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Développement Clinique de Candidats Vaccins Antimalariques au Mali

Ogobara K. Doumbo, MD, PhD Malaria Research and Training Center (MRTC)/DEAP/FMPOS

International Center of Excellence in clinical Research-USTTB-NIAID/NIH Université des Sciences, Techniques et Technologies de Bamako, MALI

Chaire d’Infectiologie des Docteurs Mérieux

19eme Journees franco-suisses de Pharmacie hospitaliere Macon-Bourgogne le 24 Avril 2015

2

Bienvenue au Mali = Pays Riche par sa Diversité

NIH

Extramural:

NIAID/ DMID/ FIC

MRTC/DEAP/FMPOS

PER-AUF, ICER-NIH

CNRS-IRD-IHU/IP

WRAIR/FDA

CDC

USAID/PMI

Government of

Mali/Uni-

Bko/MOH

EU, EDCTP grants

MalariaGEN

CVD Maryland AUF/CoopFrance

AMANET

AIEA Universities: Marseille, Maryland,

Angers, Bordeaux, Lyon, Paris,

Oxford, LSTMH, Stokholm, Nijmegen,

Tulane, Penn., JHU, ND, Dakar,

Ouagadougou, Bobo, Abidjan,

Conakry, Cotonou, Libreville,

Ndjamina

FMERIEUX

IPP/CNRS

IRD MALI-TULANE

FIC/ITGH Pharma: Sanofi-

Aventis, Novartis, GSK,

Dafra, Pfizer, Mepha, Bio-

Merieux, Guilin

MIM/TDR/WHO

Intramural :

LMIV, LMVR

FROM LAB TO THE FIELD : MRTC studies

sites

ICH/GCP sites

Other epidemio

sites

CREATING THE MRTC IN 1992: Mali-NIH

Professeur Philippe Ranque

Pr C. Soucko F0.1

Professeur ENSUP

Pr A. Diallo

Recteur Univ. Bko

Pr Y.T. Touré

OMS- Geneva

Pr A.Tounkara

Doyen FMPOS

Pr O.K. Doumbo

Directeur PER / MRTC

F1.1 A. Dolo O. Koita A. Djimde S. Doumbia M. Diallo M. Thera A. Toure S. Diop F. Traore S. Sow B. Traore

F1.2

F2.3 F2.4 F2.5 En formation Mali, Afrique, Europe, USA.

A. Dicko O.B Toure I. Sagara M. Diakite B.Poudiougou M S Sissoko K. Kayentao O. Thiero L Sangare A. Bea

Prof ag.

DER SF

FMPOS

Directeur

LBMA Chef Unité

MEDRU

Chef Unité

GIS/RS

Chef Unité

Diag.Parat.

Prof ag.

Chef Unité

MMVDU

Expert

OMS

Chef Unité

Anthro/Serefo

Directeur

CNAM

Directrice

Phar-Priv

Chef Unité

PREMA

Chef Unité

Epi/Biosta/

Data

Chef Unité

BioInformatic

Sc Doctorant

Tulane, USA

Chef Unité

Genomiq

PI -essai Vaccin

Sotuba

PI -essai Vaccin

Bancoumana

Expert

Millienium

Village

PI - Prema

Kambila /

Sikasso

Biostatics

Der SP

FMPOS

Chercheur

LBMA

Chercheur

Guinée

Vision et Stratégies du MRTC-DEAP

• Formation et Développement d’une masse critique de chercheurs au Mali

• Vaccins les plus promoteurs du stade sanguin: MSP1, MSP3, AMA1

• Vaccin bloquant la transmission: Pfs25-Pfs230

• Vaccin de stade pré érythrocytique: PfSPZ

• Capacité d’essais challenge (CHMI)

Phase Ib, IIa, IIb, III et recherche fondamentale

World Diseases Eradication programs

• Failure Hookworm

Yellow fever

Yaws

Schistosomiasis

Filariasis; Geohelminthes

Malaria

• Success Smallpox

Polio (Americas)

Measles (Americas)

• Near success Polio

Guinea worm

Rinderpest

Rubella (Americas)

Adapted from DA Henderson, malERA Zenith Week, March 2010

Vaccines= most efficient public health tools

PARASITE PREVALENCE IN CHILDREN 2-10 YEARS OLD

IN AFRICA 2000 - 2010

(Noor et al. Lancet 2014; 383:1739)

