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Inception Workshop at ILRI-Nairobi, January 27-29th 2014
“Improved vaccines for the control of ECF in cattle in Africa”
Executive summary Due to high mortality and morbidity rates livestock diseases are an impediment to the livelihoods of poor farmers in Africa, who struggle to attain food and nutritional and economic security. Vaccines can alleviate such constraints as they are among the most successful disease interventions invented. The goal of this project is to increase cattle productivity through the development of improved vaccines for the control of East Coast fever (ECF). ECF caused by the protozoan parasite Theileria parva ranks first in tick-borne disease constraints of cattle in sub-Saharan Africa and kills one animal every 30 seconds. It has a devastating impact on pastoralists and smallholder farmers because it can kill within 3-4 weeks of infection. ECF is present in 11 countries where roughly 28 million cattle are at risk, but has the potential to spread with the uncontrolled movement of infected cattle as the distribution of the tick vector and suitable tick habitats is wider than that of the parasite. Over one million cattle die of ECF each year resulting in annual losses exceeding $300 million. Our goal is to design subunit vaccines for the control of ECF. In phase 1, we proposed a range of key strategic activities in the research to product development continuum to:
• Improve aspects of the current sub-optimal live (infection and treatment method - ITM) ECF vaccine.
• Fill knowledge gaps regarding the qualitative and quantitative aspects of acquired immune responses that mediate immunity to ECF.
• Test the vaccine potential of candidate vaccine antigens and develop a more detailed antigen map.
Outputs from this phase will contribute in the short-term to production of a better quality live vaccine as an interim vaccine solution and provide proof-of-concept for an ECF subunit vaccine aimed at obtaining evidence of protection in 70~80% of animals of defined MHC genotype given a homologous parasite challenge. Success in phase 1 will contribute to our goal of developing a broad-spectrum subunit vaccine for the control of ECF (phase 2). In order to achieve these objectives we have assembled a team of multi-national experts from the field of ECF research, bovine immunology, parasitology and genomics with essential inputs from a private-public partnership and the private sector. An advisory panel will provide scientific oversight and help evaluate progress and stop-go decisions. This panel will interact with a project management committee to ensure that technical risks are reduced and activities are completed or re-directed in a timely manner, within budget and that maximum advantage is taken of knowledge and learning generated during the project. ECF activities are also funded by the Normal Borlaug Commemorative Research Initiative (NBCRI) and the CGIAR Research Program on Livestock and Fish.
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Project Objectives: 2013 - 2017 1. To improve aspects of the current live infection and treatment method ECF vaccine.
This is a short-term objective over two years that should give rise to methods for determining viable sporozoite counts and relating this to infectivity, which will enable downstream improvements to be made to the production of the ITM vaccine; e.g., stabilate titration, pre-determining smaller dose sizes and testing new cryo-protectants. Key milestone: a new method for viable sporozoite counts.
2. To induce antibody based immunity by targeting the sporozoite stage of the parasite. This is a medium-term objective over 2~4 years, which should result in re-assessment of the role of known as well as novel sporozoite molecules as candidate vaccine antigens. Key milestones: a denser map of sporozoite antigens and evidence for a role for antigens in a subunit vaccine.
3. To induce T-cell mediated immunity by targeting the schizont stage of the parasite. This is a medium-term objective over 4 years, which will improve our knowledge on how the process of ITM works, assess a variety of antigen delivery systems for priming CTLs in cattle and identify new schizont T cell antigens. Key milestones: role of other cells in priming CD8+ T cells, molecular signatures of protection, a denser map of schizont antigens, proof-of-concept of a schizont vaccine.
4. Application of evolutionary and comparative pathogen genomics to ECF vaccinology. This is a medium-term objective over 3 years, which will improve genomic resources for T. parva. Key milestones: improved genome annotation, antigen identification and a map of genetic variation.
