-304.
Alba, S., Hetzel, M. W., Goodman, C., Dil-
lip, A., Liana, J., Mshinda, H. & Lengeler, C.
(2010). Improvements in access to malaria
treatment in Tanzania after switch to artemis-
inin combination therapy and the introduc-
tion of accredited drug dispensing outlets - a
provider perspective. Malaria Journal, 9.
Alexander, N., Schellenberg, D., Ngasala,
B., Petzold, M., Drakeley, C. & Sutherland,
C. (2010). Assessing agreement between ma-
laria slide density readings. Malar J, 9, 4.
Alonso, D., Bouma, M. J. & Pascual, M.
(2011). Epidemic malaria and warmer tem-
peratures in recent decades in an East African
highland. Proceedings of the Royal Society B-
Biological Sciences, 278, 1661-1669.
Alonso, P. L., Brown, G., Arevalo-Herrera,
M., Binka, F., Chitnis, C., Collins, F., Doumbo,
O. K., Greenwood, B., Hall, B. F., Levine, M.
M., Mendis, K., Newman, R. D., Plowe, C. V.,
Rodr?Guez, M. H., Sinden, R., Slutsker, L.
& Tanner, M. (2011). A research agenda to
underpin malaria eradication. PLoS Med, 8,
e1000406.
Ansah, E. K., Narh-Bana, S., Epokor, M.,
Akanpigbiam, S., Quartey, A. A., Gyapong, J.
& Whitty, C. J. (2010). Rapid testing for ma-
laria in settings where microscopy is available
and peripheral clinics where only presump-
tive treatment is available: a randomised con-
trolled trial in Ghana. BMJ, 340, c930.
Ansong, D., Asante, K. P., Vekemans, J.,
Owusu, S. K., Owusu, R., Brobby, N. A. W.,
Dosoo, D., Osei-Akoto, A., Osei-Kwakye, K.,
Asafo-Adjei, E., Boahen, K. O., Sylverken, J.,
Adjei, G., Sambian, D., Apanga, S., Kayan, K.,
Janssens, M. H., Lievens, M. J. J., Olivier, A.
C., Jongert, E., Dubois, P., Savarese, B. M.,
Cohen, J., Antwi, S., Greenwood, B. M., Ev-
ans, J. A., Agbenyega, T., Moris, P. J. & Owu-
su-Agyei, S. (2011). T Cell Responses to the
RTS,S/AS01(E) and RTS,S/AS02(D) Malaria
Candidate Vaccines Administered According
to Different Schedules to Ghanaian Children.
PLoS ONE, 6.
Armstrong Schellenberg, J. R., Shirima, K.,
Maokola, W., Manzi, F., Mrisho, M., Mushi,
A., Mshinda, H., Alonso, P., Tanner, M. &
Schellenberg, D. M. (2010). Community ef-
fectiveness of intermittent preventive treat-
ment for infants (IPTi) in rural southern Tan-
zania. Am J Trop Med Hyg, 82, 772-81.
Asante, K. P., Abdulla, S., Agnandji, S., Lyi-
mo, J., Vekemans, J., Soulanoudjingar, S.,
Owusu, R., Shomari, M., Leach, A., Jongert,
E., Salim, N., Fernandes, J. F., Dosoo, D.,
Chikawe, M., Issifou, S., Osei-Kwakye, K.,
Lievens, M., Paricek, M., M?Ller, T., Apanga,
S., Mwangoka, G., Dubois, M. C., Madi, T.,
Kwara, E., Minja, R., Hounkpatin, A. B., Boa-
hen, O., Kayan, K., Adjei, G., Chandramohan,
D., Carter, T., Vansadia, P., Sillman, M., Sava-
rese, B., Loucq, C., Lapierre, D., Greenwood,
Tanner, M., Tinto, H., D’alessandro, U., Tanner, M., Tinto, H., D’alessandro, U., Tanner, M., Tinto, H., D’alessandro, U.,
Publications 2010-11 115
Malaria Centre Report 2010-11
B., Cohen, J., Kremsner, P., Owusu-Agyei, S.,
Tanner, M. & Lell, B. (2011). Safety and effi-
cacy of the RTS,S/AS01(E) candidate malaria
vaccine given with expanded-programme-on-
immunisation vaccines: 19 month follow-up
of a randomised, open-label, phase 2 trial.
Lancet Infect Dis.
Ashton, R. A., Kefyalew, T., Tesfaye, G.,
Counihan, H., Yadeta, D., Cundill, B., Re-
ithinger, R. & Kolaczinski, J. H. (2010).
Performance of three multi-species rapid di-
agnostic tests for diagnosis of Plasmodium
falciparum and Plasmodium vivax malaria in
Oromia Regional State, Ethiopia. Malar J, 9,
297.
Ashton, R. A., Kefyalew, T., Tesfaye, G., Pul-
lan, R. L., Yadeta, D., Reithinger, R., Kolac-
zinski, J. H. & Brooker, S. (2011). School-
based surveys of malaria in Oromia Regional
State, Ethiopia: a rapid survey method for
malaria in low transmission settings. Malar J,
10, 25.
Ashton, R. A., Kyabayinze, D. J., Opio, T.,
Auma, A., Edwards, T., Matwale, G., Onapa,
A., Brooker, S. & Kolaczinski, J. H. (2011).
The impact of mass drug administration and
long-lasting insecticidal net distribution on
Wuchereria bancrofti infection in humans and
mosquitoes: an observational study in north-
ern Uganda. Parasit Vectors, 4, 134.
Atun, R., Lazarus, J. V., Van Damme, W. &
Coker, R. (2010). Interactions between criti-
cal health system functions and HIV/AIDS,
tuberculosis and malaria programmes. Health
Policy and Planning, 25, i1-i3.
Auburn, S., Fry, A. E., Clark, T. G., Campino,
S., Diakite, M., Green, A., Richardson, A.,
Jallow, M., Sisay-Joof, F., Pinder, M., Moly-
neux, M. E., Taylor, T. E., Haldar, K., Rockett,
K. A. & Kwiatkowski, D. P. (2010). Further
evidence supporting a role for gs signal trans-
duction in severe malaria pathogenesis. PLoS
ONE, 5, e10017.
Baeza, A., Bouma, M. J., Dobson, A. P., Dhi-
man, R., Srivastava, H. C. & Pascual, M.
(2011). Climate forcing and desert malaria:
the effect of irrigation. Malaria Journal, 10.
Baiden, F., Owusu-Agyei, S., Bawah, J.,
Bruce, J., Tivura, M., Delmini, R., Gyaase,
S., Amenga-Etego, S., Chandramohan, D. &
Webster, J. (2011). An evaluation of the clini-
cal assessments of under-five febrile children
presenting to primary health facilities in rural
ghana. PLoS One, 6, e28944.
Baiden, F., Webster, J., Owusu-Agyei, S. &
Chandramohan, D. (2010). Would rational
use of antibiotics be compromised in the era
of test-based management of malaria? Trop
Med Int Health.
Baker, D. A. (2010)a. Cyclic nucleotide signal-
ling in malaria parasites. Cell Microbiol.
Baker, D. A. (2010b). Malaria Gametocyto-
genesis. Mol Biochem Parasitol.
Baschong, W., Wittlin, S., Inglis, K. A., Fair-
lamb, A. H., Croft, S. L., Kumar, T. R. S., Fi-
dock, D. A. & Brun, R. (2011). Triclosan is
minimally effective in rodent malaria models.
Nature Medicine, 17, 33-34.
Bastiaens, G. J. H., Schaftenaar, E., Ndaro, A.,
Keuter, M., Bousema, T. & Shekalaghe, S. A.
(2011). Malaria diagnostic testing and treat-
ment practices in three different Plasmodium
falciparum transmission settings in Tanzania:
before and after a government policy change.
Malaria Journal, 10.
Batwala, V., Magnussen, P., Hansen, K. S. &
Nuwaha, F. (2011). Cost-effectiveness of ma-
laria microscopy and rapid diagnostic tests
versus presumptive diagnosis: implications
for malaria control in Uganda. Malaria Jour-
nal, 10, 372.
Baum, J., Bousema, T., Dinglasan, R. & Mc-
govern, V. (2011). A Research Agenda for Ma-
laria Eradication: Basic Science and Enabling
Technologies. Plos Medicine, 8.
Behrens, R. H., Carroll, B., Hellgren, U.,
Visser, L. G., Siikam?Ki, H., Vestergaard, L.
S., Calleri, G., J?Nisch, T., Myrvang, B., Gas-
con, J. & Hatz, C. (2010). The incidence of ma-
laria in travellers to South-East Asia: is local
malaria transmission a useful risk indicator?
Malar J, 9, 266.
Bejon, P., Cook, J., Bergmann-Leitner, E.,
Olotu, A., Lusingu, J., Mwacharo, J., Veke-
mans, J., Njuguna, P., Leach, A., Lievens, M.,
Dutta, S., Von Seidlein, L., Savarese, B., Vil-
lafana, T., Lemnge, M. M., Cohen, J., Marsh,
K., Corran, P. H., Angov, E., Riley, E. M. &
Drakeley, C. J. (2011). Effect of the Pre-eryth-
rocytic Candidate Malaria Vaccine RTS,S/
AS01(E) on Blood Stage Immunity in Young
Children. Journal of Infectious Diseases, 204,
9-18.
Bejon, P., Turner, L., Lavstsen, T., Cham, G.,
Olotu, A., Drakeley, C. J., Lievens, M., Veke-
mans, J., Savarese, B., Lusingu, J., Von Se-
idlein, L., Bull, P. C., Marsh, K. & Theander,
T. G. (2011). Serological Evidence of Discrete
Spatial Clusters of Plasmodium falciparum
Parasites. PLoS ONE, 6, e21711.
Beshir, K., Sutherland, C. J., Merinopoulos,
I., Durrani, N., Leslie, T., Rowland, M. & Hal-
lett, R. L. (2010). Amodiaquine resistance in
Plasmodium falciparum malaria is associated
with the pfcrt 72-76 SVMNT allele in Afghani-
stan. Antimicrob Agents Chemother.
Beshir, K. B., Hallett, R. L., Eziefula, A. C.,
Bailey, R., Watson, J., Wright, S. G., Chiodini,
P. L., Polley, S. D. & Sutherland, C. J. (2010).
Measuring the efficacy of anti-malarial drugs
in vivo: quantitative PCR measurement of
parasite clearance. Malar J, 9, 312.
Bhadra, A., Ionides, E. L., Laneri, K., Pas-
cual, M., Bouma, M., Dhiman, R. C. & Ppe,
O. (2011). Malaria in Northwest India: Data
Analysis via Partially Observed Stochastic
Differential Equation Models Driven by Levy
Noise. Journal of the American Statistical As-
sociation, 106, 440-451.
Bojang, K., Akor, F., Bittaye, O., Conway, D.,
Bottomley, C., Milligan, P. & Greenwood, B.
(2010). A randomised trial to compare the
safety, tolerability and efficacy of three drug
combinations for intermittent preventive
treatment in children. PLoS ONE, 5, e11225.
Bojang, K. A., Akor, F., Conteh, L., Webb, E.,
Bittaye, O., Conway, D. J., Jasseh, M., Wise-
man, V., Milligan, P. J. & Greenwood, B.
116 Publications 2010-11
London School of Hygiene & Tropical Medicine
(2011). Two Strategies for the Delivery of
IPTc in an Area of Seasonal Malaria Transmis-
sion in The Gambia: A Randomised Controlled
Trial. PLoS Med, 8, e1000409.
Boulanger, D., Sarr, J. B., Fillol, F., Sokhna,
C., Cisse, B., Schacht, A. M., Trape, J. F.,
Riveau, G., Simondon, F., Greenwood, B. &
Remou?, F. (2010). Immunological conse-
quences of intermittent preventive treatment
against malaria in Senegalese preschool chil-
dren. Malar J, 9, 363.
Bouma, M. J., Baeza, A., Terveen, A. & Pas-
cual, M. (2011). Global malaria maps and
climate change: a focus on East African high-
lands. Trends Parasitol.
Bousema, T. & Drakeley, C. (2011). Epide-
miology and Infectivity of Plasmodium falci-
parum and Plasmodium vivax Gametocytes in
Relation to Malaria Control and Elimination.
Clin Microbiol Rev, 24, 377-410.
Bousema, T., Drakeley, C., Gesase, S.,
Hashim, R., Magesa, S., Mosha, F., Otieno, S.,
Carneiro, I., Cox, J., Msuya, E., Kleinschmidt,
I., Maxwell, C., Greenwood, B., Riley, E., Sau-
erwein, R., Chandramohan, D. & Gosling, R.
(2010). Identification of Hot Spots of Malaria
Transmission for Targeted Malaria Control. J
Infect Dis, 201, 1764-74.
Bousema, T., Kreuels, B. & Gosling, R.
(2011). Adjusting for heterogeneity of ma-
laria transmission in longitudinal studies. J
Infect Dis, 204, 1-3.
Bousema, T., Okell, L., Shekalaghe, S., Grif-
�in, J. T., Omar, S., Sawa, P., Sutherland, C.,
Sauerwein, R., Ghani, A. C. & Drakeley, C.
(2010). Revisiting the circulation time of Plas-
modium falciparum gametocytes: molecular
detection methods to estimate the duration of
gametocyte carriage and the effect of gameto-
cytocidal drugs. Malar J, 9, 136.
Bousema, T., Roeffen, W., Meijerink, H.,
Mwerinde, H., Mwakalinga, S., Van Gemert,
G. J., Van De Vegte-Bolmer, M., Mosha, F.,
Targett, G., Riley, E. M., Sauerwein, R. &
Drakeley, C. (2010). The Dynamics of Natu-
rally Acquired Immune Responses to Plas-
modium falciparum Sexual Stage Antigens
Pfs230 & Pfs48/45 in a Low Endemic Area in
Tanzania. PLoS ONE, 5, e14114.
Bousema, T., Sutherland, C. J., Churcher, T.
S., Mulder, B., Gouagna, L. C., Riley, E. M.,
Targett, G. A. & Drakeley, C. J. (2010). Hu-
man immune responses that reduce the trans-
mission of Plasmodium falciparum in African
populations. Int J Parasitol.
Bousema, T., Youssef, R. M., Cook, J., Cox, J.,
Alegana, V. A., Amran, J., Noor, A. M., Snow,
R. W. & Drakeley, C. (2010). Serologic mark-
ers for detecting malaria in areas of low en-
demicity, somalia, 2008. Emerg Infect Dis, 16,
392-9.
Bowyer, P. W., Simon, G. M., Cravatt, B. F.
& Bogyo, M. (2011). Global profiling of pro-
teolysis during rupture of Plasmodium fal-
ciparum from the host erythrocyte. Mol Cell
Proteomics, 10, M110.001636.
Boyle, M. J., Wilson, D. W., Richards, J. S.,
Riglar, D. T., Tetteh, K. K. A., Conway, D. J.,
Ralph, S. A., Baum, J. & Beeson, J. G. (2010).
Isolation of viable Plasmodium falciparum
merozoites to define erythrocyte invasion
events and advance vaccine and drug develop-
ment. Proceedings of the National Academy of
Sciences of the United States of America, 107,
14378-14383.
Bretscher, M. T., Maire, N., Chitnis, N., Fel-
ger, I., Owusu-Agyei, S. & Smith, T. (2011).
The distribution of Plasmodium falciparum
infection durations. Epidemics, 3, 109-18.
Briet, O., N’guessan, R., Hardy, D., Chitnis,
N. & Rowland, M. (2011). Epidemiological
effectiveness of insecticide treated nets in the
presence of pyrethroid resistance. In: Tropi-
cal Medicine & International Health, Oct 140-
140.
Brooker, S., Okello, G., Njagi, K., Dubeck,
M. M., Halliday, K. E., Inyega, H. & Jukes, M.
C. H. (2010). Improving educational achieve-
ment and anaemia of school children: design
of a cluster randomised trial of school-based
malaria prevention and enhanced literacy in-
struction in Kenya. Trials, 11, 93.
Cairns, M., Cisse, B., Sokhna, C., Cames, C.,
Simondon, K., Ba, E. H., Trape, J. F., Gaye, O.,
Greenwood, B. M. & Milligan, P. J. (2010).
Amodiaquine dosage and tolerability for in-
termittent preventive treatment to prevent
malaria in children. Antimicrob Agents Che-
mother.