2000 2010

Key antimalarial interventions & strategies (adapted from Robert Newman, GMP/WHO)

Prevention

Insecticide-treated

bednets (ITNs) /

Long-lasting ITNs

(LLINs)

Indoor Residual

Spraying In areas of moderate to high

and stable transmission

IPT in pregnancy

(IPTp),

IPTi (infant)

IPTc (U5 = SMC)

Diagnosis & Treatment Parasite based diagnosis

Microscopy Rapid Diagnostic

Tests

Artemisinin-based combination therapies (ACTs)

Case management:

Health facilities

Community Case

Management (aka HMM)

Private sector

Surveillance, M & E

Routine HMIS

Malaria surveillance

and response systems

Household surveys

ROLE OF SMC, MDA

Malaria Vaccines ?

Strengthening health systems, Research and Human

Resources for scientific evidences: “evidences based public

health strategies

Artemisinin resistance is a Tsunami coming into Africa

?

?

?

IMPACT DE LA MALARIA SUR LA QUALITE DE LA SCOLARISATION AU MALI ET IMPORTANCE DE LA PARASITEMIE SUB-MICROSCOPICQUE

(Josselin et al., Soc. Sci. Med., 2010

Mosquito Plasmodium

interface mosquito-plasmodium

= adaptation

Human

Changing Epidemiology in Africa and Acquired Immunity to Malaria and Diseases: Ages Switch?

Vaccins antipaludiques: Stades et Impact

Pré-érythrocytique Vaccins pour prévenir l’infection

et impacter sur la maladie

Stade Sanguins Vaccins pour éliminer la maladie

Bloquant la Transmission Vaccins pour prévenir la transmission

Vaccins qui interrompent la Transmission du Paludisme

http://images.google.com/imgres?imgurl=www.mosquitozapper.com/Aedes-treehole-mosquito.gif&imgrefurl=http://www.mosquitozapper.com/danger.html&h=175&w=296&prev=/images?q=mosquito&start=20&svnum=10&hl=en&lr=&ie=UTF-8&oe=UTF-8&sa=N

• 1920s-40s Experiments in bird malaria models

• 1960s Irradiated sporozoites protect in mice

• 1970s Irradiated sporozoites protect in man (Clyde, et.al. University of Maryland)

• 1980s Recombinant DNA techniques – Heterologous expression systems

• Viruses, bacteria, yeast transformed with Plasmodia DNA

– Sub-unit peptide vaccine candidates

• 1990s DNA vaccines

• 2000s Live attenuated whole organism vaccines

Malaria vaccines: History

Malaria Parasite Biologic Complexity

Organism Genome (Mb) HIV 0.01

Polio 0.08

Haemophilus influenzae 1.8

Streptococcus pneumoniae 2.2

Saccharomyces cerevisiae 13

Plasmodium falciparum 30

14 chromosomes, 5200 genes,

epigenetics?

MALARIA SPECIES IN HOMO SAPIENS

• 1] Plasmodium falciparum (Africa)

• 2] Plasmodium malaria (Africa)

• 3] Plasmodium vivax (Africa)

• 4] Plasmodium ovale (Africa)

– Plasmodium ovale wallikeri

– Plasmodium ovale curtisi

• 5] Plasmodium knowlesi (SEA)

growth

mg

hc

What new in Plasmodium biology, transmission and building of natural

immunity in vertebral host

Hafalla et al., 2011

Pre-Erythrocytic Phases/Forms

20

SPOROGONIC DEVELOPMENT AND

DIPLOID AND HAPLOID STAGES IN

ANOPHELES

21

BIOLOGY OF PREGNANCY ASSOCIATED MALARIA and Vaccines developt

Receptors

• CSA -

Thrombomodulin

Betaglycan

• Hyaluronic Acid

• Fc IgG

• others receptors ?

Placenta, CSA Phenotypes

/var2CSA

Micro vessel, CD36, ICAM1….

Adhesion molecules

CD36, ICAM-1, E-Selectin,

VECAM, PECAM-1/CD31 etc..

Fried & Duffy, 1996, 1998, 2000 and others from field

to labs and toward PAM vaccines candidates, PhaseIa,b

Kaplan-Meier curves for the cumulative proportion of children with ⩾1

episode of clinical malaria.