5. To test if a combined antibody and T-cell mediated immune response is more efficacious than either one alone. This is a medium- term objective in the second half of the project, which will test if targeting immune responses to both the sporozoite and schizont stage of the parasite works synergistically. These experiments will be especially useful if testing of sporozoite and schizont antigens in isolation does not provide high levels of immunity. Key milestone: proof-of-concept vaccine targeting two parasite stages.
The proposed Consortium and its collaborators constitute a group of experienced scientists with a long history of research in ECF. This initiative brings together for the first time vast experience in immunology, vaccine development and infectious disease research. Thus, we are confident that we will make significant progress in our goal of developing a broad-spectrum subunit vaccine for the control of ECF. It is difficult to predict where the science breakthroughs will occur in this project and we are aware that stop-go decisions will need to be made to cease unproductive research and to divert focus to new avenues and allow for innovation. The Results Framework, regular scientific updates and reporting will help the latter and an External Advisory Committee (EAC) will play a critical role in meeting the stated objectives.
Scientific management of the project will occur through a Project Management Committee (PMC). The PMC will interact with an External Advisory Committee (EAC) and other members of the consortium at the start of the project and on an annual basis to help review, provide scientific oversight and help evaluate go-no-go decisions and redirection of research to maintain flexibility within the scope of the project. A fifth and final meeting will be held at the completion of the project.
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Project Management Committee Project Director: Vish Nene Institute of Tropical Medicine, Antwerp: Dirk Berkvens GALVmed: Peter Jefferies ILRI: Lucilla Steinaa Institute for Genome Sciences (IGS): Joana Carneiro da Silva Roslin Institute: Ivan Morrison Royal Vet College (RVC): Declan McKeever USDA-ARS: Don Knowles Washington State University (WSU): Wendy Brown External Advisory Committee Tony Musoke (Chair), Simon Draper, Shahid Khan All members of the PMC are senior scientists with proven expertise and track records in implementing and completing research projects. Each member of the Consortium will submit annual work plans, key results areas and budget reports, which will be used to assess performance and progress. The PMC will hold electronic meetings at monthly intervals to assess the project, learn from each other, troubleshoot problems and resolve conflicts. Minutes of each meeting and action points will be recorded. The ILRI Knowledge Management and Information Systems (KMIS) team will help implement and update a project website for communication, tracking and management of projected related activities. A Program Management Officer at ILRI will be responsible for day-to-day administrative functions and will work closely with the PI, the ILRI Deputy Director of Biosciences, Suzanne Bertrand, and sub-grantee Financial and Administrative staff. Fiduciary oversight will be the responsibility of the ILRI Director of Corporate Services, Martin van Weerdenburg. ILRI assesses internal performance via key results areas, which are defined on an annual basis and modified as required through continual assessment, as a means of tracking, measuring and monitoring progress. These frameworks will help in the implementation and assessment of the proposed research. ILRI will submit annual science and financial reports to the Foundation and at the completion of the proposed activities.
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Inception workshop draft agenda – day 1 Day 1 – 27th January 2014 08.30-0.900 Registration outside JVC Auditorium
Session 1 Introductions
Chair: Nene
09.00 - 09.10 Welcome to ILRI Smith 09.10 - 09.20 BMGF – alignment with strategy Sam T or Peters 09.20 - 09.30 NBCRI & Feed the Future – alignment with strategy Parish or Herrera 09.30 – 10.00 Introduction of participants (expectations) and External
Advisory Committee Nene
10.00 – 10.30 COFFEE BREAK
Session 2 Brief overviews on East Coast fever Chair: Peters 10.30 - 10.45 Theileriosis caused by T. parva: background, disease
syndrome, economic impact, Livestock and Fish CRP Nene
10.45 - 11.00 T. parva whole genome sequence databases Nene 11.00 - 11.15 Molecular markers for strains/isolates/Muguga cocktail Pelle 11.15 – 11.30 Anti-sporozoite based immunity Steinaa 11.30 – 12.00 Anti-schizont based immunity Morrison 12.00 – 12.30 GENERAL DISCUSSION
12:30 – 13:30 LUNCH BREAK
13:30 – 14.00 Production process of an ITM vaccine and status on the Muguga cocktail
Jefferies (Mbao, Chaka?)