Cairns, M., Ghani, A., Okell, L., Gosling, R.,
Carneiro, I., Anto, F., Asoala, V., Owusu-
Agyei, S., Greenwood, B., Chandramohan,
D. & Milligan, P. (2011). Modelling the pro-
tective efficacy of alternative delivery sched-
ules for intermittent preventive treatment of
malaria in infants and children. PLoS ONE, 6,
e18947.
Cairns, M., Gosling, R., Carneiro, I., Ge-
sase, S., Mosha, J. F., Hashim, R., Kaur, H.,
Lemnge, M., Mosha, F. W., Greenwood, B.
& Chandramohan, D. (2010). Duration of
protection against clinical malaria provided
by three regimens of intermittent preventive
treatment in tanzanian infants. PLoS ONE, 5,
e9467.
Calleri, G., Behrens, R. H., Schmid, M. L.,
Gobbi, F., Grobusch, M. P., Castelli, F., Gas-
con, J., Bisof�i, Z., Jelinek, T. & Caramello,
P. (2011). Malaria chemoprophylaxis recom-
mendations for immigrants to Europe, visit-
ing relatives and friends - a Delphi method
study. Malar J, 10, 137.
Campino, S., Auburn, S., Kivinen, K., Zongo,
I., Ouedraogo, J. B., Mangano, V., Djimde, A.,
Doumbo, O. K., Kiara, S. M., Nzila, A., Bor-
rmann, S., Marsh, K., Michon, P., Mueller, I.,
Siba, P., Jiang, H. Y., Su, X. Z., Amaratunga,
C., Socheat, D., Fairhurst, R. M., Imwong, M.,
Anderson, T., Nosten, F., White, N. J., Gwil-
liam, R., Deloukas, P., Macinnis, B., New-
bold, C. I., Rockett, K., Clark, T. G. & Kwi-
atkowski, D. P. (2011). Population Genetic
Analysis of Plasmodium falciparum Parasites
Using a Customized Illumina GoldenGate Ge-
notyping Assay. PLoS ONE, 6.
Publications 2010-11 117
Malaria Centre Report 2010-11
Caputo, B., Santolamazza, F., Vicente, J. L.,
Nwakanma, D. C., Jawara, M., Palsson, K.,
Jaenson, T., White, B. J., Mancini, E., Petrar-
ca, V., Conway, D. J., Besansky, N. J., Pinto, J.
& Della Torre, A. (2011). The “far-west” of
Anopheles gambiae molecular forms. PLoS
One, 6, e16415.
Carlson, M., Smith Paintain, L., Bruce, J.,
Webster, J. & Lines, J. (2011). Who attends
antenatal care and expanded programme on
immunization services in Chad, Mali and Ni-
ger? the implications for insecticide-treated
net delivery. Malar J, 10, 341.
Carneiro, I., Roca-Feltrer, A., Grif�in, J. T.,
Smith, L., Tanner, M., Schellenberg, J. A.,
Greenwood, B. & Schellenberg, D. (2010).
Age-patterns of malaria vary with sever-
ity, transmission intensity and seasonality in
sub-saharan Africa: a systematic review and
pooled analysis. PLoS ONE, 5, e8988.
Carneiro, I., Smith, L., Ross, A., Roca-Fel-
trer, A., Greenwood, B., Schellenberg, J.
A., Smith, T. & Schellenberg, D. (2010). In-
termittent preventive treatment for malaria
in infants: a decision-support tool for sub-
Saharan Africa. Bull World Health Organ, 88,
807-14.
Cathcart, S. J., Lawrence, J., Grant, A., Quinn,
D., Whitty, C. J. M., Jones, J., Chiodini, P. L.
& Fraser, G. (2010). Estimating unreported
malaria cases in England: a capture-recapture
study. Epidemiology and Infection, 138, 1052-
1058.
Ceesay, S. J., Casals-Pascual, C., Nwakan-
ma, D. C., Walther, M., Gomez-Escobar,
N., Fulford, A. J., Takem, E. N., Nogaro, S.,
Bojang, K. A., Corrah, T., Jaye, M. C., Taal,
M. A., Sonko, A. A. & Conway, D. J. (2010).
Continued decline of malaria in The Gambia
with implications for elimination. PLoS ONE,
5, e12242.
Chaccour, C., Lines, J. & Whitty, C. J. (2010).
Effect of Ivermectin on Anopheles gambiae
Mosquitoes Fed on Humans: The Potential of
Oral Insecticides in Malaria Control. J Infect
Dis.
Chaki, P. P., Dongus, S., Fillinger, U., Kelly,
A. & Killeen, G. F. (2011). Community-owned
resource persons for malaria vector control:
enabling factors and challenges in an opera-
tional programme in Dar es Salaam, United
Republic of Tanzania. HUMAN RESOURCES
FOR HEALTH, 9.
Chanda, E., Hemingway, J., Kleinschmidt,
I., Rehman, A. M., Ramdeen, V., Phiri, F.
N., Coetzer, S., Mthembu, D., Shinondo, C.
J., Chizema-Kawesha, E., Kamuliwo, M.,
Mukonka, V., Baboo, K. S. & Coleman, M.
(2011). Insecticide Resistance and the Future
of Malaria Control in Zambia. PLoS ONE, 6.
Chandler, C. I., Hall-Clifford, R., Asaph, T.,
Pascal, M., Clarke, S. & Mbonye, A. K. (2011).
Introducing malaria rapid diagnostic tests at
registered drug shops in Uganda: Limitations
of diagnostic testing in the reality of diagno-
sis. Soc Sci Med.
Chandler, C. I., Whitty, C. J. & Ansah, E. K.
(2010). How can malaria rapid diagnostic
tests achieve their potential? A qualitative
study of a trial at health facilities in Ghana.
Malar J, 9, 95.
Chandre, F., Dabire, R. K., Hougard, J. M.,
Djogbenou, L. S., Irish, S. R., Rowland, M. &
N’guessan, R. (2010). Field efficacy of pyre-
throid treated plastic sheeting (durable lin-
ing) in combination with long lasting insecti-
cidal nets against malaria vectors. Parasites &
Vectors, 3.
Chellan, P., Nasser, S., Vivas, L., Chibale, K. &
Smith, G. S. (2010). Cyclopalladated complex-
es containing tridentate thiosemicarbazone
ligands of biological significance: Synthesis,
structure and antimalarial activity. Journal of
Organometallic Chemistry, 695, 2225-2232.
Chico, R. M. & Chandramohan, D. (2010).
Quinine for the treatment of malaria in preg-
nancy. Lancet Infect Dis, 10, 140-1.
Chico, R. M. & Chandramohan, D. (2011a).
Azithromycin plus chloroquine: combination
therapy for protection against malaria and
sexually transmitted infections in pregnancy.
Expert Opin Drug Metab Toxicol.
Chico, R. M. & Chandramohan, D. (2011b).
Intermittent preventive treatment of ma-
laria in pregnancy: at the crossroads of pub-
lic health policy. Trop Med Int Health, 16,
774?785.
Clements, A. C. A., Deville, M. A., Ndayishi-
miye, O., Brooker, S. & Fenwick, A. (2010).
Spatial co-distribution of neglected tropical
diseases in the East African Great Lakes re-
gion: revisiting the justification for integrated
control. Tropical Medicine & International
Health, 15, 198-207.
Cohen, J. M., Sabot, O., Sabot, K., Gordon,
M., Gross, I., Bishop, D., Odhiambo, M.,
Ipuge, Y., Ward, L., Mwita, A. & Goodman, C.
(2010). A pharmacy too far? Equity and spa-
tial distribution of outcomes in the delivery
of subsidized artemisinin-based combination
therapies through private drug shops. BMC
Health Services Research, 10.
Conteh, L., Patouillard, E., Kweku, M., Le-
good, R., Greenwood, B. & Chandramohan,
D. (2010). Cost effectiveness of seasonal in-
termittent preventive treatment using amo-
diaquine & artesunate or sulphadoxine-pyri-
methamine in ghanaian children. PLoS ONE,
5.
Conteh, L., Sicuri, E., Manzi, F., Hutton, G.,
Obonyo, B., Tediosi, F., Biao, P., Masika, P.,
Matovu, F., Otieno, P., Gosling, R. D., Hamel,
M., Odhiambo, F. O., Grobusch, M. P., Krem-
sner, P. G., Chandramohan, D., Aponte, J.
J., Egan, A., Schellenberg, D., Macete, E.,
Slutsker, L., Newman, R. D., Alonso, P.,
Men?Ndez, C. & Tanner, M. (2010). The cost-
effectiveness of intermittent preventive treat-
ment for malaria in infants in Sub-Saharan
Africa. PLoS ONE, 5, e10313.
Conteh, L. & Yeung, S. (2011). Assessing the
cost-effectiveness of prereferral rectal arte-
sunate for treatment of severe childhood ma-
laria. Expert Review of Pharmacoeconomics &
Outcomes Research, 11, 141-145.
118 Publications 2010-11
London School of Hygiene & Tropical Medicine
Cook, J., Kleinschmidt, I., Schwabe, C.,
Nseng, G., Bousema, T., Corran, P. H., Ri-
ley, E. M. & Drakeley, C. J. (2011). Serologi-
cal markers suggest heterogeneity of effec-
tiveness of malaria control interventions on
bioko island, equatorial Guinea. PLoS ONE, 6,
e25137.
Cook, J., Reid, H., Iavro, J., Kuwahata, M.,
Taleo, G., Clements, A., Mccarthy, J., Val-
lely, A. & Drakeley, C. (2010). Using serologi-
cal measures to monitor changes in malaria
transmission in Vanuatu. Malaria Journal, 9.
Cook, J. I., Majeed, S., Ignell, R., Pickett, J. A.,
Birkett, M. A. & Logan, J. G. (2011). Enantio-
meric selectivity in behavioural and electro-
physiological responses of Aedes aegypti and
Culex quinquefasciatus mosquitoes. Bulletin
of Entomological Research, 101, 541-550.
Corredor, V., Murillo, C., Echeverry, D.
F., Benavides, J., Pearce, R. J., Roper, C.,
Guerra, A. P. & Osorio, L. (2010). Origin
and dissemination across Colombian Andes
mountain range of Plasmodium falciparum
Sulfadoxine-Pyrimethamine resistance. Anti-
microb Agents Chemother.
Couper, K. N., Barnes, T., Hafalla, J. C.,
Combes, V., Ryffel, B., Secher, T., Grau, G. E.,
Riley, E. M. & De Souza, J. B. (2010). Parasite-
Derived Plasma Microparticles Contribute
Significantly to Malaria Infection-Induced
Inflammation through Potent Macrophage
Stimulation. PLoS Pathog, 6, e1000744.
Cox, F. E. (2010). History of the discovery of
the malaria parasites and their vectors. Para-
sit Vectors, 3, 5.
Cunnington, A. J., De Souza, J. B., Walther,
M. & Riley, E. M. (2011). Malaria impairs
resistance to Salmonella through heme- and
heme oxygenase-dependent dysfunctional
granulocyte mobilization. Nat Med.
Cunnington, A. J. & Riley, E. M. (2010). Sup-
pression of vaccine responses by malaria:
insignificant or overlooked? Expert Rev Vac-
cines, 9, 409-29.
Damiani, C., Ricci, I., Crotti, E., Rossi, P.,
Rizzi, A., Scuppa, P., Capone, A., Ulissi,
U., Epis, S., Genchi, M., Sagnon, N., Faye,
I., Kang, A., Chouaia, B., Whitehorn, C.,
Moussa, G. W., Mandrioli, M., Esposito, F.,
Sacchi, L., Bandi, C., Daffonchio, D. & Favia,
G. (2010). Mosquito-Bacteria Symbiosis: The
Case of Anopheles gambiae and Asaia. Micro-
bial Ecology, 60, 644-654.
De Souza, J. B., Okomo, U., Alexander, N. D.,
Aziz, N., Owens, B. M., Kaur, H., Jasseh, M.,
Muangnoicharoen, S., Sumariwalla, P. F.,
Warhurst, D. C., Ward, S. A., Conway, D. J.,
Ulloa, L., Tracey, K. J., Foxwell, B. M., Kaye,
P. M. & Walther, M. (2010). Oral activated
charcoal prevents experimental cerebral ma-
laria in mice and in a randomized controlled
clinical trial in man did not interfere with the
pharmacokinetics of parenteral artesunate.
PLoS ONE, 5, e9867.
De Souza, J. B., Runglall, M., Corran, P. H.,
Okell, L. C., Kumar, S., Gowda, D. C., Couper,
K. N. & Riley, E. M. (2010). Neutralization of
malaria GPI in vitro by serum IgG from malar-
ia exposed individuals. Infect Immun.
Dery, D. B., Brown, C., Asante, K. P., Adams,
M., Dosoo, D., Amenga-Etego, S., Wilson,
M., Chandramohan, D., Greenwood, B. &
Owusu-Agyei, S. (2010). Patterns and sea-
sonality of malaria transmission in the forest-
savannah transitional zones of Ghana. Malar
J, 9, 314.
Dessens, J. T., Saeed, S., Tremp, A. Z. & Cart-
er, V. (2011). Malaria crystalloids: specialized
structures for parasite transmission? Trends
Parasitol, 27, 106-10.
Diagnoses, M. C. G. O., Diagnostics & Schel-
lenberg, D. (2011). A research agenda for
malaria eradication: diagnoses and diagnos-
tics. PLoS Med, 8, e1000396.
Dicko, A., Barry, A., Dicko, M., Diallo, A. I.,
Tembine, I., Dicko, Y., Dara, N., Sidibe, Y.,
Santara, G., Conare, T., Chandramohan,
D., Cousens, S., Milligan, P. J., Diallo, D. A.,
Doumbo, O. K. & Greenwood, B. (2011). Ma-
laria Morbidity in Children in the Year after
They Had Received Intermittent Preventive
Treatment of Malaria in Mali: A Randomized
Control Trial. PLoS ONE, 6.
Dicko, A., Diallo, A. I., Tembine, I., Dicko,
Y., Dara, N., Sidibe, Y., Santara, G., Diawara,
H., Conar?, T., Djimde, A., Chandramohan,
D., Cousens, S., Milligan, P. J., Diallo, D. A.,
Doumbo, O. K. & Greenwood, B. (2011).
Intermittent Preventive Treatment of Ma-
laria Provides Substantial Protection against
Malaria in Children Already Protected by an
Insecticide-Treated Bednet in Mali: A Ran-
domised, Double-Blind, Placebo-Controlled
Trial. PLoS Med, 8, e1000407.
Dlamini, S. V., Beshir, K. & Sutherland, C. J.
(2010). Markers of anti-malarial drug resis-
tance in Plasmodium falciparum isolates from
Swaziland: identification of pfmdr1-86F in
natural parasite isolates. Malar J, 9, 68.
Dodoo, D., Atuguba, F., Bosomprah, S., An-
sah, N. A., Ansah, P., Lamptey, H., Egyir, B.,
Oduro, A. R., Gyan, B., Hodgson, A. & Koram,
K. A. (2011). Antibody levels to multiple ma-
laria vaccine candidate antigens in relation
to clinical malaria episodes in children in the
Kasena-Nankana district of Northern Ghana.
Malar J, 10, 108.
Dondorp, A. M., Fanello, C. I., Hendriksen, I.
C., Gomes, E., Seni, A., Chhaganlal, K. D., Bo-
jang, K., Olaosebikan, R., Anunobi, N., Mait-
land, K., Kivaya, E., Agbenyega, T., Nguah, S.
B., Evans, J., Gesase, S., Kahabuka, C., Mtove,
G., Nadjm, B., Deen, J., Mwanga-Amump-
aire, J., Nansumba, M., Karema, C., Umulisa,
N., Uwimana, A., Mokuolu, O. A., Adedoyin,
O. T., Johnson, W. B., Tshefu, A. K., Onyam-
boko, M. A., Sakulthaew, T., Ngum, W. P.,
Silamut, K., Stepniewska, K., Woodrow, C.
J., Bethell, D., Wills, B., Oneko, M., Peto, T.
E., Von Seidlein, L., Day, N. P., White, N. J. &
Aquamat Group (2010). Artesunate versus
quinine in the treatment of severe falciparum
malaria in African children (AQUAMAT): an
open-label, randomised trial. Lancet, 376,
1647-57.