Sacarlal J et al. J Infect Dis. 2009;200:329-336

Sustained efficacy of RTS,S (VE=~50%

Efficacy 30-60% against clinical disease and infection

2010 2011 2012 2013 2014 2015 2016

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

Timeline for RTS,S Phase 3 trial and data

availability (adapted from the RTS,S Consortium)

1

1 2

3 2

1 2 3

Phase 3

trial ends

Legend

= Study reports completed

= Projected submissions to EMEA for Scientific Opinion

= Projected submissions to NRAs

3

Figure 2: Nombre de cas de paludisme et pluviométrie hebdomadaire à Bandiagara.

Community Permission/Consent, Diallo, Doumbo et al., CID 2005

Steps

Procedures

Time, Personnel, and

resources

Study of the community

Elucidate community’s

sociocultural structure and

health system

Identify political and traditional

leadership

9 months for initial study, then

yearly

PI, Medical Anthro, Local

guides, driver

Car

Introductory meeting with

leaders

Introduce research team

Explain the project

Identify best way for community

permission

2-3 hours meeting

PI, local health director, local

guides, driver

car

Formal meeting with leaders

Explain project, risks, benefits,

etc.

Receive and answer questions

2-3 hours meeting

PI, Local health director, local

guides

Broadcasting by local radio

($3.0)

Personal visits to leaders

Visit leaders personally in their

homes for further explanation

and opportunity to answer

specific questions

30 mn – 1 hour

PI, local director, local guides

Car, “Cola-nuts”

Meeting with traditional health

providers

Develop formal agreement with

them for collaboration on the

project

30mn – 1 hour meeting


guides

Car, cola-nuts

Obtaining permission/consent

as a dynamic process

Conduct a modified consultation

process with leaders at each

modification in the protocol or

new research project

2 -3 hours meeting


guides

Broadcasting by local radio

17 malaria vaccine trials completed by MRTC

investigators & collaborators 2003-2015

Site and vaccine Trial design Primary funder Publication

Bandiagara

MSP1 AS02A Phase 1 adults NIAID Mali-Maryland contract Thera et al. PLoS Clin Trials 2006

AMA1 AS02A Phase 1 adults NIAID Mali-Maryland contract Thera et al. PLoS ONE 2008

AMA1 AS02A Phase 1 children NIAID Mali-Maryland ICIDR Thera et al. PLoS ONE 2010

AMA1 AS02A Phase 2 children NIAID Mali-Maryland ICIDR Thera et al. in NEJM 2011

AMA1 Alhydrogel Phase 1 adults AMANET Coulibaly et al. in preparation

Doneguebougou

AMA1C1 Alhydrogel Phase 1 adults Intramural NIAID MVDB Dicko et al. PLoS ONE 2007

AMA1C1 Alhydrogel Phase 1 children Intramural NIAID MVDB Dicko et al. PLoS ONE 2008

AMA1C1 Alhydrogel/CPG MSP 3-Alam Pf-SPZ IV -SANARIA

Phase 1 adults Phase IIb children Phase Ib adults

Intramural NIAID MVDB Pierre Druilhe NIAID-SANARIA

Sagara et al. Vaccine 2009 2011-2012 On Going 2014

Bancoumana

AMA1C1 Alhydrogel/CPG Pf25-EBA et Pfs25-230

Phase 1/2 children Phase Ib adults

Intramural NIAID NIAID/LMIV

Sagara et al. Vaccine 2009 On going 2014-2015

Sotuba

MSP3 Alhydrogel Phase 2 Children AMANET/IPP Cissoko et al., in preparation

Doneguebougou

Malaria Research Center

Site of 3 intramural NIAID malaria vaccine trials Extramural NIAID Tropical Medicine Research Center 1995-2000 Malaria Vaccine Development Branch (MVDB), LMIV-NIH

Site of 1 Vac-4-All consortium malaria vaccine trial (MSP3)