14.00 – 14.30 ECF Target product profile and project Results Framework Peters, Nene Session 3 Anti-sporozoite based immunity
Chair: Naessens
Objective 2: To induce antibody based immunity by targeting the sporozoite stage of the parasite.
14.30 – 15.00 2.1. Re-assessment of the sporozoite p67 molecule as a candidate vaccine antigen – thoughts on NIT assays
Pelle, LaCasta
15.00 – 15.15 2.2. Skewing the bovine antibody response to sporozoite neutralizing determinants on PIM
Geysen, de Goeyse
15.15 – 15.30 2.3. Characterization of sporozoite ligands and host cell receptors that mediate the infection process
Geysen
15.30 – 16.00 COFFEE BREAK
16.00 – 16.15 2.3. Characterization of sporozoite ligands and host cell receptors that mediate the infection process
Pelle
16.15 – 16.30 2.4. Test new and combinations of sporozoite molecules (LD70 versus LD100 debate?)
Steinaa, Nene
16.30 – 17.30 SPOROZOITE DISCUSSION
To be announced
TRANSPORT TO HOTELS
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Inception workshop draft agenda – day 2
DAY 2 – 28th January 2014 Session 4 The Infection and treatment method (ITM) of
immunization Chair: Kiara
Objective 1: To improve aspects of the current live infection and treatment method ECF vaccine.
09.00 – 09.30 1.1. Improve the ITM production process Geysen 09.30 – 10.00 1.1. Improve the ITM production process Tindih 10.00 – 10.30 ITM DISCUSSION
10.30 – 11.00 COFFEE BREAK
Session 5 Anti-schizont based immunity
Chair: Nene
Objective 3: To induce T-cell mediated immunity by targeting the schizont stage of the parasite
11.00 – 11.30 3.1. Characterize the magnitude and kinetics of specific T cell responses following immunization and challenge
Morrison
11.30 – 12.00 3.2. Assess the requirements for induction of a protective T cell response
McKeever
12.00 – 12.30 3.3. Transcriptional and functional profiles of a protective T cell response
Morrison
12.30 – 13.30 LUNCH BREAK
13.30 – 14.00 3.4. Identify additional antigens recognized by T. parva-specific T cells: CD8 antigens
Morrison
14.00 – 14.30 3.4. Identify additional antigens recognized by T. parva-specific T cells: CD4 antigens
Brown
14.30 – 15.00 COFFEE BREAK
15.00 – 15.30 3.5. Evaluate different antigen delivery systems using known schizont T-cell candidate vaccine antigens
Steinaa
15.30 – 16.00 3.5. Evaluate different antigen delivery systems using known schizont T-cell candidate vaccine antigens
Connelley
16.00 – 16.30 3.5. Evaluate different antigen delivery systems using known schizont T-cell candidate vaccine antigens
McKeever
16.30 -16.40 3.6. Vaccine trials of schizont antigens using selected antigen delivery systems
Steinaa
16.40 - 17.30 SCHIZONT DISCUSSION
18.00 – 21.00 COCKTAIL - ILRI COURTYARD
To be announced
TRANSPORT TO HOTELS
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Inception workshop draft agenda – day 3 DAY 3 – 29th JANUARY 2014
Session 6 T. parva genomics
Chair: Bishop
Objective 4: Application of evolutionary and comparative pathogen genomics to ECF vaccinology
09.00 – 09.30 4.1. Generation of a genome wide locus specific map of genetic variation of T. parva
Carniero de Silva
09.30 – 10.00 4.2. Use a genomics approach to prioritize genes as candidate vaccine antigens
Carniero de Silva
Session 7 Combined anti-sporozoite and anti-schizont immunity
Chair: Nene
Objective 5: To test if a combined antibody and T-cell mediated immune response is more efficacious than either one alone
10.00 – 10.30 5.1. Vaccine trials with best bet combinations of sporozoite and schizont candidate vaccine antigens and antigen delivery systems
Steinaa, Nene
10.30 – 11.00 COFFEE BREAK