Publications 2010-11 119
Malaria Centre Report 2010-11
Dondorp, A. M., Yeung, S., White, L., Nguon,
C., Day, N. P., Socheat, D. & Von Seidlein, L.
(2010). Artemisinin resistance: current status
and scenarios for containment. Nat Rev Mi-
crobiol, 8, 272-80.
Drake, T. L., Okello, G., Njagi, K., Halliday, K.
E., Jukes, M. C. H., Mangham, L. & Brooker,
S. (2011). Cost analysis of school-based inter-
mittent screening and treatment of malaria in
Kenya. Malar J, 10, 273.
Duah, N. O., Miles, D. J., Whittle, H. C. & Con-
way, D. J. (2010). Acquisition of antibody iso-
types against Plasmodium falciparum blood
stage antigens in a birth cohort. Parasite Im-
munol, 32, 125-34.
Dunyo, S., Sirugo, G., Sesay, S., Bisseye, C.,
Njie, F., Adiamoh, M., Nwakanma, D., Diatta,
M., Janha, R., Joof, F. S., Temple, B., Snell, P.,
Conway, D., Walton, R., Cheung, Y. B. & Mil-
ligan, P. (2011). Randomized Trial of Safety
and Effectiveness of Chlorproguanil-Dapsone
and Lumefantrine-Artemether for Uncompli-
cated Malaria in Children in The Gambia. PLoS
ONE, 6.
Dvorin, J. D., Martyn, D. C., Patel, S. D., Grim-
ley, J. S., Collins, C. R., Hopp, C. S., Bright, A.
T., Westenberger, S., Winzeler, E., Black-
man, M. J., Baker, D. A., Wandless, T. J. &
Duraisingh, M. T. (2010). A plant-like kinase
in Plasmodium falciparum regulates parasite
egress from erythrocytes. Science, 328, 910-2.
Evans, J. H., Horowitz, A., Mehrabi, M., Wise,
E. L., Pease, J. E., Riley, E. M. & Davis, D. M.
(2011). A distinct subset of human NK cells
expressing HLA-DR expand in response to
IL-2 and can aid immune responses to BCG.
European Journal of Immunology, 41, 1924-
1933.
Ewing, V. L., Lalloo, D. G., Phiri, K. S., Roca-
Feltrer, A., Mangham, L. J. & Sanjoaquin, M.
A. (2011). Seasonal and geographic differenc-
es in treatment-seeking and household cost
of febrile illness among children in Malawi.
Malaria Journal, 10.
Farenhorst, M., Knols, B. G. J., Thomas, M.
B., Howard, A. F. V., Takken, W., Rowland, M.
& N’guessan, R. (2010). Synergy in Efficacy
of Fungal Entomopathogens and Permethrin
against West African Insecticide-Resistant
Anopheles gambiae Mosquitoes. PLoS ONE, 5.
Feachem, R. G. A., Phillips, A. A., Hwang, J.,
Cotter, C., Wielgosz, B., Greenwood, B. M.,
Sabot, O., Rodriguez, M. H., Abeyasinghe, R.
R., Ghebreyesus, T. A. & Snow, R. W. (2010).
Malaria Elimination 1 Shrinking the malaria
map: progress and prospects. Lancet, 376,
1566-1578.
Feachem, R. G. A., Phillips, A. A., Targett, G.
A. & Snow, R. W. (2010). Call to action: pri-
orities for malaria elimination. Lancet, 376,
1517-1521.
Fillinger, U. & Lindsay, S. W. (2011). Larval
source management for malaria control in Af-
rica: myths and reality. Malar J, 10, 353.
Findlay, E. G., Greig, R., Stumhofer, J. S., Ha-
falla, J. C. R., De Souza, J. B., Saris, C. J., Hunt-
er, C. A., Riley, E. M. & Couper, K. N. (2010).
Essential Role for IL-27 Receptor Signaling in
Prevention of Th1-Mediated Immunopathol-
ogy during Malaria Infection. Journal of Im-
munology, 185, 2482-2492.
Finney, O. C., Riley, E. M. & Walther, M.
(2010). Regulatory T cells in malaria - friend
or foe? Trends Immunol.
Fitchett, J. R. & Cooke, M. K. (2010). Geneti-
cally engineered parasites: the solution to de-
signing an effective malaria vaccine? Trends
Parasitol.
Friesen, J., Silvie, O., Putrianti, E. D., Ha-
falla, J. C., Matuschewski, K. & Borrmann,
S. (2010). Natural immunization against ma-
laria: causal prophylaxis with antibiotics. Sci
Transl Med, 2, 40ra49.
Gadalla, N. B., Adam, I., Elzaki, S. E., Bashir,
S., Mukhtar, I., Oguike, M., Gadalla, A.,
Mansour, F., Warhurst, D., El-Sayed, B. B.
& Sutherland, C. J. (2011). Increased pfm-
dr1 copy number and sequence polymor-
phisms in Plasmodium falciparum isolates
from Sudanese malaria patients treated with
artemether-lumefantrine. Antimicrob Agents
Chemother, 55, 5408-11.
Gadalla, N. B., Elzaki, S. E., Mukhtar, E., War-
hurst, D. C., El-Sayed, B. & Sutherland, C. J.
(2010). Dynamics of pfcrt alleles CVMNK and
CVIET in chloroquine-treated Sudanese pa-
tients infected with Plasmodium falciparum.
Malar J, 9, 74.
Garbash, M., Round, J., Whitty, C. J., Chiodi-
ni, P. L., Riordan, F. A., Shingadia, D. & Lad-
hani, S. (2010). Intensive care admissions for
children with imported malaria in the united
kingdom. Pediatr Infect Dis J, 29, 1140-1142.
Garcia-Basteiro, A. L., Schwabe, C., Ara-
gon, C., Baltazar, G., Rehman, A., Matias, A.,
Nseng, G. & Kleinschmidt, I. (2011a). Fac-
tors influencing bed net use in children un-
der five and household bed net ownership on
Bioko island, Equatorial Guinea. In: Tropical
Medicine & International Health, 142-142.
Garcia-Basteiro, A. L., Schwabe, C., Aragon,
C., Baltazar, G., Rehman, A. M., Matias, A.,
Nchama, G. N. & Kleinschmidt, I. (2011).
Determinants of bed net usage in children
under 5 and household bed net ownership in
Bioko island, Equatorial Guinea. In: Journal of
Epidemiology and Community Health, A333-
A333.
Garcia-Basteiro, A. L., Schwabe, C., Aragon,
C., Baltazar, G., Rehman, A. M., Matias, A.,
Nseng, G. & Kleinschmidt, I. (2011b)b. De-
terminants of bed net use in children under
five and household bed net ownership on
Bioko Island, Equatorial Guinea. Malaria Jour-
nal, 10.
Gingrich, C. D., Hanson, K., Marchant, T.,
Mulligan, J. A. & Mponda, H. (2011). Price
subsidies and the market for mosquito nets
in developing countries: A study of Tanzania’s
discount voucher scheme. Social Science &
Medicine, 73, 160-168.
Gingrich, C. D., Hanson, K. G., Marchant,
T. J., Mulligan, J. A. & Mponda, H. (2010).
Household demand for insecticide-treated
120 Publications 2010-11
London School of Hygiene & Tropical Medicine
bednets in Tanzania and policy options for in-
creasing uptake. Health Policy Plan.
Gitonga, C. W., Karanja, P. N., Kihara, J.,
Mwanje, M., Juma, E., Snow, R. W., Noor, A.
M. & Brooker, S. (2010). Implementing school
malaria surveys in Kenya: towards a national
surveillance system. Malar J, 9, 306.
Gomez-Escobar, N., Amambua-Ngwa, A.,
Walther, M., Okebe, J., Ebonyi, A. & Conway,
D. J. (2010). Erythrocyte Invasion and Merozo-
ite Ligand Gene Expression in Severe and Mild
Plasmodium falciparum Malaria. Journal of In-
fectious Diseases, 201, 444-452.
Gosling, R. D., Cairns, M. E., Chico, R. M. &
Chandramohan, D. (2010). Intermittent pre-
ventive treatment against malaria: an update.
Expert Rev Anti Infect Ther, 8, 589-606.
Gosling, R. D., Okell, L., Mosha, J. & Chan-
dramohan, D. (2011). The role of antimalarial
treatment in the elimination of malaria. Clin
Microbiol Infect.
Greenwood, B. (2010). Anti-malarial drugs
and the prevention of malaria in the population
of malaria endemic areas. Malar J, 9 Suppl 3, S2.
Greenwood, B. (2011). Immunological corre-
lates of protection for the RTS,S candidate ma-
laria vaccine. Lancet Infect Dis.
Greenwood, B., Bojang, K., Tagbor, H. & Pa-
gnoni, F. (2011). Combining community case
management and intermittent preventive treat-
ment for malaria. Trends Parasitol.
Greenwood, B. & Targett, G. (2011a). The
mysteries of immunity to malaria. Lancet.
Greenwood, B. M. & Targett, G. A. (2011b).
Malaria vaccines and the new malaria agenda.
Clin Microbiol Infect.
Grif�in, J. T., Cairns, M., Ghani, A. C., Roper, C.,
Schellenberg, D., Carneiro, I., Newman, R. D.,
Grobusch, M. P., Greenwood, B., Chandramo-
han, D. & Gosling, R. D. (2010). Protective
efficacy of intermittent preventive treatment
of malaria in infants (IPTi) using sulfadoxine-
pyrimethamine and parasite resistance. PLoS
ONE, 5, e12618.
Grif�in, J. T., Hollingsworth, T. D., Okell, L.
C., Churcher, T. S., White, M., Hinsley, W.,
Bousema, T., Drakeley, C. J., Ferguson, N. M.,
Basanez, M. G. & Ghani, A. C. (2010). Reducing
Plasmodium falciparum Malaria Transmission
in Africa: A Model-Based Evaluation of Inter-
vention Strategies. Plos Medicine, 7.
Gross, K., Alba, S., Schellenberg, J., Kessy, F.,
Mayumana, I. & Obrist, B. (2011). The com-
bined effect of determinants on coverage of
intermittent preventive treatment of malaria
during pregnancy in the Kilombero Valley, Tan-
zania. Malaria Journal, 10.
Hafalla, J. C., Burgold, J., Dorhoi, A., Gross, O.,
Ruland, J., Kaufmann, S. H. & Matuschewski,
K. (2011). Experimental cerebral malaria de-
velops independently of Card9 signalling. Infect
Immun.
Hafalla, J. C., Silvie, O. & Matuschewski, K.
(2011). Cell biology and immunology of ma-
laria. Immunol Rev, 240, 297-316.
Hendriksen, I. C. E., Mtove, G., Pedro, A. J.,
Gomes, E., Silamut, K., Lee, S. J., Mwam-
buli, A., Gesase, S., Reyburn, H., Day, N. P. J.,
White, N. J., Von Seidlein, L. & Dondorp, A. M.
(2011). Evaluation of a PfHRP(2) and a pLDH-
based Rapid Diagnostic Test for the Diagnosis
of Severe Malaria in 2 Populations of African
Children. Clinical Infectious Diseases, 52, 1100-
1107.
Hensen, B., Paintain, L. S., Shretta, R., Bruce,
J., Jones, C. & Webster, J. (2011). Taking stock:
provider prescribing practices in the presence
and absence of ACT stock. Malar J, 10, 218.
Horowitz, A., Behrens, R. H., Okell, L., Fooks,
A. R. & Riley, E. M. (2010). NK Cells as Effectors
of Acquired Immune Responses: Effector CD4+
T Cell-Dependent Activation of NK Cells Follow-
ing Vaccination. J Immunol.
Horowitz, A., Newman, K. C., Evans, J. H., Ko-
rbel, D. S., Davis, D. M. & Riley, E. M. (2010).
Cross-Talk between T Cells and NK Cells Gener-
ates Rapid Effector Responses to Plasmodium
falciparum-Infected Erythrocytes. J Immunol.
Howard, A. F. V., N’guessan, R., Koenraadt,
C. J. M., Asidi, A., Farenhorst, M., Akogbeto,
M., Knols, B. G. J. & Takken, W. (2011). First
report of the infection of insecticide-resistant
malaria vector mosquitoes with an entomo-
pathogenic fungus under field conditions. Ma-
laria Journal, 10.
Howard, A. F. V., N’guessan, R., Koenraadt, C.
J. M., Asidi, A., Farenhorst, M., Akogbeto, M.,
Thomas, M. B., Knols, B. G. J. & Takken, W.
(2010). The entomopathogenic fungus Beau-
veria bassiana reduces instantaneous blood
feeding in wild multi-insecticide-resistant Cu-
lex quinquefasciatus mosquitoes in Benin, West
Africa. Parasites & Vectors, 3.
Howard, N., Durrani, N., Sanda, S., Beshir, K.,
Hallett, R. & Rowland, M. (2011). Clinical trial
of extended-dose chloroquine for treatment
of resistant falciparum malaria among Afghan
refugees in Pakistan. Malar J, 10, 171.
Howard, N., Sha�i, A., Jones, C. & Rowland,
M. (2010). Malaria control under the Taliban
regime: insecticide-treated net purchasing,
coverage, and usage among men and women in
eastern Afghanistan. Malar J, 9, 7.
Imbahale, S. S., Fillinger, U., Githeko, A., Muk-
abana, W. R. & Takken, W. (2010). An explor-
atory survey of malaria prevalence and people’s
knowledge, attitudes and practices of mosquito
larval source management for malaria control
in western Kenya. Acta Tropica, 115, 248-256.
Jawara, M., Awolola, T. S., Pinder, M., Jeffries,
D., Smallegange, R. C., Takken, W. & Conway,
D. J. (2011). Field testing of different chemi-
cal combinations as odour baits for trapping
wild mosquitoes in the gambia. PLoS ONE, 6,
e19676.
Juliano, J. J., Gadalla, N., Sutherland, C. J.
& Meshnick, S. R. (2010). The perils of PCR:
can we accurately ‘correct’ antimalarial trials?
Trends Parasitol, 26, 119-24.
Kangwana, B., Kedenge, S., Alegana, V., Noor,
A., Fegan, G., Brooker, S., Todd, J., Snow,
R., Goodman, C., Nyandigisi, A. & Pandit, J.
(2011). The impact of retail-sector delivery of
Publications 2010-11 121
Malaria Centre Report 2010-11
artemether-lumefantrine on malaria treatment
of children under five in Kenya: cluster random-
ized controlled trial. In: Tropical Medicine & In-
ternational Health. 132-132.
Kangwana, B. P., Kedenge, S. V., Noor, A. M.,
Alegana, V. A., Nyandigisi, A. J., Pandit, J., Fe-
gan, G. W., Todd, J. E., Brooker, S., Snow, R. W.
& Goodman, C. A. (2011). The Impact of Retail-
Sector Delivery of Artemether-Lumefantrine
on Malaria Treatment of Children under Five in
Kenya: A Cluster Randomized Controlled Trial.
Plos Medicine, 8.
Kariuki, S. M., Rockett, K., Clark, T. G., Rey-
burn, H., Agbenyega, T., Taylor, T. E., Wil-
liams, T. N. & Newton, C. R. (2011). Human
genetic polymorphisms and the risk of malaria-
associated seizures in African populations. Epi-
lepsia, 52, 92-92.
Kaur, H., Green, M. D., Hostetler, D. M., Fern,
Ndez, F. M. & Newton, P. N. (2010). Antima-
larial drug quality: methods to detect suspect
drugs. Therapy, 7, 49-57.
Kelly, A. (2011a). Entomological Extensions:
Model Huts and Fieldworks. In: JEANETTE, E. &
MAJA, P.-S. (eds.) Recombinant Knowledge: Or
How Strathernian concepts travel. Cambridge
University Press.
Kelly, A. H. (2011b). Will He Be There?: Mediat-
ing malaria, immobilizing science. J Cult Econ,
4, 65-79.
Kelly, A. H. & Beisel, U. (2011). Neglected ma-
larias: The frontlines and back alleys of global
health. Biosocieties, 6, 71-87.
Killeen, G. F., Okumu, F. O., N’guessan, R., Co-
osemans, M., Adeogun, A., Awolola, S., Etang,
J., Dabire, R. K. & Corbel, V. (2011). The im-
portance of considering community-level ef-
fects when selecting insecticidal malaria vector
products. Parasites & Vectors, 4.