Bougoula Clinical Research Center

• Site of 2 malaria vaccine trials

• Site of several malaria drug trials

– WANECAM consortium

– Vacc-4-All consortium

Bandiagara Malaria Project

• Site of 5 malaria vaccine trials

– Mali-Maryland contract 1998-2006

– Mali-Maryland ICIDR* 2005-2015

*International Center for Infectious Diseases Research

MRTC Support Facilities

• Biostatistics and Medical Informatics Training Lab

• Data Management and Epidemiology Unit

• Clinical lab: CAP/CSLI certified in 2011

FMP2.1/AS02A

– Preuve du concept de protection clinique par un vaccin de stade sanguins établi

– Démonstration efficacité spécifique de souche

• A prendre en compte pour la mise au point des vaccins de seconde génération

AMA-1:

protéine de 83 kD exprimée au

niveau des micronèmes

34 MA THERA, MRTC/DEAP/FMOS - ISFRA

Antigène de la Membrane Apicale 1 (8/10)

Tolérance et Immunogénicité d’un vaccin basé sur AMA-1 chez l’adulte: Phase Ib


Méthodologie

• Essai randomisé en double aveugle

• Dose croissante • 25µg FMP2.1/0,25ml AS02A

• 50µg FMP2.1/0,5ml AS02A

• Vaccin témoin: vaccin antirabique (RabAvert®)

• 3 immunisations à 0, 1 et 2 mois d’intervalle dans le deltoïde gauche


MA THERA, MRTC/DEAP/FMOS - ISFRA 37

Résultats


Tolérance et Immunogénicité d’un vaccin basé sur AMA-1 chez l’enfant: Phase IIa



Résultats


Tolérance, Immunogénicité et Efficacité d’un vaccin basé sur AMA-

1 chez l’enfant en fonction de la diversité antigénique: Phase IIb



Génotypage à Bandiagara

• 748 séquences – 506 infections uniques ou prédominantes

– 242 infections multiples

• 77 SNPs – 62 positions polymorphiques des amino acides

• Domaine I – 36; Domaine II – 11; Domaines III – 8

• 214 haplotypes/506 infections uniques ou prédominantes – Fréquence des haplotypes : 0.2% - 3.6%

– 3.0% correspondent exactement à 3D7


214 AMA-1 haplotypes à Bandiagara

45

Souche vaccinale

3D7 : 3%

MA THERA, MRTC/DEAP/FMOS - ISFRA

Modifications d’aas au niveau c1L sont associées à un risque accru d’épisode clinique de paludisme

46 Takala et al 2009, Dutta et al 2007 MA THERA, MRTC/DEAP/FMOS - ISFRA

Efficacité du vaccin candidat FMP2.1/AS02A contre le premier épisode clinique de paludisme

Efficacité 17,4% IC à 95% [-8,9 – 37,4] p=0,175


Impact FMP2.1/AS02A sur parasitémie A

ire

so

us la

co

urb

e d

e l

a p

ara

sit

ém

ie t

ota

le c

um

ulé

e

Tro

ph

ozo

ïtes

de

P.

falc

ipa

rum

/mm

3

Jour d’étude

Efficacité spécifique d’allèle contre l’épisode clinique de paludisme causé par des parasites similaires à 3D7 au niveau des 8 positions

polymorphiques d’aminoacides

Efficacité 64,3% IC à 95% [14,0 – 91,6]

Protection upon follow-up in 2 cohorts of MSP3 immunized children

Vs control (engerix): Sirima et al., NEJM 2011; Phase Iib enfant au Mali

NEXT GENERATION OF MALARIA VACCINES

1-WHOLE PARASITES Organism VACCINES

a-ATTENUATED SPOROZOITES: SANARIA=S.HOFFMAN, USA

b-SPZ+CQ: CVAC: ROBERT S, NJEMEGEN, NETHERLANDS.

C-ATTENUATED SCHIZONES: M. GOOD, AUSTRALIA

2-COMBINE HAPLOTYPES OF DIFFERENTS PARASITES POPULATION

3- Transmission Blocking Vaccines: Pfs25-230

3-COMBINE STAGES OF PARASITES LIFE CYCLE

PERV + BSV + TBV

Phase 1b Trial to Assess the Safety and Immunogenicity of Direct Venous

Inoculation with Radiation Attenuated Plasmodium falciparum NF54 Sporozoites (PfSPZ Vaccine) in Healthy Malian Adults