Session 8 Alignment with NBCRI Feed the Future funding Chair: Parish 11.00 – 11.30 Overview of activities Knowles 11.30 – 12.00 Overview of activities Nene 12.00 – 12.30 GENERAL DISCUSSION
12.30 – 13.30 LUNCH BREAK
Session 9 Project Administration and Management (PMC and EAC members only)
Chair: Nene
13.30 – 16.30 Adjust Results Framework timelines Intellectual Property, global access, DDQ Data & reagent sharing, release and publications Budget management and reporting Science reporting 15.00 – 15.30 COFFEE BREAK
On line meetings, minutes, archiving, PR Annual meetings External Advisory Committee Session 10 Ad hoc group discussions (non-PMC/EAC members) Chair: Pelle 13.30 – 16.30 To be announced 15.00 – 15.30 COFFEE BREAK
Session 11 CLOSE OF MEETING Chair: Peters 16.30 – 17.00 Report to whole group on session 9
Nene
17.00 – 17.30 Wrap up Musoke, Sam T, Parish, Herrera Bertrand
To be announced
TRANSPORT TO HOTELS
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Attendees
ECF Consortium members Belgium Dirk Berkvens, Dirk Geysen, Ine de Goeyse Kenya Richard Bishop, Henry Kiara, Jan Naessens, Vish Nene, Roger Pelle, Tatjana Sitt, Lucilla Steinaa, Phil Toye, Nicholas Svitek, Anna La Casta, Elias Awino, Rosemary Saya, Thomas Njoroge, John Wasilwa, Charity Muthoni, Benjamin Nzau, Stephen Munyao, Sarah Nyongesa, David Kiereini, Jerome Wendoh, Suzanne Bertrand, Jimmy Smith Malawi George Chaka (to be confirmed) UK Tim Connelley, Simon Graham, Declan McKeever, Dirk Werling, Niall McHugh, Ivan Morrison, Peter Jefferies, Heshbrone Tindih, Victor Mbao (to be confirmed) USA Wendy Brown, Don Knowles, David Prieur, Joana Carneiro de Silva
Donor Observers BMGF Samuel Thevasagayam, Andy Peters USAID (NBCRI & Feed the Future) Lindsay Parish, Cynthia Baldwin USDA-ARS Eileen Herrera, Eileen Thacker
External Advisory Committee members Tony Musoke – Chair Simon Draper Shahid Khan One more position to be filled Simon Graham (as a resource person for the first EAC meeting)
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CURRENT MEMBERS OF THE EXTERNAL ADVISORY COMMITTEE (EAC) Tony Musoke Chair of EAC
Plot# 5A Buwaya View Road, Entebbe, Uganda c/o LKM Medicial Laboratories and Consultancies Lumumba Road Plot #2 P. O. Box 33686, Kampala, Uganda E-‐mail: [email protected] Phone: +256 787 274965 Tony Musoke is currently a private Consultant and a partner in a human Diagnostic Laboratory, in Kampala. Prior to this he took over the stewardship of Onderstepoort Veterinary Institute as the Research Institute Manager (Director) until September 2013, after serving the
Institute for nine years. Research I worked at The East African Community Laboratories, (now KARI) where I contributed to the design/formulation and carrying out experiments that gave rise to the development of the infection and treatment method of immunization. During my tenure at ILRAD/ILRI, I was engaged in research to develop control strategies for tick-‐borne pathogens and African trypanosomes. This work involved looking for an immunological control for these vector-‐borne pathogens and development of diagnostic tools for both tick-‐borne diseases and trypanosomes. My Group was also involved in defining the protective immune mechanisms in Contagious Bovine Pleuro-‐Pneumonia (CBPP) as well as Contagious Caprine Pleuro-‐Pneumonia (CCPP). The work on Trypanosomes showed the dynamics of antibody production in cattle infected with the disease and also led to the discovery that trypanosomes reappear during an infection, an indication that the parasites may exhaust their repertoire of variable surface antigens (VSGs). My research group initiated studies that led to the identification of p67, a sporozoite surface molecule of Theileria.parva, as the first