Kirby, M. J., Bah, P., Jones, C. O., Kelly, A. H.,
Jasseh, M. & Lindsay, S. W. (2010). Social ac-
ceptability and durability of two different house
screening interventions against exposure to
malaria vectors, Plasmodium falciparum in-
fection, and anemia in children in the Gambia,
West Africa. Am J Trop Med Hyg, 83, 965-72.
Kitua, A., Folb, P., Warsame, M., Binka, F.,
Faiz, A., Ribeiro, I., Peto, T., Gyapong, J., Bin
Yunus, E., Rahman, R., Baiden, F., Clerk, C.,
Mrango, Z., Makasi, C., Kimbute, O., Hossain,
A., Samad, R. & Gomes, M. (2010). The use of
placebo in a trial of rectal artesunate as initial
treatment for severe malaria patients en route
to referral clinics: ethical issues. Journal of
Medical Ethics, 36, 116-120.
Kitua, A., Ogundahunsi, O., Lines, J. & Mgone,
C. (2011). Conquering malaria: enhancing the
impact of effective interventions towards elimi-
nation in the diverse and changing epidemiol-
ogy. J Glob Infect Dis, 3, 161-5.
Konat?, A. T., Yaro, J. B., Ou?Draogo, A. Z., Di-
arra, A., Gansan?, A., Soulama, I., Kangoy?, D.
T., Kabor?, Y., Ou?Draogo, E., Ou?Draogo, A.,
Tiono, A. B., Ou?Draogo, I. N., Chandramo-
han, D., Cousens, S., Milligan, P. J., Sirima,
S. B., Greenwood, B. & Diallo, D. A. (2011).
Intermittent Preventive Treatment of Malaria
Provides Substantial Protection against Malaria
in Children Already Protected by an Insecticide-
Treated Bednet in Burkina Faso: A Randomised,
Double-Blind, Placebo-Controlled Trial. PLoS
Med, 8, e1000408.
Konate, A. T., Yaro, J. B., Ouedraogo, A. Z., Di-
arra, A., Gansane, A., Soulama, I., Kangoye, D.
T., Kabore, Y., Ouedraogo, E., Ouedraogo, A.,
Tiono, A. B., Ouedraogo, I. N., Chandramo-
han, D., Cousens, S., Milligan, P. J., Sirima, S.
B., Greenwood, B. M. & Diallo, D. A. (2011).
Morbidity from Malaria in Children in the Year
after They Had Received Intermittent Preven-
tive Treatment of Malaria: A Randomised Trial.
PLoS ONE, 6.
Kordes, M., Matuschewski, K. & Hafalla, J.
C. (2011). Caspase-1 Activation of Interleukin-
1{beta} (IL-1{beta}) and IL-18 Is Dispensable
for Induction of Experimental Cerebral Malaria.
Infect Immun, 79, 3633-41.
Kreuel, B., Verra, F., Adjei, S., Ehmen, C.,
Ayim-Akonor, M., Kobbe, R., Kreuzberg,
C., Drakeley, C. & May, J. (2011). The roles
of haemoglobin S, haemoglobin C and alpha-
thalassaemia in the development of acquired
humoral immunity against malaria. In: Tropi-
cal Medicine & International Health. 143-144.
Kyabayinze, D. J., Asiimwe, C., Nakanjako, D.,
Nabakooza, J., Counihan, H. & Tibenderana,
J. K. (2010). Use of RDTs to improve malaria di-
agnosis and fever case management at primary
health care facilities in Uganda. Malaria Journal,
9.
Kyabayinze, D. J., Tibenderana, J. K., Nassali,
M., Tumwine, L. K., Riches, C., Montague, M.,
Counihan, H., Hamade, P., Van Geertruyden,
J.-P. & Meek, S. (2011). Placental Plasmodium
falciparum malaria infection: Operational accu-
racy of HRP2 rapid diagnostic tests in a malaria
endemic setting. Malaria Journal, 10, 306.
Ladhani, S., Garbash, M., Whitty, C. J., Chio-
dini, P. L., Aibara, R. J., Riordan, F. A. & Shin-
gadia, D. (2010). Prospective, National Clinical
and Epidemiologic Study on Imported Child-
hood Malaria in the United Kingdom and the
Republic of Ireland. Pediatr Infect Dis J, 29,
434-438.
Laneri, K., Bhadra, A., Ionides, E. L., Bouma,
M., Dhiman, R. C., Yadav, R. S. & Pascual, M.
(2010). Forcing Versus Feedback: Epidemic
Malaria and Monsoon Rains in Northwest India.
Plos Computational Biology, 6.
Langhorne, J., Buffet, P., Galinski, M., Good,
M., Harty, J., Leroy, D., Mota, M. M., Pasini, E.,
Renia, L., Riley, E., Stins, M. & Duffy, P. (2011).
The relevance of non-human primate and ro-
dent malaria models for humans. Malaria Jour-
nal, 10.
Laurent, A., Schellenberg, J., Shirima, K., Ke-
tende, S. C., Alonso, P. L., Mshinda, H., Tanner,
M. & Schellenberg, D. (2010). Performance of
HRP-2 based rapid diagnostic test for malaria
and its variation with age in an area of intense
malaria transmission in southern tanzania. Ma-
lar J, 9, 294.
Lee, K. S., Divis, P. C., Zakaria, S. K., Matusop,
A., Julin, R. A., Conway, D. J., Cox-Singh, J. &
Singh, B. (2011). Plasmodium knowlesi: Reser-
voir Hosts and Tracking the Emergence in Hu-
mans and Macaques. PLoS Pathog, 7, e1002015.
122 Publications 2010-11
London School of Hygiene & Tropical Medicine
Leslie, T., Brice?O, M., Mayan, I., Mohammed,
N., Klinkenberg, E., Sibley, C. H., Whitty, C. J. &
Rowland, M. (2010). The Impact of Phenotypic
and Genotypic G6PD Deficiency on Risk of Plas-
modium vivax Infection: A Case-Control Study
amongst Afghan Refugees in Pakistan. PLoS
Med, 7, e1000283.
Liljander, A., Chandramohan, D., Kweku, M.,
Olsson, D., Montgomery, S. M., Greenwood,
B. & Farnert, A. (2010). Influences of Intermit-
tent Preventive Treatment and Persistent Mul-
ticlonal Plasmodium falciparum Infections on
Clinical Malaria Risk. PLoS ONE, 5.
Lindsay, S. W., Hole, D. G., Hutchinson, R. A.,
Richards, S. A. & Willis, S. G. (2010). Assess-
ing the future threat from vivax malaria in the
United Kingdom using two markedly different
modelling approaches. Malaria Journal, 9.
Littrell, M., Gatakaa, H., Evance, I., Poyer, S.,
Njogu, J., Solomon, T., Munroe, E., Chapman,
S., Goodman, C., Hanson, K., Zinsou, C., Aku-
layi, L., Raharinjatovo, J., Arogundade, E.,
Buyungo, P., Mpasela, F., Adjibabi, C. B., Ag-
bango, J. A., Ramarosandratana, B. F., Coker,
B., Rubahika, D., Hamainza, B., Shewchuk, T.,
Chavasse, D. & O’connell, K. A. (2011). Moni-
toring fever treatment behaviour and equitable
access to effective medicines in the context of
initiatives to improve ACT access: baseline re-
sults and implications for programming in six
African countries. Malar J, 10, 327.
Logan, J. G., Stanczyk, N. M., Hassanali, A., Ke-
mei, J., Santana, A. E., Ribeiro, K. A., Pickett,
J. A. & Mordue Luntz, A. J. (2010). Arm-in-cage
testing of natural human-derived mosquito re-
pellents. Malar J, 9, 239.
Lubell, Y., Mills, A. J., Whitty, C. J. M. & Staed-
ke, S. G. (2010). An Economic Evaluation of
Home Management of Malaria in Uganda: An
Interactive Markov Model. PLoS ONE, 5.
Lubell, Y., Riewpaiboon, A., Dondorp, A. M.,
Von Seidlein, L., Mokuolu, O. A., Nansumba,
M., Gesase, S., Kent, A., Mtove, G., Olaosebi-
kan, R., Ngum, W. P., Fanello, C. I., Hendrik-
sen, I., Day, N. P. J., White, N. J. & Yeung, S.
(2011). Cost-effectiveness of parenteral artesu-
nate for treating children with severe malaria
in sub-Saharan Africa. Bulletin of the World
Health Organization, 89, 504-512.
Lubell, Y., Staedke, S. G., Greenwood, B. M.,
Kamya, M. R., Molyneux, M., Newton, P. N.,
Reyburn, H., Snow, R. W., D’alessandro, U.,
English, M., Day, N., Kremsner, P., Dondorp,
A., Mbacham, W., Dorsey, G., Owusu-Agyei,
S., Maitland, K., Krishna, S., Newton, C., Pas-
vol, G., Taylor, T., Von Seidlein, L., White, N. J.,
Binka, F., Mills, A. & Whitty, C. J. (2011). Likely
health outcomes for untreated acute febrile ill-
ness in the tropics in decision and economic
models; a delphi survey. PLoS ONE, 6, e17439.
Lusingu, J., Olotu, A., Leach, A., Lievens, M.,
Vekemans, J., Olivier, A., Benns, S., Olomi, R.,
Msham, S., Lang, T., Gould, J., Hallez, K., Guer-
ra, Y., Njuguna, P., Awuondo, K. O., Malabeja,
A., Abdul, O., Gesase, S., Dekker, D., Malle, L.,
Ismael, S., Mturi, N., Drakeley, C. J., Savarese,
B., Villafana, T., Ballou, W. R., Cohen, J., Riley,
E. M., Lemnge, M. M., Marsh, K., Bejon, P. &
Von Seidlein, L. (2010). Safety of the Malaria
Vaccine Candidate, RTS,S/AS01(E) in 5 to 17
Month Old Kenyan and Tanzanian Children.
PLoS ONE, 5.
Lynch, C. & Roper, C. (2011). The transit phase
of migration: circulation of malaria and its mul-
tidrug-resistant forms in Africa. PLoS Med, 8,
e1001040.
Mackenzie, G., Ceesay, S. J., Hill, P. C., Walther,
M., Bojang, K. A., Satoguina, J., Enwere, G.,
D’alessandro, U., Saha, D., Ikumapayi, U. N.
A., O’dempsey, T., Mabey, D. C. W., Corrah, T.,
Conway, D. J., Adegbola, R. A. & Greenwood,
B. M. (2010). A Decline in the Incidence of Inva-
sive Non-Typhoidal Salmonella Infection in the
Gambia Temporally Associated with a Decline
in Malaria Infection. PLoS ONE, 5.
Maia, M. F. & Moore, S. J. (2011). Plant-based
insect repellents: a review of their efficacy, de-
velopment and testing. Malar J, 10 Suppl 1, S11.
Maia, M. F., Robinson, A., John, A., Mgando,
J., Simfukwe, E. & Moore, S. J. (2011). Com-
parison of the CDC Backpack aspirator and the
Prokopack aspirator for sampling indoor- and
outdoor-resting mosquitoes in southern Tanza-
nia. Parasit Vectors, 4, 124.
Majambere, S., Pinder, M., Fillinger, U., Ameh,
D., Conway, D. J., Green, C., Jeffries, D., Jawara,
M., Milligan, P. J., Hutchinson, R. & Lindsay,
S. W. (2010). Is Mosquito Larval Source Man-
agement Appropriate for Reducing Malaria in
Areas of Extensive Flooding in The Gambia? A
Cross-over Intervention Trial. Am J Trop Med
Hyg, 82, 176-84.
Malera Consultative Group on Vector Con-
trol, )., Alonso, P. L., Besansky, N. J., Burkot,
T. R., Collins, F. H., Hemingway, J., James, A.
A., Lengeler, C., Lindsay, S., Liu, Q., Lobo, N. F.,
Mnzava, A., Tanner, M. & Zwiebel, L. (2011). A
research agenda for malaria eradication: vector
control. PLoS Med, 8, e1000401.
Malisa, A., Pearce, R., Mutayoba, B., Abdul-
lah, S., Mshinda, H., Kachur, P., Bloland, P. &
Roper, C. (2011). Media, Health Workers, and
Policy Makers’ Relationship and Their Impact
on Antimalarial Policy Adoption: A Population
Genetics Perspective. Malaria Research and
Treatment, (2011).
Malisa, A. L., Pearce, R. J., Abdulla, S., Mshin-
da, H., Kachur, P. S., Bloland, P. & Roper, C.
(2010). Drug coverage in treatment of malaria
and the consequences for resistance evolution
- evidence from the use of sulphadoxine/pyri-
methamine. Malaria Journal, 9.
Malisa, A. L., Pearce, R. J., Mutayoba, B.
M., Abdulla, S., Mshinda, H., Kachur, P. S.,
Bloland, P. & Roper, C. (2011). The evolution
of pyrimethamine resistant dhfr in Plasmodium
falciparum of south-eastern Tanzania: compar-
ing selection under SP alone vs SP+artesunate
combination. Malar J, 10, 317.
Mangham, L. J., Cundill, B., Achonduh, O. A.,
Ambebila, J. N., Lele, A. K., Metoh, T. N., Ndive,
S. N., Ndong, I. C., Nguela, R. L., Nji, A. M.,
Orang-Ojong, B., Wiseman, V., Pamen-Ngako,
J. & Mbacham, W. F. (2011). Malaria preva-
lence and treatment of febrile patients at health
facilities and medicine retailers in Cameroon.
Trop Med Int Health.
Publications 2010-11 123
Malaria Centre Report 2010-11
Mangham, L. J., Cundill, B., Ezeoke, O., Nwala,
E., Uzochukwu, B. S., Wiseman, V. & Onwuje-
kwe, O. (2011). Treatment of uncomplicated
malaria at public health facilities and medicine
retailers in south-eastern Nigeria. Malar J, 10,
155.
Manjurano, A., Okell, L., Lukindo, T., Rey-
burn, H., Olomi, R., Roper, C., Clark, T. G., Jo-
seph, S., Riley, E. M. & Drakeley, C. (2011). As-
sociation of sub-microscopic malaria parasite
carriage with transmission intensity in north-
eastern Tanzania. Malar J, 10, 370.
Maokola, W., Chemba, M., Hamisi, Y., Mrisho,
M., Shirima, K., Manzi, F., Masanja, M., Willey,
B., Alonso, P., Mshinda, H., Tanner, M., Schel-
lenberg, J. R. M. A. & Schellenberg, D. (2011).
Safety of sulfadoxine/pyrimethamine for in-
termittent preventive treatment of malaria in
infants: evidence from large-scale operational
research in southern Tanzania. 3, 154-159.
Maokola, W., Willey, B. A., Shirima, K., Chem-
ba, M., Armstrong Schellenberg, J. R., Mshin-
da, H., Alonso, P., Tanner, M. & Schellenberg,
D. (2011). Enhancing the routine health infor-
mation system in rural southern Tanzania: suc-
cesses, challenges and lessons learned. Trop
Med Int Health.
Marchant, T., Hanson, K., Nathan, R., Mpon-
da, H., Bruce, J., Jones, C., Sedekia, Y., Mshin-
da, H. & Schellenberg, J. (2011). Timing of
delivery of malaria preventive interventions in
pregnancy: results from the Tanzania national
voucher programme. J Epidemiol Community
Health, 65, 78-82.
Marchant, T., Schellenberg, D., Nathan, R.,
Armstrong-Schellenberg, J., Mponda, H.,
Jones, C., Sedekia, Y., Bruce, J. & Hanson,
K. (2010). Assessment of a national voucher
scheme to deliver insecticide-treated mosquito
nets to pregnant women. CMAJ, 182, 152-6.
Marti, F., Chadwick, J., Amewu, R. K., Burrell-
Saward, H., Srivastava, A., Ward, S. A., Shar-
ma, R., Berry, N. & O’neill, P. M. (2011). Sec-
ond generation analogues of RKA182: synthetic
tetraoxanes with outstanding in vitro and in
vivo antimalarial activities. Medchemcomm, 2,
661-665.
Marti, F., Chadwick, J., Amewu, R. K.,
Burrell-Saward, H., Srivastava, A., Ward, S.