Sara A. Healy, Mahamadou S. Sissoko, Freda Omaswa, Abdoulaye Katile, Bourama Kamate, Yacouba Samake, Kourane Sissoko, Amagana Dolo, Karamoko Niare, Amadou Niangaly, Merepen A. Guindo, Erin Gabriel, Michael Fay, Irfan Zaidi, Eric James, Anita Manoj, Anusha Gunasekera,

B. Kim Lee Sim, Peter Billingsley, Stephen L. Hoffman, Ogobara Doumbo, Michael Walther, Patrick Duffy

November 2014

Background Whole Organism Clinical Trials:

Irradiated Sporozoites via Mosquito Bite

1950 1960 1970 1980 1990 2000 2010 1940

Established that human volunteers could be

protected against controlled human malaria

infection(CHMI) with infectious mosquitoes

after being bitten by mosquitoes carrying

irradiated sporozoites

Clyde et al. Am J Med Sci. 1973; Clyde et al. Am J Med Sci. 1973; Clyde et al. Am J Trop Med Hyg. 1975;

Rieckmann et al. Trans R Soc Trop Med Hyg. 1974; Rieckmann et al. Bull World Health Organ. 1979;

Rieckmann et al. Bull World Health Organ. 1990’; McCarthy and Clyde. Exp Parasitol. 1977

2014

Background Whole Organism Clinical Trials:

Irradiated Sporozoites via Mosquito Bite

1950 1960 1970 1980 1990 2000 2010 1940

Continued validation and definition of

the irradiated sporozoite model as

protective – various degrees of

irradiation, heterologous challenge,

and number of immunizing bites.

Herrington et al. Am J Trop Med Hyg. 1991; Edelman et al. J Infect Dis. 1993; Egan et al. Am J Trop Med

Hyg. 1993.

2014

>1,000 mosquito bites <1 year from last dose to challenge

Protected/Tested Volunteers

P falciparum homologous challenge

14/15

P falciparum heterologous challenge

4/4

Background Irradiated Sporozoites via Mosquito Bite

• Development had not been previously pursued due to:

– Considered technically impractical or impossible

– Considered unnecessary since modern subunit vaccines would solve the problem

Background Irradiated Sporozoites via Injection:

PfSPZ Vaccine • Sanaria, Inc.

– Harvest sporozoites from the salivary glands of irradiated mosquitoes

– Purified and cryopreserved the irradiated sporozoites from aseptic mosquitoes in the quantities necessary for vaccination

Background Clinical Trials: PfSPZ DVI Trial

1950 1960 1970 1980 1990 2000 2010 1940

Open-label evaluation of the safety,

tolerability, immunogenicity and protective

efficacy against CHMI of the PfSPZ

vaccine at successively higher dosages.

Subjects are enrolled in a step-wise, dose-

escalation manner

2014

Seder et al. Science. 2013

• 57 subjects enrolled, 44 underwent CHMI: – Group 1: 2,000 SPZ dose (n=3); 1-2 doses – safety – Group 2: 7,500 SPZ dose (n=6); 4-6 doses – Group 3: 30,000 SPZ dose (n=11); 4-6 doses – Group 4: 135,000 SPZ dose (n=15); 4-5 doses

• Well tolerated and safe • Sterile immunity at highest doses

– 6/6 subjects with 5 doses of 135K sporozoites protected – PfSPZ Vaccine is potent and highly protective in humans.

Seder et al. Science. 2013

• Donéguébougou & Surrounding villages – 30 km NE of Bamako

– ~ 7,000 inhabitants

• Malaria transmission is highly seasonal, with a transmission season taking place from June until December.

• Entomological inoculation rates is > 100 infectious bites per person/ transmission season.

PfSPZ Trial Site in Mali

Dicko A. t al. Am J Trop Med Hyg. Dec 2007;77(6):1028-1033

Primary Objective

• To test Sanaria, Inc. product in malaria endemic African population, we are conducting a Phase Ib, double blind, randomized, controlled clinical trial:

– to assess the repeated DVI PfSPZ Vaccine’s safety in malaria exposed healthy adults, 18-35 years, Malians.