experimental subunit vaccine against the parasite. Immunization with recombinant p67 reduced mortality by at least 50% against laboratory and field challenge. This was the first demonstration that humoral responses are involved in the protection against East Coast fever infection in cattle, discrediting the dogma that antibodies had no role in immunity against the disease. The Group was granted patents by the USA and Kenyan intellectual properties offices for this work. I received the Ciba-‐Geigy Research Prize in 1992 in recognition of my efforts and was also awarded the Kenya Veterinarian/Researcher of the year prize in the same year. More recently, I was awarded (October 2008) the Elsdon -‐ Dew Award by The Parasitological Society of Southern Africa, for my contribution to parasitology.
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Simon Draper Member of EAC The Jenner Institute, Old Road Campus Research Building Roosevelt Drive, Oxford, OX3 7DQ Tel: +44-‐1865-‐617624 E-‐mail: [email protected] Principal areas of research: Blood-‐stage and transmission-‐blocking malaria vaccine development; adenovirus and MVA vaccines; malaria immunology My undergraduate degree was in Molecular and Cellular Biochemistry at Trinity College, Oxford University, and included research projects at the Institute for Hormone and Fertility Research in Hamburg, Germany,
and at the Weatherall Institute of Molecular Medicine in Oxford with Dr Chris Norbury. I subsequently joined Prof Adrian Hill’s research group in the Nuffield Department of Medicine at Oxford University. The subject of my DPhil thesis was the development of new antibody-‐inducing vectored vaccines against the blood-‐stage of malaria infection. I have since stayed on at the Jenner Institute, first as a Junior Research Fellow of Merton College, and subsequently as a MRC Career Development Fellow. The aim of my work is to develop and translate new vaccine candidates for malaria into proof-‐of-‐concept human clinical studies. My group has a particular interest in optimising antibody induction by vectored vaccines, as well as better understanding vaccine-‐induced immunity to the blood-‐ and mosquito-‐stages of malaria infection. Shahid Khan Member of EAC
Leiden University Medical Center Building 1, Room P4-‐31 Postzone L4-‐Q P.O. Box 9600 2300 RC Leiden The Netherlands Tel: +31(0)715261405 E-‐mail: [email protected] Principle areas of research: Parasitology – Malaria; Cell Biology; Molecular Biology and Proteomics Shahid Khan is an Assistant Professor in the Leiden Malaria Research Group, Leiden University Medical Center, Netherlands. Shahid graduated with a degree in Parasitology from the University of Glasgow, after which
he worked for one year as a Research Assistant in the Institute of Medical Medicine, University of Oxford (in the group of Chris Newbold). For his PhD he moved to the University of Cambridge (Cambridge, UK), where his studies were focused on genetic and physical chromosomal mapping of another medically important Apicomplexan parasite, Toxoplasma gondii. For post-‐doctoral research he moved to the National Institute for Medical Research (London, UK) retuning to research on malaria, where he examined the expansion and expression of multi-‐gene families involved in parasite invasion of red blood cells. After this he moved to Leiden, Netherlands and to the group of Chris Janse and Andy Waters, and in collaboration with the group Matthias Mann (then Odense, Denmark), performed in depth and large scale proteome analyses on different stages of the malaria parasite and coupled this with the targeted deletion of parasite genes to uncover novel aspects of the parasite’s biology.