A., Sharma, R., Berry, N., O’neill, P. M. & Se,
D. A. (2011). Second generation analogues of
RKA182: synthetic tetraoxanes with outstand-
ing in vitro and in vivo antimalarial activities.
Medchemcomm, 2, 661-665.
Massad, E., Behrens, B. C., Coutinho, F. A. &
Behrens, R. H. (2011). Cost risk benefit analy-
sis to support chemoprophylaxis policy for
travellers to malaria endemic countries. Malar
J, 10, 130.
Matowo, J., Kulkarni, M. A., Mosha, F. W., Ox-
borough, R. M., Kitau, J. A., Tenu, F. & Row-
land, M. (2010). Biochemical basis of perme-
thrin resistance in Anopheles arabiensis from
Lower Moshi, north-eastern Tanzania. Malaria
Journal, 9.
Matteelli, A., Stauffer, W. M., Barnett, E. D.,
Macpherson, D. W., Loutan, L., Hatz, C. & Beh-
rens, R. H. (2010). Is a new definition required
for travelers who visit friends and relatives? J
Travel Med, 17, 430-431.
Matuschewski, K., Hafalla, J. C., Borrmann,
S. & Friesen, J. (2011). Arrested Plasmodium
liver stages as experimental anti-malaria vac-
cines. Human Vaccines, 7, 16-21.
Mbacham, W. F., Evehe, M. S. B., Netongo, P.
M., Ateh, I. A., Mimche, P. N., Ajua, A., Nji, A.
M., Irenee, D., Echouffo-Tcheugui, J. B., Tawe,
B., Hallett, R., Roper, C., Targett, G. & Green-
wood, B. (2010). Efficacy of amodiaquine,
sulphadoxine-pyrimethamine and their com-
bination for the treatment of uncomplicated
Plasmodium falciparum malaria in children in
Cameroon at the time of policy change to ar-
temisinin-based combination therapy. Malaria
Journal, 9.
Mbonye, A. K., Ndyomugyenyi, R., Turinde,
A., Magnussen, P., Clarke, S. & Chandler, C.
(2010). The feasibility of introducing rapid
diagnostic tests for malaria in drug shops in
Uganda. Malaria Journal, 9.
Mbugi, E. V., Meijerink, M., Veenemans, J.,
Jeurink, P. V., Mccall, M., Olomi, R. M., Shao,
J. F., Verhoef, H. & Savelkoul, H. F. J. (2010).
Alterations in early cytokine-mediated immune
responses to Plasmodium falciparum infection
in Tanzanian children with mineral element
deficiencies: a cross-sectional survey. Malaria
Journal, 9.
Mccall, M. B. B., Hopman, J., Daou, M., Maiga,
B., Dara, V., Ploemen, I., Nganou-Makamdop,
K., Niangaly, A., Tolo, Y., Arama, C., Bousema,
J. T., Van Der Meer, J. W., Van Der Ven, A.,
Troye-Blomberg, M., Dolo, A., Doumbo, O. K.
& Sauerwein, R. W. (2010). Early Interferon-
gamma Response against Plasmodium falci-
parum Correlates with Interethnic Differences
in Susceptibility to Parasitemia between Sym-
patric Fulani and Dogon in Mali. Journal of In-
fectious Diseases, 201, 142-152.
Mens, P., De Bes, L., Moers, A., Hallett, R., Ver-
weij, J., Overmeir, C., Lee�lang, M., Van Am-
erongen, A., Tinto, H. & Schallig, H. (2011).
Development and evaluation of simplified mo-
lecular diagnostic devices for malaria. In: Trop-
ical Medicine & International Health. 98-98.
Merson, M., Black, R. & Mills, A. (eds.) (2011).
International Public Health, third edition, Bos-
ton: Jones and Bartlett Publishers.
Mikhail, A. F., Leslie, T. J., Mayan, M. I., Zekria,
R., Mohammad, N., Hasanzai, M. A., Sa�i, N.,
Whitty, C. J. & Rowland, M. (2011). Field trial
of three different Plasmodium vivax-detecting
rapid diagnostic tests with and without evapo-
rative cool box storage in Afghanistan. Malar J,
10, 169.
Mimche, P. N., Taramelli, D. & Vivas, L. (2011).
The plant-based immunomodulator curcumin
as a potential candidate for the development of
an adjunctive therapy for cerebral malaria. Ma-
lar J, 10 Suppl 1, S10.
Mng’ong’o, F. C., Sambali, J. J., Sabas, E.,
Rubanga, J., Magoma, J., Ntamatungiro, A.
J., Turner, E. L., Nyogea, D., Ensink, J. H. J. &
Moore, S. J. (2011). Repellent Plants Provide
Affordable Natural Screening to Prevent Mos-
quito House Entry in Tropical Rural Settings-
Results from a Pilot Efficacy Study. Plos One, 6.
124 Publications 2010-11
London School of Hygiene & Tropical Medicine
Mombo-Ngoma, G., Oyakhirome, S., Ord, R.,
Gabor, J. J., Greut?Laers, K. C., Profanter, K.,
Greut?Laers, B., Kurth, F., Lell, B., Kun, J. F.,
Issifou, S., Roper, C., Kremsner, P. G. & Gro-
busch, M. P. (2011). High prevalence of dhfr
triple mutant and correlation with high rates
of sulphadoxine-pyrimethamine treatment fail-
ures in vivo in Gabonese children. Malar J, 10,
123.
Mombo-Ngoma, G., Oyakhirome, S., Ord, R.,
Gabor, J. J., Greutelaers, K. C., Profanter, K.,
Greutelaers, B., Kurth, F., Lell, B., Kun, J. F. J.,
Issifou, S., Roper, C., Kremsner, P. G. & Gro-
busch, M. P. (2011). High prevalence of dhfr
triple mutant and correlation with high rates
of sulphadoxine-pyrimethamine treatment
failures in vivo in Gabonese children. Malaria
Journal, 10.
Moonen, B., Cohen, J. M., Snow, R. W., Slutsk-
er, L., Drakeley, C., Smith, D. L., Abeyasinghe,
R. R., Rodriguez, M. H., Maharaj, R., Tanner,
M. & Targett, G. (2010). Operational strategies
to achieve and maintain malaria elimination.
Lancet, 376, 1592-603.
Mosha, J. F., Conteh, L., Tediosi, F., Gesase,
S., Bruce, J., Chandramohan, D. & Gosling, R.
(2010). Cost implications of improving malaria
diagnosis: findings from north-eastern Tanza-
nia. PLoS ONE, 5, e8707.
Mpimbaza, A., Filler, S., Katureebe, A., Kina-
ra, S. O., Nzabandora, E., Quick, L., Ratcliffe,
A., Wabwire-Mangen, F., Chandramohan,
D. & Staedke, S. G. (2011). Validity of Verbal
Autopsy Procedures for Determining Malaria
Deaths in Different Epidemiological Settings in
Uganda. Plos One, 6.
Mtove, G., Amos, B., Nadjm, B., Hendriksen,
I. C., Dondorp, A. M., Mwambuli, A., Kim, D.
R., Ochiai, R. L., Clemens, J. D., Von Seidlein,
L., Reyburn, H. & Deen, J. (2011). Decreasing
incidence of severe malaria and community-
acquired bacteraemia among hospitalized chil-
dren in Muheza, north-eastern Tanzania, 2006-
(2010). Malar J, 10, 320.
Mtove, G., Hendriksen, I. C., Amos, B., Mrema,
H., Mandia, V., Manjurano, A., Muro, F., Sykes,
A., Hildenwall, H., Whitty, C. J. & Reyburn, H.
(2011). Treatment guided by rapid diagnostic
tests for malaria in Tanzanian children: safety
and alternative bacterial diagnoses. Malar J, 10,
290.
Mtove, G., Nadjm, B., Amos, B., Hendriksen,
I. C., Muro, F. & Reyburn, H. (2011). Use of
an HRP2-based rapid diagnostic test to guide
treatment of children admitted to hospital in a
malaria-endemic area of north-east Tanzania.
Trop Med Int Health.
Mubyazi, G. M., Bloch, P., Magnussen, P., Ol-
sen, O. E., Byskov, J., Hansen, K. S. & Bygbjerg,
I. C. (2010). Women’s experiences and views
about costs of seeking malaria chemopreven-
tion and other antenatal services: a qualitative
study from two districts in rural Tanzania. Ma-
lar J, 9, 54.
N’guessan, R., Asidi, A., Boko, P., Odjo, A., Ak-
ogbeto, M., Pigeon, O. & Rowland, M. (2010).
An experimental hut evaluation of PermaNet(?)
3.0, a deltamethrin-piperonyl butoxide combi-
nation net, against pyrethroid-resistant Anoph-
eles gambiae and Culex quinquefasciatus mos-
quitoes in southern Benin. Trans R Soc Trop
Med Hyg.
N’guessan, R., Boko, P., Odjo, A., Chabi, J., Ak-
ogbeto, M. & Rowland, M. (2010). Control of
pyrethroid and DDT-resistant Anopheles gam-
biae by application of indoor residual spraying
or mosquito nets treated with a long-lasting
organophosphate insecticide, chlorpyrifos-
methyl. Malar J, 9, 44.
Nadjm, B., Amos, B., Mtove, G., Ostermann,
J., Chonya, S., Wangai, H., Kimera, J., Msuya,
W., Mtei, F., Dekker, D., Malahiyo, R., Olomi,
R., Crump, J. A., Whitty, C. J. & Reyburn, H.
(2010). WHO guidelines for antimicrobial treat-
ment in children admitted to hospital in an area
of intense Plasmodium falciparum transmis-
sion: prospective study. BMJ, 340, c1350.
Naidoo, I. & Roper, C. (2010). Following the
path of most resistance: dhps K540E disper-
sal in African Plasmodium falciparum. Trends
Parasitol, 26, 447-456.
Naidoo, I. & Roper, C. (2011). Drug resistance
maps to guide intermittent preventive treat-
ment of malaria in African infants. Parasitology,
1-11.
Nankabirwa, J., Cundill, B., Clarke, S., Kabat-
ereine, N., Rosenthal, P. J., Dorsey, G., Brook-
er, S. & Staedke, S. G. (2010). Efficacy, safety,
and tolerability of three regimens for preven-
tion of malaria: a randomized, placebo-con-
trolled trial in ugandan schoolchildren. PLoS
ONE, 5, e13438.
Ndenga, B. A., Simbauni, J. A., Mbugi, J. P.,
Githeko, A. K. & Fillinger, U. (2011). Produc-
tivity of Malaria Vectors from Different Habitat
Types in the Western Kenya Highlands. PLoS
ONE, 6.
Ndiaye, J. L. A., Faye, B., Gueye, A., Tine, R.,
Ndiaye, D., Tchania, C., Ndiaye, I., Barry, A.,
Cisse, B., Lameyre, V. & Gaye, O. (2011). Re-
peated treatment of recurrent uncomplicated
Plasmodium falciparum malaria in Senegal
with fixed-dose artesunate plus amodiaquine
versus fixed-dose artemether plus lumefan-
trine: a randomized, open-label trial. Malaria
Journal, 10.
Ndyomugyenyi, R., Clarke, S. E., Hutchison, C.
L., Hansen, K. S. & Magnussen, P. (2011). Ef-
ficacy of malaria prevention during pregnancy
in an area of low and unstable transmission:
an individually-randomised placebo-controlled
trial using intermittent preventive treatment
and insecticide-treated nets in the Kabale High-
lands, southwestern Uganda. Transactions of
the Royal Society of Tropical Medicine and Hy-
giene, 105, 607-616.
Neave, P. E., Jones, C. O. & Behrens, R. H.
(2010a). A review of risk factors for imported
malaria in the European African diaspora. J
Travel Med, 17, 346-50.
Neave, P. E., Jones, C. O. H. & Behrens, R. H.
(2010b). A Review of Risk Factors for Imported
Malaria in the European African Diaspora. Jour-
nal of Travel Medicine, 17, 346-350.
Newton, P. N., Green, M. D., Mildenhall, D. C.,
Plancon, A., Nettey, H., Nyadong, L., Hostetler,
Publications 2010-11 125
Malaria Centre Report 2010-11
D. M., Swamidoss, I., Harris, G. A., Powell, K.,
Timmermans, A. E., Amin, A. A., Opuni, S. K.,
Barbereau, S., Faurant, C., Soong, R. C. W.,
Faure, K., Thevanayagam, J., Fernandes, P.,
Kaur, H., Angus, B., Stepniewska, K., Guerin,
P. J. & Fernandez, F. M. (2011). Poor quality vi-
tal anti-malarials in Africa - an urgent neglected
public health priority. Malaria Journal, 10, 352.
Ngufor, C., N’guessan, R., Boko, P., Odjo, A., Vi-
gninou, E., Asidi, A., Akogbeto, M. & Rowland,
M. (2011). Combining indoor residual spraying
with chlorfenapyr and long-lasting insecticidal
bed nets for improved control of pyrethroid-
resistant Anopheles gambiae: an experimental
hut trial in Benin. Malar J, 10, 343.
Nogaro, S. I., Hafalla, J. C., Walther, B., Re-
marque, E. J., Tetteh, K. K., Conway, D. J., Riley,
E. M. & Walther, M. (2011). The breadth, but
not the magnitude, of circulating memory B cell
responses to P. falciparum increases with age/
exposure in an area of low transmission. PLoS
One, 6, e25582.
Noor, A. M., Mohamed, M. B., Mugyenyi, C. K.,
Osman, M. A., Guessod, H. H., Kabaria, C. W.,
Ahmed, I. A., Nyonda, M., Cook, J., Drakeley,
C. J., Mackinnon, M. J. & Snow, R. W. (2011).
Establishing the extent of malaria transmission
and challenges facing pre-elimination in the Re-
public of Djibouti. Bmc Infectious Diseases, 11.
O’connell, K. A., Gatakaa, H., Poyer, S., Njogu,
J., Evance, I., Munroe, E., Solomon, T., Good-
man, C., Hanson, K., Zinsou, C., Akulayi, L., Ra-
harinjatovo, J., Arogundade, E., Buyungo, P.,
Mpasela, F., Adjibabi, C. B., Agbango, J. A., Ra-
marosandratana, B. F., Coker, B., Rubahika,
D., Hamainza, B., Chapman, S., Shewchuk, T.
& Chavasse, D. (2011). Got ACTs? Availability,
price, market share and provider knowledge of
anti-malarial medicines in public and private
sector outlets in six malaria-endemic countries.
Malar J, 10, 326.
O’meara, W. P., Mangeni, J. N., Steketee, R. &
Greenwood, B. (2010). Changes in the burden
of malaria in sub-Saharan Africa. Lancet Infec-
tious Diseases, 10, 545-555.
Obaro, S. & Greenwood, B. (2011). Malaria
and bacteraemia in African children. Lancet,
378, 1281-1282.
Ochola, L. I., Tetteh, K. K., Stewart, L. B., Ri-
itho, V., Marsh, K. & Conway, D. J. (2010). Al-
lele frequency-based and polymorphism-ver-
sus-divergence indices of balancing selection in
a new filtered set of polymorphic genes in Plas-
modium falciparum. Mol Biol Evol, 27, 2344-51.
Ogoma, S. B., Lweitoijera, D. W., Ngonyani,
H., Furer, B., Russell, T. L., Mukabana, W. R.,
Killeen, G. F. & Moore, S. J. (2010). Screening
Mosquito House Entry Points as a Potential
Method for Integrated Control of Endophagic
Filariasis, Arbovirus and Malaria Vectors. Plos
Neglected Tropical Diseases, 4.
Oguike, M. C., Betson, M., Burke, M., Nolder,
D., Stothard, J. R., Kleinschmidt, I., Proi-
etti, C., Bousema, T., Ndounga, M., Tanabe,
K., Ntege, E., Culleton, R. & Sutherland, C. J.
(2011). Plasmodium ovale curtisi and Plasmo-
dium ovale wallikeri circulate simultaneously
in African communities. Int J Parasitol.
Ogutu, B. R., Baiden, R., Diallo, D., Smith, P. G.
& Binka, F. N. (2010). Sustainable development
of a GCP-compliant clinical trials platform in
Africa: the Malaria Clinical Trials Alliance per-
spective. Malaria Journal, 9.