Trial profile Community Consent (n=4)

Screened (n=296)

Enrolled (n=109)

Pilot Safety Group

Vac #1 (Day 0) -- 1.35x105 PfSPZ Vaccine (n=12)

Vac #2 (Day 14) – 2.7x105 PfSPZ Vaccine (n=12)




Main Phase

Vac #1 (Day 0) – 2.7x105 PfSPZ Vaccine or placebo (n=93)





199 screen

failures: EKG,

HBS+, Sickle cell

trait, ABP,…

Total Vaccine Dose: 12.15 x 105 PfSPZ

Vaccine

Total Vaccine Dose:13.5 x 105 PfSPZ

Vaccine

PfSPZ Vaccine Coordination and Administration

• PfSPZ Vaccine is cryopreserved in aliquots of 20 microL in 0.5 mL cryovials and stored in LNVP at below -150oC.

• Diluent : PBS and HSA. Stored in controlled room.

• Normal saline as Placebo for the control Group

Safety: Incidence & Severity of Local/Systemic AEs

#OF AE’S

FOLLOWING

Vac #1

(N=105)

#OF AE’S

FOLLOWING

Vac #2

(N=102)

#OF AE’S

FOLLOWING

Vac #3

(N=99)

#OF AE’S

FOLLOWING

Vac #4

(N=99)

#OF AE’S

FOLLOWING

Vac #5

(N=97)

TOTAL 3 4 5 4 6

Mild 3 4 5 4 6

Moderate 0 0 0 0 0

Severe 0 0 0 0 0

Potential Life

threatening

0 0 0 0 0

•4 local reactogenicity: all local injection site pain

•18 solicited systemic reactogenicity: Headache (11), Fatigue (3), Myalgia

(2), Pyrexia (2) •All solicited AEs are deemed possibly/probably/definitely related to the

investigational product given the timing of their occurrence post

vaccination.

Safety: Unsolicited AEs

Number of

Unsolicited AEs

Related

TOTAL 181 47 (26.1%)

Mild 151 43 (28.5%)

Moderate 25 4 (16.0%)

Severe 5 0 (0.0%)

Potential Life

threatening

0 0 (0.0%)

•The most commonly reported AEs have been :

•Lab AEs (Grade 1 ): leukopenia (20), granulocyte count decreased (13), and hemoglobin decreased

(11).

•Clinical AEs (Grade 1): rhinitis (16), headache (13), and clinical malaria (12).

•25 reported Grade 2 AEs (14%): among them 4 AEs were deemed related to the investigational product given

the timing of their occurrence post vaccination.

•5 reported Grade 3 AEs (2.8%): influenza-like illness, sinobronchitis, and malaria in three subjects. All

deemed by the investigator to be not related to the investigational product.

Conclusion and future of PfSPZ in Mali

• MS Sissoko et al., results of PhaseI1/2 Mali in NEJM 2015 in preparation

• Phase II in 2015 Mali in preparation

• CHMI vs Heterologous natural challenge

• International Vaccinology course in Africa 2015: Oxford university, CICM/FMerieux, MRTC: Bamako Octobre 2015

Model for “exhausted” memory B cells in persistent infections.

Moir et al, JEM 2008 (CD20hi/ CD27-/ CD21lo/FcRL4+)

‘Exhausted’ or ‘atypical’ memory B cells are greatly expanded in children and adults in malaria-endemic Mali.

Weiss et al, J Immunol, 2009

Differential susceptibility to malaria in sympatric

ethnic groups in Mali: Dogon vs Fulani A

Farouk, Dolo et al., 2005

↑ DC activation ↑ IFN-g normal TLR responses → Potent T cell activation? ↑ humoral immunity

Impaired DC activation ↓ IFN-g

impaired TLR responses → poor T cell activation? ↓ humoral immunity

Disease Protection

Fulani Dogon

Possible mechanism of protection against

malaria: the Fulani-Dogon in Mali

P. falciparum

Charles Arama, MRTC & Wenner-Gren Institute, Department of Immunology 15-03-2012

New tools in Infectious Diseases studies: Serological profiling against many falciparum peptides: Arrays/OMICs

Crompton P D et al. PNAS 2010;107:6958-6963

THE CHARMS OF THE MRTC

LUNCH AT THE BANCOMANO FIELD STATION, 1997:

H Varmus , LH Miller, and MRTC team

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Développement Clinique de Candidats Vaccins Antimalariques ...jfsph.net/files/uploads/Developpement_clinique_vaccins_antimalaria... · Développement Clinique de Candidats Vaccins