Okebe, J. U., Walther, B., Bojang, K., Dram-
meh, S., Schellenberg, D., Conway, D. J. &
Walther, M. (2010). Prescribing practice for
malaria following introduction of artemether-
lumefantrine in an urban area with declining
endemicity in West Africa. Malaria Journal, 9.
Okell, L. C., Grif�in, J. T., Kleinschmidt, I., Hol-
lingsworth, T. D., Churcher, T. S., White, M.
J., Bousema, T., Drakeley, C. J. & Ghani, A. C.
(2011). The Potential Contribution of Mass
Treatment to the Control of Plasmodium falci-
parum Malaria. PLoS ONE, 6.
Okumu, F., Biswaro, L., Mbeleyela, E., Killeen,
G. F., Mukabana, R. & Moore, S. J. (2010). Us-
ing Nylon Strips to Dispense Mosquito Attrac-
tants for Sampling the Malaria Vector Anophe-
les gambiae s.s. Journal of Medical Entomology,
47, 274-282.
Okumu, F. O., Killeen, G. F., Ogoma, S., Biswa-
ro, L., Smallegange, R. C., Mbeyela, E., Titus,
E., Munk, C., Ngonyani, H., Takken, W., Mshin-
da, H., Mukabana, W. R. & Moore, S. J. (2010).
Development and field evaluation of a synthetic
mosquito lure that is more attractive than hu-
mans. PLoS One, 5, e8951.
Okumu, F. O. & Moore, S. J. (2011). Combining
indoor residual spraying and insecticide-treat-
ed nets for malaria control in Africa: a review
of possible outcomes and an outline of sugges-
tions for the future. Malaria Journal, 10.
Oliver, S. V., Kaiser, M. L., Wood, O. R., Coe-
tzee, M., Rowland, M. & Brooke, B. D. (2010).
Evaluation of the pyrrole insecticide chlorfena-
pyr against pyrethroid resistant and suscep-
tible Anopheles funestus (Diptera: Culicidae).
Tropical Medicine & International Health, 15,
127-131.
Olotu, A., Lusingu, J., Leach, A., Lievens, M.,
Vekemans, J., Msham, S., Lang, T., Gould, J.,
Dubois, M. C., Jongert, E., Vansadia, P., Carter,
T., Njuguna, P., Awuondo, K. O., Malabeja, A.,
Abdul, O., Gesase, S., Mturi, N., Drakeley, C. J.,
Savarese, B., Villafana, T., Lapierre, D., Bal-
lou, W. R., Cohen, J., Lemnge, M. M., Peshu,
N., Marsh, K., Riley, E. M., Von Seidlein, L. &
Bejon, P. (2011). Efficacy of RTS,S/AS01E ma-
laria vaccine and exploratory analysis on anti-
circumsporozoite antibody titres and protec-
tion in children aged 5-17 months in Kenya and
Tanzania: a randomised controlled trial. Lancet
Infectious Diseases, 11, 102-109.
Onwujekwe, O., Hanson, K. & Uzochukwu, B.
(2011). Do poor people use poor quality provid-
ers? Evidence from the treatment of presump-
tive malaria in Nigeria. Trop Med Int Health.
Onwujekwe, O., Hanson, K., Uzochukwu,
B., Ezeoke, O., Eze, S. & Dike, N. (2010). Geo-
graphic inequities in provision and utilization
of malaria treatment services in southeast Ni-
geria: Diagnosis, providers and drugs. Health
Policy, 94, 144-149.
Osier, F. H., Murungi, L. M., Fegan, G., Tuju, J.,
Tetteh, K. K., Bull, P. C., Conway, D. J. & Marsh,
K. (2010). Allele-specific antibodies to Plasmo-
126 Publications 2010-11
London School of Hygiene & Tropical Medicine
dium falciparum merozoite surface protein-2
and protection against clinical malaria. Parasite
Immunol, 32, 193-201.
Osier, F. H., Weedall, G. D., Verra, F., Murun-
gi, L., Tetteh, K. K., Bull, P., Faber, B. W., Re-
marque, E., Thomas, A., Marsh, K. & Conway,
D. J. (2010). Allelic diversity and naturally ac-
quired allele-specific antibody responses to
Plasmodium falciparum apical membrane anti-
gen 1 in Kenya. Infect Immun.
Ou?Draogo, A. L., Bousema, T., De Vlas, S. J.,
Cuzin-Ouattara, N., Verhave, J. P., Drakeley,
C., Luty, A. J. & Sauerwein, R. (2010). The plas-
ticity of Plasmodium falciparum gametocytae-
mia in relation to age in Burkina Faso. Malar J,
9, 281.
Ouedraogo, A. L., Roeffen, W., Luty, A. J. F.,
De Vlas, S. J., Nebie, I., Ilboudo-Sanogo, E.,
Cuzin-Ouattara, N., Teleen, K., Tiono, A. B.,
Sirima, S. B., Verhave, J. P., Bousema, T. & Sau-
erwein, R. (2011). Naturally Acquired Immune
Responses to Plasmodium falciparum Sexual
Stage Antigens Pfs48/45 and Pfs230 in an Area
of Seasonal Transmission. Infection and Immu-
nity, 79, 4957-4964.
Oxborough, R. M., Kitau, J., Matowo, J., Mn-
deme, R., Feston, E., Boko, P., Odjo, A., Meton-
nou, C. G., Irish, S., N’guessan, R., Mosha, F. W.
& Rowland, M. W. (2010). Evaluation of indoor
residual spraying with the pyrrole insecticide
chlorfenapyr against pyrethroid-susceptible
Anopheles arabiensis and pyrethroid-resistant
Culex quinquefasciatus mosquitoes. Trans R
Soc Trop Med Hyg, 104, 639-45.
Pacorel, B., Leung, S. C., Stachulski, A. V., Da-
vies, J., Vivas, L., Lander, H., Ward, S. A., Kai-
ser, M., Brun, R. & O’neill, P. M. (2010). Modu-
lar Synthesis and in Vitro and in Vivo Antima-
larial Assessment of C-10 Pyrrole Mannich Base
Derivatives of Artemisinin. Journal of Medicinal
Chemistry, 53, 633-640.
Pagnoni, F., Mukanga, D., Tiono, A., Any-
origiyia, T., Cousens, S. & Barnish, G. Year.
Impact of community case management
of malaria and pneumonia on clinical out-
come and rational use of drugs: results from
a multi-country study in Sub-Saharan Af-
rica. In: Tropical Medicine & International
Health, Oct (2011). 59-59.
Patouillard, E., Conteh, L., Webster, J., Kweku,
M., Chandramohan, D. & Greenwood, B.
(2011). Coverage, adherence and costs of inter-
mittent preventive treatment of malaria in chil-
dren employing different delivery strategies in
jasikan, ghana. PLoS One, 6, e24871.
Patouillard, E., Hanson, K. G. & Goodman, C.
A. (2010). Retail sector distribution chains for
malaria treatment in the developing world: a
review of the literature. Malar J, 9, 50.
Picado, A., Singh, S. P., Vanlerberghe, V., Ura-
nw, S., Ostyn, B., Kaur, H., Das, M. L., Sundar,
S., Rijal, S., Tungu, P., Boelaert, M. & Row-
land, M. (2011). Residual activity and integrity
of PermaNet(?) 2.0 after 24 months of house-
hold use in a community randomised trial of
long lasting insecticidal nets against visceral
leishmaniasis in India and Nepal. Trans R Soc
Trop Med Hyg.
Pickett, J. A., Birkett, M. A., Dewhirst, S. Y.,
Logan, J. G., Omolo, M. O., Torto, B., Pelletier,
J., Syed, Z. & Leal, W. S. (2010). Chemical ecol-
ogy of animal and human pathogen vectors in a
changing global climate. J Chem Ecol, 36, 113-
21.
Pinder, M., Jawara, M., Jarju, L. B., Kandeh, B.,
Jeffries, D., Lluberas, M. F., Mueller, J., Park-
er, D., Bojang, K., Conway, D. J. & Lindsay, S.
W. (2011). To assess whether indoor residual
spraying can provide additional protection
against clinical malaria over current best prac-
tice of long-lasting insecticidal mosquito nets
in The Gambia: study protocol for a two-armed
cluster-randomised trial. Trials, 12, 147.
Pinder, M., Moorthy, V. S., Akanmori, B. D.,
Genton, B. & Brown, G. V. (2010). MALVAC
2009: progress and challenges in development
of whole organism malaria vaccines for endem-
ic countries, 3-4 June 2009, Dakar, Senegal. Vac-
cine, 28, 4695-702.
Prentice, A. M., Cox, S. E. & Nweneka, C. V.
(2010). Asymptomatic malaria in the etiology
of iron deficiency anemia: a nutritionist’s view-
point. Am J Clin Nutr.
Proietti, C., Pettinato, D. D., Kanoi, B. N.,
Ntege, E., Crisanti, A., Riley, E. M., Egwang,
T. G., Drakeley, C. & Bousema, T. (2011). Con-
tinuing intense malaria transmission in north-
ern Uganda. Am J Trop Med Hyg, 84, 830-7.
Pullan, R. L., Bukirwa, H., Snow, R. W. &
Brooker, S. (2010). Heritability of Plasmodium
parasite density in a rural Ugandan community.
Am J Trop Med Hyg, 83, 990-5.
Pullan, R. L., Bukirwa, H., Staedke, S. G.,
Snow, R. W. & Brooker, S. (2010). Plasmodium
infection and its risk factors in eastern Uganda.
Malar J, 9, 2.
Pullan, R. L., Kabatereine, N. B., Bukirwa, H.,
Staedke, S. G. & Brooker, S. (2011). Heteroge-
neities and Consequences of Plasmodium Spe-
cies and Hookworm Coinfection: A Population
Based Study in Uganda. J Infect Dis, 203, 406-
17.
Raman, J., Little, F., Roper, C., Kleinschmidt,
I., Cassam, Y., Maharaj, R. & Barnes, K. I.
(2010). Five Years of Large-Scale dhfr and dhps
Mutation Surveillance Following the Phased
Implementation of Artesunate Plus Sulfadox-
ine-Pyrimethamine in Maputo Province, South-
ern Mozambique. American Journal of Tropical
Medicine and Hygiene, 82, 788-794.
Ranson, H., N’guessan, R., Lines, J., Moiroux,
N., Nkuni, Z. & Corbel, V. (2011). Pyrethroid
resistance in African anopheline mosquitoes:
what are the implications for malaria control?
Trends Parasitol, 27, 91-8.
Rehman, A. M., Coleman, M., Schwabe, C.,
Baltazar, G., Matias, A., Roncon Gomes, I.,
Yellott, L., Aragon, C., Nseng Nchama, G.,
Mzilahowa, T., Rowland, M. & Kleinschmidt,
I. (2011). How much does malaria vector con-
trol quality matter: the epidemiological impact
of holed nets and inadequate indoor residual
spraying. PLoS ONE, 6, e19205.
Reyburn, H. (2010). New WHO guidelines for
the treatment of malaria. BMJ, 340, c2637.
Publications 2010-11 127
Malaria Centre Report 2010-11
Riley, E. M., Couper, K. N., Helmby, H., Hafalla,
J. C. R., De Souza, J. B., Langhorne, J., Jarra, W.
& Zavala, F. (2010). Neuropathogenesis of hu-
man and murine malaria. Trends in Parasitol-
ogy, 26, 277-278.
Robinson, T., Campino, S. G., Auburn, S., As-
sefa, S. A., Polley, S. D., Manske, M., Macin-
nis, B., Rockett, K. A., Maslen, G. L., Sanders,
M., Quail, M. A., Chiodini, P. L., Kwiatkowski,
D. P., Clark, T. G. & Sutherland, C. J. (2011).
Drug-Resistant Genotypes and Multi-Clonality
in Plasmodium falciparum Analysed by Direct
Genome Sequencing from Peripheral Blood of
Malaria Patients. PLoS ONE, 6.
Roca-Feltrer, A., Carneiro, I., Smith, L., Schel-
lenberg, J. R., Greenwood, B. & Schellenberg,
D. (2010). The age patterns of severe malaria
syndromes in sub-Saharan Africa across a
range of transmission intensities and seasonal-
ity settings. Malar J, 9, 282.
Russell, T. L., Govella, N. J., Azizi, S., Drakeley,
C. J., Kachur, S. P. & Killeen, G. F. (2011). In-
creased proportions of outdoor feeding among
residual malaria vector populations following
increased use of insecticide-treated nets in ru-
ral Tanzania. Malaria Journal, 10.
Saeed, S., Carter, V., Tremp, A. Z. & Dessens,
J. T. (2010). Plasmodium berghei crystalloids
contain multiple LCCL proteins. Mol Biochem
Parasitol, 170, 49-53.
Sambo, M. R., Trovoada, M. J., Benchimol,
C., Quinhentos, V., Gon?Alves, L., Velosa, R.,
Marques, M. I., Sep?Lveda, N., Clark, T. G.,
Mustafa, S., Wagner, O., Coutinho, A. & Penha-
Gon?Alves, C. (2010). Transforming growth
factor beta 2 and heme oxygenase 1 genes are
risk factors for the cerebral malaria syndrome
in Angolan children. PLoS ONE, 5, e11141.
Sangare, L. R., Stergachis, A., Brentlinger, P.
E., Richardson, B. A., Staedke, S. G., Kiwuwa,
M. S. & Weiss, N. S. (2010). Determinants of
Use of Intermittent Preventive Treatment of
Malaria in Pregnancy: Jinja, Uganda. PLoS ONE,
5.
Sangare, L. R., Weiss, N. S., Brentlinger, P. E.,
Richardson, B. A., Staedke, S. G., Kiwuwa, M.
S. & Stergachis, A. (2011). Patterns of anti-ma-
larial drug treatment among pregnant women
in Uganda. Malaria Journal, 10.
Schellenberg, D., Willey, B. & Grobusch, M. P.
(2010). Improved patient care with better ma-
laria diagnosis. Therapy, 7, 7-10.
Schellenberg, J. R., Maokola, W., Shirima, K.,
Manzi, F., Mrisho, M., Mushi, A., Alonso, P.,
Mshinda, H., Tanner, M. & Schellenberg, D.
M. (2011). Cluster-randomized study of inter-
mittent preventive treatment for malaria in in-
fants (IPTi) in southern Tanzania: evaluation of
impact on survival. Malar J, 10, 387.
Schousboe, M. L., Rajakaruna, R. S., Amer-
asinghe, P. H., Konradsen, F., Ord, R., Pearce,
R., Bygbjerg, I. C., Roper, C. & Alifrangis, M.
(2011). Analysis of Polymorphisms in the Mer-
ozoite Surface Protein-3? Gene and Two Micro-
satellite Loci in Sri Lankan Plasmodium vivax:
Evidence of Population Substructure in Sri Lan-
ka. Am J Trop Med Hyg, 85, 994-1001.
Schwank, S., Sutherland, C. J. & Drakeley, C.
J. (2010). Promiscuous Expression of ?-Tubulin
II in Maturing Male and Female Plasmodium
falciparum Gametocytes. PLoS ONE, 5, e14470.
Sesay, S., Milligan, P., Touray, E., Sowe, M.,
Webb, E. L., Greenwood, B. M. & Bojang, K. A.
(2011). A trial of intermittent preventive treat-
ment and home-based management of malaria
in a rural area of The Gambia. Malar J, 10, 2.
Shekalaghe, S. A., Ter Braak, R., Daou, M.,
Kavishe, R., Van Den Bijllaardt, W., Van Den
Bosch, S., Koenderink, J. B., Luty, A. J., Whitty,
C. J., Drakeley, C., Sauerwein, R. W. & Bouse-
ma, T. (2010). Haemolysis after a single dose of
primaquine co-administered with an artemis-
inin is not restricted to glucose-6-phosphate
dehydrogenase (G6PD A- variant) deficient in-
dividuals in Tanzania. Antimicrob Agents Che-
mother.
Shewchuk, T., O’connell, K. A., Goodman,
C., Hanson, K., Chapman, S. & Chavasse, D.
(2011). The ACTwatch project: methods to de-
scribe anti-malarial markets in seven countries.
Malaria Journal, 10.
Shi, J. G., Mcintosh, R. S., Adame-Gallegos, J.,
Dehal, P. K., Van Egmond, M., Van De Winkel,
J., Draper, S. J., Forbes, E. K., Corran, P. H.,
Holder, A. A., Woof, J. M. & Pleass, R. J. (2011).
The generation and evaluation of recombinant
human IgA specific for Plasmodium falciparum
merozoite surface protein 1-19 (PfMSP1(19)).
Bmc Biotechnology, 11.
Sikulu, M., Dowell, K. M., Hugo, L. E., Wirtz,
R. A., Michel, K., Peiris, K. H. S., Moore, S.,
Killeen, G. F. & Dowell, F. E. (2011). Evaluating
RNAlater (R) as a preservative for using near-
infrared spectroscopy to predict Anopheles
gambiae age and species. Malaria Journal, 10.
Sirima, S. B., Cousens, S. & Druilhe, P. (2011).
Protection against Malaria by MSP3 Candidate
Vaccine. New England Journal of Medicine, 365,
1062-1064.
Smith, D. L., Drakeley, C. J., Chiyaka, C. & Hay,
S. I. (2010). A quantitative analysis of transmis-
sion efficiency versus intensity for malaria. Nat
Commun, 1, 108.
Smith, L. A., Bruce, J., Gueye, L., Helou, A.,
Diallo, R., Gueye, B., Jones, C. & Webster, J.
(2010). From fever to anti-malarial: the treat-
ment-seeking process in rural Senegal. Malar J,
9, 333.
Smith, L. A., Jones, C., Adjei, R. O., Antwi, G. D.,
Afrah, N. A., Greenwood, B., Chandramohan,
D., Tagbor, H. & Webster, J. (2010). Intermit-
tent screening and treatment versus intermit-
tent preventive treatment of malaria in preg-
nancy: user acceptability. Malar J, 9, 18.
Smith Paintain, L., Antwi, G. D., Jones, C.,
Amoako, E., Adjei, R. O., Afrah, N. A., Green-
wood, B., Chandramohan, D., Tagbor, H. &
Webster, J. (2011). Intermittent Screening
and Treatment versus Intermittent Preventive
Treatment of Malaria in Pregnancy: Provider
Knowledge and Acceptability. PLoS ONE, 6,
e24035.
Stanczyk, N. M., Brook�ield, J. F., Ignell, R.,
Logan, J. G. & Field, L. M. (2010). Behavioral
insensitivity to DEET in Aedes aegypti is a ge-
netically determined trait residing in changes
128 Publications 2010-11
London School of Hygiene & Tropical Medicine
in sensillum function. Proc Natl Acad Sci U S A,
107, 8575-80.
Sutherland, C. J., Babiker, H., Mackinnon,
M. J., Ranford-Cartwright, L. & Sayed, B. B.
(2011). Rational deployment of antimalarial
drugs in Africa: should first-line combination
drugs be reserved for paediatric malaria cases?
Parasitology, 1-10.
Sutherland, C. J., Tanomsing, N., Nolder, D.,
Oguike, M., Jennison, C., Pukrittayakamee, S.,
Dolecek, C., Hien, T. T., Do Ros?Rio, V. E., Arez,
A. P., Pinto, J., Michon, P., Escalante, A. A., Nos-
ten, F., Burke, M., Lee, R., Blaze, M., Otto, T. D.,
Barnwell, J. W., Pain, A., Williams, J., White, N.
J., Day, N. P., Snounou, G., Lockhart, P. J., Chio-
dini, P. L., Imwong, M. & Polley, S. D. (2010).
Two Nonrecombining Sympatric Forms of the
Human Malaria Parasite Plasmodium ovale Oc-
cur Globally. J Infect Dis, 201, 1544-50.
Swysen, C., Vekemans, J., Bruls, M., Oyakhi-
rome, S., Drakeley, C., Kremsner, P., Green-
wood, B., Ofori-Anyinam, O., Okech, B., Vil-
lafana, T., Carter, T., Savarese, B., Duse, A.,
Reijman, A., Ingram, C., Frean, J., Ogutu, B.
& Clinical Trials Partnership, C. (2011). De-
velopment of standardized laboratory methods
and quality processes for a phase III study of
the RTS, S/AS01 candidate malaria vaccine. Ma-
laria Journal, 10.
Systems, M. C. G. O. H., Research, O. & Schel-
lenberg, D. (2011). A research agenda for ma-
laria eradication: health systems and opera-
tional research. PLoS Med, 8, e1000397.
Tabernero Estevez, P., Satoguina, J., Nwakan-
ma, D. C., West, S., Conway, D. J. & Drakeley,
C. J. (2011). Human saliva as a source of anti-
malarial antibodies to examine population ex-
posure to Plasmodium falciparum. Malar J, 10,
104.
Tagbor, H., Bruce, J., Agbo, M., Greenwood,
B. & Chandramohan, D. (2010). Intermittent
screening and treatment versus intermittent
preventive treatment of malaria in pregnancy:
a randomised controlled non-inferiority trial.
PLoS ONE, 5, e14425.
Tagbor, H., Cairns, M., Nakwa, E., Browne, E.,
Sarkodie, B., Counihan, H., Meek, S. & Chan-
dramohan, D. (2010). The clinical impact of
combining intermittent preventive treatment
with home management of malaria in children
aged below 5?years: cluster randomised trial.
Trop Med Int Health.
Tahar, R., Vivas, L., Basco, L., Thompson, E.,
Ibrahim, H., Boyer, J. & Nepveu, F. (2011).
Indolone-N-oxide derivatives: in vitro activity
against fresh clinical isolates of Plasmodium
falciparum, stage specificity and in vitro inter-
actions with established antimalarial drugs.
Journal of Antimicrobial Chemotherapy, 66,
2566-2572.
Targett, G. (2011). Malaria elimination: how
far can we go without a vaccine? Clinical Medi-
cine, 11, 422-423.
Tetteh, K. K. & Conway, D. J. (2011). A poly-
valent hybrid protein elicits antibodies against
the diverse allelic types of block 2 in Plasmo-
dium falciparum merozoite surface protein 1.
Vaccine.
Thomson, R., Festo, C., Bruxvoort, K.,
Thwing, J., Kalolella, A., Nchimbi, H., Taylor,
M., Kachur, S. P. & Goodman, C. (2011). De-
terminants of access to acts and malaria diag-
nosis: results from a household survey in three
regions of Tanzania. In: Tropical Medicine &
International Health. 124-124.
Thwing, J., Fillinger, U., Gimnig, J., Newman,
R. & Lindsay, S. (2011). Mosquito larval source
management for controlling malaria. Cochrane
Database of Systematic Reviews.
Thwing, J. I., Njau, J. D., Goodman, C.,
Munkondya, J., Kahigwa, E., Bloland, P. B.,
Mkikima, S., Mills, A., Abdulla, S. & Kachur,
S. P. (2011). Drug dispensing practices during
implementation of artemisinin-based combina-
tion therapy at health facilities in rural Tanza-
nia, 2002-2005. Trop Med Int Health.
Tsuang, A., Lines, J. & Hanson, K. (2010).
Which family members use the best nets? An
analysis of the condition of mosquito nets and
their distribution within households in Tanza-
nia. Malaria Journal, 9.
Tungu, P., Magesa, S., Maxwell, C., Malima,
R., Masue, D., Sudi, W., Myamba, J., Pigeon,
O. & Rowland, M. (2010). Evaluation of Per-
maNet 3.0 a deltamethrin-PBO combination
net against Anopheles gambiae and pyrethroid
resistant Culex quinquefasciatus mosquitoes:
an experimental hut trial in Tanzania. Malar J,
9, 21.
Valecha, N., Staedke, S., Filler, S., Mpimba-
za, A., Greenwood, B. & Chandramohan, D.
(2011). Malaria-attributed death rates in India.
Lancet, 377, 992-993.
Veenemans, J., Jansen, E. J. S., Baidjoe, A. Y.,
Mbugi, E. V., Demir, A. Y., Kraaijenhagen, R.
J., Savelkoul, H. F. J. & Verhoef, H. (2011). Ef-
fect of alpha(+)-thalassaemia on episodes of
fever due to malaria and other causes: a com-
munitybased cohort study in Tanzania. Malaria
Journal, 10.
Veenemans, J., Milligan, P., Prentice, A. M.,
Schouten, L. R., Inja, N., Van Der Heijden,
A. C., De Boer, L. C., Jansen, E. J., Koopmans,
A. E., Enthoven, W. T., Kraaijenhagen, R. J.,
Demir, A. Y., Uges, D. R., Mbugi, E. V., Savelk-
oul, H. F. & Verhoef, H. (2011). Effect of supple-
mentation with zinc and other micronutrients
on malaria in tanzanian children: a randomised
trial. PLoS Med, 8, e1001125.
Vekemans, J., Marsh, K., Greenwood, B.,
Leach, A., Kabore, W., Soulanoudjingar, S.,
Asante, K. P., Ansong, D., Evans, J., Sacarlal, J.,
Bejon, P., Kamthunzi, P., Salim, N., Njuguna,
P., Hamel, M. J., Otieno, W., Gesase, S., Schel-
lenberg, D. & The Clinical Trials Partner-
ship Committee (2011). Assessment of severe
malaria in a multicenter, phase III, RTS,S/AS01
malaria candidate vaccine trial: case definition,
standardization of data collection and patient
care. Malar J, 10, 221.
Verhoef, H. (2010). Asymptomatic malaria in
the etiology of iron deficiency anemia: a malari-
ologist’s viewpoint. Am J Clin Nutr, 92, 1285-6.
Villegas-Mendez, A., De Souza, J. B., Murungi,
L., Hafalla, J. C., Shaw, T. N., Greig, R., Riley, E.
M. & Couper, K. N. (2011). Heterogeneous and
Tissue-Specific Regulation of Effector T Cell Re-
Publications 2010-11 129
Malaria Centre Report 2010-11
sponses by IFN-{gamma} during Plasmodium
berghei ANKA Infection. J Immunol, 187, 2885-
97.
Waage, J., Banerji, R., Campbell, O., Chirwa,
E., Collender, G., Dieltiens, V., Dorward, A.,
Godfrey-Faussett, P., Hanvoravongchai, P.,
Kingdon, G., Little, A., Mills, A., Mulholland,
K., Mwinga, A., North, A., Patcharanarumol,
W., Poulton, C., Tangcharoensathien, V. & Un-
terhalter, E. (2010). The Millennium Develop-
ment Goals: a cross-sectoral analysis and prin-
ciples for goal setting after 2015. Lancet, 376,
991-1023.
Warhurst, D. (2010a). Introduction to malaria.
In: GILLESPIE, S. (ed.) Antibiotic Resistance:
From genes to global prevalence. London: Hen-
ry Stewart Talks Ltd.
Warhurst, D. (2010b). Malaria: mode of ac-
tion of drugs and resistance mechanisms. In:
GILLESPIE, S. (ed.) Antibiotic Resistance: From
genes to global prevalence. London: Henry
Stewart Talks Ltd.
Wasunna, B., Zurovac, D., Bruce, J., Jones, C.,
Webster, J. & Snow, R. W. (2010). Health work-
er performance in the management of paediat-
ric fevers following in-service training and ex-
posure to job aids in Kenya. Malaria Journal, 9.
Webster, J., Chandramohan, D. & Hanson, K.
(2010). Methods for evaluating delivery sys-
tems for scaling-up malaria control interven-
tion. BMC Health Services Research, 10.
Webster, J., Kweku, M., Dedzo, M., Tinkorang,
K., Bruce, J., Lines, J., Chandramohan, D. &
Hanson, K. (2010). Evaluating delivery sys-
tems: complex evaluations and plausibility in-
ference. Am J Trop Med Hyg, 82, 672-7.
White, M. T., Grif�in, J. T., Drakeley, C. J. &
Ghani, A. C. (2010). Heterogeneity in malaria
exposure and vaccine response: implications
for the interpretation of vaccine efficacy trials.
Malaria Journal, 9.
White, M. T., Grif�in, J. T., Riley, E. M., Drakeley,
C. J., Moorman, A. M., Sumba, P. O., Kazura, J.
W., Ghani, A. C. & John, C. C. (2010). Efficacy
model for antibody-mediated pre-erythrocytic
malaria vaccines. Proc Biol Sci.
Whitty, C. J. (2011). The RTS,S malaria vaccine.
BMJ, 343, d6986.
Whitty, C. J., Leslie, T., Chandler, C. I. & Staed-
ke, S. G. (2010). Management of malaria and
other severe infections in rural Africa and Asia.
BMJ, 340, c1527.
Willey, B. A., Armstrong Schellenberg, J. R.,
Maokola, W., Shirima, K., Chemba, M., Mshin-
da, H., Alonso, P., Tanner, M. & Schellenberg,
D. (2011). Evaluating the effectiveness of IPTi
on malaria using routine health information
from sentinel health centres in southern Tanza-
nia. Malar J, 10, 41.
Wilson, A. L. & On Behalf of the Iptc Task-
force (2011). A Systematic Review and Meta-
Analysis of the Efficacy and Safety of Intermit-
tent Preventive Treatment of Malaria in Chil-
dren (IPTc). PLoS ONE, 6, e16976.
Wipasa, J., Okell, L., Sakkhachornphop, S.,
Suphavilai, C., Chawansuntati, K., Liewsa-
ree, W., Hafalla, J. C. R. & Riley, E. M. (2011).
Short-Lived IFN-gamma Effector Responses,
but Long-Lived IL-10 Memory Responses, to
Malaria in an Area of Low Malaria Endemicity.
Plos Pathogens, 7.
Wipasa, J., Suphavilai, C., Okell, L. C., Cook,
J., Corran, P. H., Thaikla, K., Liewsaree, W.,
Riley, E. M. & Hafalla, J. C. (2010). Long-lived
antibody and B Cell memory responses to the
human malaria parasites, Plasmodium falci-
parum and Plasmodium vivax. PLoS Pathog, 6,
e1000770.
Worrall, E. & Fillinger, U. (2011). Large-scale
use of mosquito larval source management for
malaria control in Africa: a cost analysis. Malar
J, 10, 338.
Yadouleton, A., N’guessan, R., Allagbe, H.,
Asidi, A., Boko, M., Gazard, K. & Akogbeto,
M. (2011). Impact of the expansion of urban
vegetable farming on malaria transmission in
major cities of Benin. Tropical Medicine & In-
ternational Health, 16, 134-134.
130 Members
London School of Hygiene & Tropical Medicine
Members
Central Services
Catherine Fletcher: Programme Development
LIDC
Anne Mills: Vice Director
Faculty of Infectious & Tropical Diseases
Dawn Britten: Senior Scientific Officer
Martina Burke: MLSO Staff
Paul Lansdell: MRL Technical staff
Sue Passarelli: MLSO Staff
Claire Rogers: MLSO Staff
Julie Tucker: MLSO Staff
Emma Victory: Scientific Officer
Cheryl Whitehorn: Senior Scientific Officer
John Williams: Clinical Scientist
Department of Clinical Research
Robin Bailey: Professor of Tropical Medicine
Ron Behrens: Senior Lecturer in Tropical and
Travel Medicine
Michael Brown: Senior lecturer
Deborah DiLiberto: Research Assistant
Bianca DSouza: Manager - ACT Consortium
Alison Elliott: Professor of Tropical Medicine
Peter Godfrey-Faussett: Professor of Interna-
tional Health
Benjamin Judkewitz: Sir Henry Wellcome
Postdoctoral Fellow
Harparkash Kaur: Lecturer of Pharmacology
David Mabey: Professor of Communicable Dis-
eases
Naiela Malik: Scientific Officer Malaria Re-
search and Control Technician
Alexandra Miller: Programme Manager
Chris DrakeleyMalaria Centre Director Reader in Infection & Immunity
Mark RowlandMalaria Centre Deputy DiretorReader in Medical Entomology and Head of Department
Dalia IskanderMalaria Centre Coordinator
Steering CommitteeDavid Baker: Reader in Parasite Molecular
Biology
Amit Bhasin: Manager, Malaria Capacity De-
velopment Consortium
Clare Chandler: Lecturer
Daniel Chandramohan: Professor of Public
Health
Brian Greenwood: Professor of Clinical Tropi-
cal Medicine
Kara Hanson: Reader and Head of Depart-
ment
Immo Kleinschmidt: Reader in Epidemiology
Paul Milligan: Reader in Epidemiology and
Medical Statistics
Eleanor Riley: Professor of Immunology
David Schellenberg: Reader in Epidemiology
and International Health; ACT Consortium Di-
rector, MCDC Deputy Director
Colin Sutherland: Reader in Parasitology
Behzad Nadjm: Lecturer
Paul Newton: Honorary Senior Lecturer
Seth Owusu-Agyei: Research Fellow
Sarah Staedke: Senior Lecturer
Rebecca Tremain: PA to ACT Consortium Di-
rector
Albert VanWyk: Research Fellow Pharmacol-
ogy
Philippe Verstraete: Assistant Manager - ACT
Consortium
Christopher Whitty: Professor of Internation-
al Health
Department of Disease Control
Patricia Aiyenuro: Research Assistant
Helen Allwood: Assistant Manager, Malaria
Capacity Development Consortium
David Bradley: Professor
Cecile Bremont: Team Administrator
Members 131
Malaria Centre Report 2010-11
Simon Brooker: Reader
Jane Bruce: Research Fellow
Mary Cameron: Senior Lecturer
Ilona Carneiro: Lecturer
Francesco Checchi: Senior Lecturer
Matthew Chico: Research Fellow of Epidemi-
ology
Badara Cisse: Lecturer in Epidemiology
Manuela Claite: Overseas Project Coordinator
Sian Clarke: Lecturer
Frank Cox: Visiting Professor
Jonathan Cox: Senior Lecturer
Diadier Diallo: Lecturer
Caterina Fanello: Honorary Lecturer
Ulrike Fillinger: Research Fellow
Caroline Jones: Senior Lecturer
Matt Kirby: Research Fellow of Medical Ento-
mology
Sham Lal: Research Assistant - ACT Consor-
tium
Toby Leslie: Research Fellow ACT Consortium
Steve Lindsay: Professor of Public Health En-
tomology
Jo Lines: Reader in Malaria Control & Vector
Biology
James Logan: Lecturer in Medical Entomology
and Chief Scientific Officer for arctec
Lena Lorenz: Research Fellow in Medical En-
tomology
Caroline Lynch: Lecturer Malaria Research
and Control
Marta Maia: Research Fellow Medical Ento-
mology
Tanya Marchant: Lecturer
Caroline Maxwell: Research Fellow
Hazel Mccullough: Professional Development
and Educational Advisor - Malaria Capacity
Development Consortium
Amy Mikhail: Research Fellow
Sarah Moore: Lecturer in Medical Entomology
Corine Ngufor: Research Assistant in Medical
Entomology
Raphael N’Guessan: Research Fellow of Medi-
cal Entomology
Terri O’Halloran: Overseas Project Adminis-
trator
Richard Oxborough: Research Fellow
Lucy Paintain: Research Fellow
Rachel Pullan: Lecturer
Hugh Reyburn: Senior Lecturer in Clinical Epi-
demiology
Arantxa Roca-Feltrer: Honorary Lecturer
Epidemiology
Joanna Schellenberg: Reader in Epidemiology
& International Health
Wolf-Peter Schmidt: Research Fellow in Epi-
demiology
Karen Slater: PA to Prof Greenwood
Jennifer Stevenson: Research Fellow
Harry Tagbor: Clinical Lecturer, MiP Trial Co-
ordinator
Jayne Webster: Lecturer
Arouna Woukeu: Data Management Coordi-
nator
Department of Immunology & Infection
Khalid Beshir: Research Assistant
Teun Bousema: Lecturer
Michael Bretscher: Visiting Research Fellow
Hollie Burrell-Saward: Research Assistant
Rebekah Burrow: Trainee Scientific Officer
Patrick Corran: Honorary Lecturer
Kevin Couper: Lecturer
Simon Croft: Head of ITD and Professor of
Parasitology
Aubrey Cunnington: Visiting Clinical Re-
search Fellow
Brian deSouza: Honorary Senior Lecturer
Hazel Dockrell: Professor of Immunology
Emily Findlay: Research Fellow
Julius Hafalla: Lecturer
Rachel Hallett: Lecturer
Helena Helmby: Lecturer
Gisela Henriques: Visiting Academic
Mary Oguike: Research Assistant
Brighid O’Neill: Project Assistant - MALA-
CRETES Consortium
Carla Proietti: Visiting Research Assistant
Alison Rand: Scientific Officer
Tovah Shaw: Research Assistant
Lynn Spencer: Scientific Officer
Carolyn Stanley: Laboratory Manager
Geoff Targett: Emeritus Professor of Immunol-
ogy of Parasitic Diseases
Ana Villegas-Mendez: Research Fellow
Department of Pathogen Molecular Biology
Paul Bowyer: Research Fellow
David Conway: Professor of Biology
Johannes Dessens: Senior Lecturer in Parasite
Cell Biology
John Kelly: Professor of Molecular Biology
Michael Miles: Professor of Medical Protozool-
ogy
Debbie Nolder: Principal Scientific Officer
Cally Roper: Senior Lecturer in Malaria Genet-
ics
Lindsay Stewart: Laboratory Technician
Kevin Tetteh: Lecturer
Eloise Thompson: Higher Scientific Officer
Annie Tremp: Research Assistant
David Warhurst: Emeritus Professor of Proto-
zoan Chemotherapy
Faculty of Epidemiology & Population Health
Department of Infectious Disease Epidemiology
Neal Alexander: Clinical Research Fellow
John Bradley: Research Fellow
Matthew Cairns: Research Fellow
Simon Cousens: Professor of Epidemiology
and Medical Statistics
Bonnie Cundill: Lecturer in Medical Statistics
& Epidemiology
John Edmunds: Professor and Head of IDE
Paul Fine: Professor of Communicable Disease
Epidemiology
Neil French: Reader in Infectious Disease Epi-
demiology
David Heymann: Chair of the Health Protec-
tion Agency
Andrea Mann: Lecturer
Peter Smith: Professor of Tropical Epidemiol-
ogy
Emily Webb: Lecturer in Epidemiology and
Medical Statistics
132 Members
London School of Hygiene & Tropical Medicine
Department of Nutrition & Public Health Intervention Research
Sharon Cox: Lecturer
Paula Dominguez-Salas: Research Fellow of
Public Health Nutrition
Seyi Soremekun: Research Fellow Postdoc-
toral, Epidemiology
Hans Verheof: Senior Lecturer
Department of Population Studies
Jim Todd: Lecturer
Department of Medical Statistics
Diana Elbourne: Professor of Healthcare
Evaluation
Department of Nutrition & Public Health Intervention Research
Taane Clark: Reader in Genetic Epidemiology
and Statistics
Lorna Gibson: Lecturer
Dorothea Nitsch: Lecturer
Marcus Keogh-Brown: Lecturer
Silke Lutzelschwab: Research Fellow
Lindsay Mangham-Jefferies: Research Fellow
in Health Economics
Benjamin Palafox: Research Fellow in Phar-
maceutical Policy & Economics
Edith Patouillard: Research Fellow Health
Economics and Systems Analysis
Catherine Pitt: Research Fellow in Health Eco-
nomics
Joanna Reynolds: Research Fellow in Social
Science
Annemarie terVeen: Lecturer
Sarah Tougher: Research Fellow in Health
Economics
Barbara Willey: Research Fellow in Epidemi-
ology and Medical Statistics
Shunmay Yeung: Senior Lecturer
Department of Health Services Research & Policy
Andreia Santos: Lecturer in Health Econom-
ics
Nuno Sepulveda: Research Fellow in Statisti-
cal Genetics and Epidemiology
Richard Smith: Professor of Health System
Economics
Faculty of Public Health & Policy
Richard Smith: Professor of Health System
Economics
Department of Global Health & Development
Uli Beisel: Postdoctoral Research Fellow
Richard Coker: Professor of Public Health
Tom Drake: Research Fellow
Catherine Goodman: Senior Lecturer in
Health Economics and Policy
Ulla Griffiths: Lecturer in Health Economics
Kristian Hansen: Lecturer in Malaria
Natasha Howard: Research Fellow
Eleanor Hutchinson: Research Fellow
Frida Kasteng: Research Fellow in Health Eco-
nomics
Ann Kelly: Lecturer in Anthropology
PhD StudentsKatia Bruxvoort
Vanessa Chen-Hussey
Matthew Chico
Ifeyinwa Chijioke-Nwauche
Mary Cooke
Aubrey Cunnington
Bismarck Dinko
Laura Drought
Chi Eziefula
Nahla Gadalla
Caroline Gitonga
Roly Gosling
Mary Grace Dacuma
Nazma Habib
Katherine Halliday
Luke Harman
Gisela Henriques
Alexandra Hiscox
Amir Horowitz”
Lauren Hutchinson
Coll Hutchison
Seth Irish
Sophie Jones
Sham Lal
Mirza Lalani
Jenny Luchavez
Frank Clause Mng’ong’o
Victor Mobegi
Inbarani Naidoo
Penny Neave
Corine Ngufor
Enesia Ngulube
Sarah Nogaro
Abraham Oduro
Sheila Ogoma
Fredros Okumu
Peter Onyang
Richard Oxborough
Lucy Paintain
Bhargavi Rao
Maha Saeed
Sadia Saeed
Peter Sangoro
Mette Schousboe
Gillian Stresman
Annie Tremp
Patrick Tungu
Sobia Wahid
Beatrice Wasunna
Philippa West
John Williams
Issaka Zongo
MCDC LSHTM linked PhD StudentsAlberta Amu-Quartey
Victor Asoala
Jovin Kitau
Johnson Matowo
Jacklin Mosha
Joaniter Nankabirwa
Youssoupha Ndiaye
Harold Ochola
Sanie Sesay
Members 133
Malaria Centre Report 2010-11
In Focus: Professor Sir Brian Greenwood.Sir Brian Greenwood, Manson Professor of Clinical Tropical Medicine at LSHTM, recently received the 2012
Canada Gairdner Global Health Award, the latest of a number of prestigious international awards made
to him in recognition of an outstanding research career that has been dedicated throughout to enhancing
means of prevention, treatment and control of malaria and other infectious diseases of importance in the
developing world.
That career included holding substantive positions in Africa, notably nine years at the then newly es-
tablished Medical School at Ahmadu Bello University in Zaria, Nigeria, and fifteen years as Director of the
UK Medical Research Council Research Laboratories in The Gambia. Brian’s research is particularly note-
worthy for the many clinical and community trials he devised and ran, their rigorous design, conduct, and
analysis directed towards making major improvements in treatment, prevention or control measures. In
malaria his many important contributions include the first clear proof of the effectiveness of insecticide-
treated bed nets; primary studies on Artimisinin-based Combination Therapy; demonstration of the sub-
stantial benefits achievable by use of seasonal malaria chemoprevention, and major contributions to trials
of malaria vaccines. Additionally, he has been a driving force in the development of meningococcal vac-
cines, the successful integration of vaccination against Haemophilus influenza type b into EPI programmes,
and the testing and subsequent use of pneumococcal vaccines. Capacity development in Africa has been
central to much of what Brian has done, notably as a substantial component of the Gates Malaria Partner-
ship (http://www.gatesmalariapartnership.org/) US$40m award in 2000 from the Gates Foundation, and
its extension - the Malaria Capacity Development Consortium.
Academic recognition of his achievements included election as a Fel-
low of the Royal Society, London, and Fellow of the Academy of Medical Sci-
ences, UK. He was particularly pleased and proud to be elected as a found-
ing Fellow of the West African College of Physicians (WACP) since so much
of his research has been conducted in West Africa. Amongst his many other
awards and prizes, he received the first Hideyo Noguchi African Prize for
Medical Research in 2008 and now the Canada Gairdner Global Health
Award, both international accolades of the highest order.
Brian initiated the establishment of the Malaria Centre, the strengths
and benefits of which are well recognized by those of us who are part of the
centre, and others much further afield.Professor Brian Greenwood at WACP meeting in The Gambia in 1989.
134 Abbreviations
London School of Hygiene & Tropical Medicine
ACT - Artemisinin-based Combi-nation Therapy
AL - Artemether-Lumefantrine
AMFm - Affordable Medicines Fa-cility-Malaria
ANC - Antenatal Care
API - Annual Parasitic Incidence
AQ - Amodiaquine
ARCTEC - Arthropod Control
Product Test Centre
ARV - Anti-Retro Viral
ARVT - Anti-Retro Viral Therapy
AS - Artesunate
B cell - B-Lymphocyte
CARTA - Consortium for Advanced Research Training in Africa
CCMm - Community Case Manage-ment of malaria.
CDC - Centres for Disease Control
CGH - Comparative genomic hy-bridization
CHW - Community Health Worker
CMD - Community Medicine Dis-tributor
CNV - Copy Number Variation
CORP - Community Owned Re-source Persons.
CQ - Chloroquine
CS - Circumsporozoite
DDT - DichloroDiphenylTrichloro-ethane
DFiD - Department for Interna-tional Development
DHA - Dihydroartemisin
DNA- Deoxyribonucleic acid
DSDOM - Distributeurs de soins à domicile
EG - Equatorial Guinea
ELISA - Enzyme-Linked Immuno-sorbent Assay
EPI - Expanded Programme on Immunization
EU - European Union
FGD - Focus Group Discussion
GP - General Practitioner
GPI - Glycosylphosphatidylinositol
GSA - Gametocyte Surface Antigen
GSK - GlaxoSmithKline
HBS - Hepatitis B Surface Antigen
HFI - Health Facility Intervention
HIV - Human immunodeficiency
virus
HO-1 - Heme Oxygenase-1
HPLC - High-Performance Liquid Chromatography
HTD - Hospital for Tropical Dis-eases
iCCM - Integrated Community Case Management
ICER - Incremental Cost-Effective-ness Ratio
IDI – In-Depth Interview
IPT - Intermittent Preventive Treatment
IPTc - Intermittent Preventive Treatment for malaria in children
IPTi - Intermittent Preventive Treatment for malaria in infants
IPTp - Intermittent Preventive Treatment for malaria in preg-nancy
IRR - Incidence Rate Ratio
IRS - Indoor Residual Spraying
IST - Intermittent Screening and Treatment
ITN - Insecticide Treated Net
ITT - Intention To Treat
ITPS - Insecticide Treated Plastic
Abbreviations 135
Malaria Centre Report 2010-11
Sheeting
IVCC - Innovative Vector Control Consortium
LCS - Licensed Chemical Seller
LSHTM - London School of Hy-giene & Tropical Medicine
LLIN - Long Lasting Insecticide-treated Net
MBC – Memory B Cell
MCDC - Malaria Capacity Devel-opment Consortium
MSF - Médecins Sans Frontières
MTBV – Malaria Blocking Trans-mission Vaccine
MQ - Mefloquine
Mt – Mitochondrial
MiP - Malaria in Pregnancy
NGO – Non Governmental Organi-zation
NGST - Next Generation Sequenc-ing Technologies
NHS - National Health Service (UK)
NK cell - Natural Killer Cells
NTS - Nontyphoidial Salmonella
ORS - Oral Rehydration Solution
PAMVERC - Pan African Malaria Vector Research Consortium
PBO - Piperonyl butoxide
PDE - Phosphodiesterase
PDP - Personal Development Plan-ning
Pf - Plasmodium falciparum
PfSE - Plasmodium falciparum schizont extract
PfPKG - Plasmodium falciparum cGMP-Dependent Protein Kinase
Pf-RBC - Plasmodium falciparum-infected Red Blood Cells
PCR - Polymerase Chain Reaction
PKG - Protein Kinase
PoC – Point of Care
PQ- Piperaquine
RDT - Rapid Diagnostic Test
RNA - Ribonucleic acid
SA - Sialic Acid
SACIDS - Southern African Centre for Infectious Disease Surveillance
SCR - Sero-Conversion Rate
SMC – Seasonal Malaria Chemo-prevention
SNOWS - Scientists Networked for
Outcomes from Water and Sanita-tion
SNP - Single Nucleotide Polymor-phism
SP - Sulphadoxine-Pyrimethamine
SST – Single Screening and Treat-ment
SV - Structural Variation
T cell - T Lymphocyte
THRiVE - Training Health Re-searchers into Vocational Excel-lence
UK - United Kingdom
USA – United States America
USD - United States Dollars
VHW - Village health worker
VFR - Visiting Friends and Rela-tives
WACP - West African College of Physicians
WHO -World Health Organisation
WHOPES - World Health Orga-nization Pesticide Evaluation Scheme
WTP – Willingness to Pay
WWARN - World-Wide Antimalar-ial Resistance Network