1. Malaria vaccine development: Recent progress, future challenges Christian Loucq, MD Director, PATH Malaria Vaccine Initiative All Party Parliamentary Group on Malaria and Neglected Tropical Diseases October 26, 2009

2. 2 A world free from malaria Established in 1999 as a program of PATH. Current donors: Bill & Melinda Gates Foundation, USAID, ExxonMobil Foundation, private individuals PATH Malaria Vaccine Initiative Mission and vision To accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world

3. MVI: a global program of PATH PATH : a catalyst for global health

4. 4 Role of MACEPA Many groups/organizations involved in the purchasing and distribution of bednets, few are measuring impact of the interventions One of the important roles of MACEPA— supported the coordination of malaria M&E in Zambia Partner in the development of the RBM MERG Malaria Indicator Survey (MIS) Document and disseminate success stories

5. 5 PATH background International nonprofit to help provide appropriate health technologies and vital strategies to improve global health and well-being Particular focus on: –HIV, TB, and malaria (MACEPA and MVI) –Health technologies designed for low-resource settings –Safer childbirth and healthy children –Health equity for women –Basic protection of vaccines

6. 6 Why a malaria vaccine? Malaria –900,000 deaths –US$ 12 billion –40 percent of public health spending Control Elimination / Eradication

7. Why a malaria vaccine?

8. 8 Malaria 101 A parasitic infection transmitted to humans through the bite of infected female Anopheles mosquitoes Five Plasmodium sp. infect humans; falciparum and vivax cause the vast majority of clinical cases Almost all serious disease/deaths are caused by P. falciparum malaria in children under 5 years of age

9. 9 Challenges to developing malaria vaccines Scientific: –No vaccine is in human use against a parasite –Malaria parasite has ~6,000 genes, many more than a virus –How best to provoke immune response? –How to predict a vaccine candidate’s success? Commercial: –Limited market in developed countries –Endemic countries mostly poor –High-risk, high-level investment

10. Where are we today? World’s most clinically advanced vaccine candidate is RTS,S Collaboration with GSK Bio (Belgium), 11 study centers (in seven African countries), and Northern institutions Phase 3 trial now up and running in all seven countries, 10 of 11 sites

11. KCCR, Kumasi Gabon IRSS - Centre Muraz Burkina Faso KHRC, Kintampo Ghana HAS, Lambaréné Kenya Tanzania IHDRC, Bagamoyo, Tanzania KEMRI/WRAIR – Kombewa JMP, Korogwe, Tanzania KEMRI/CDC – Siaya KEMRI/Kilifi UNC, Lilongwe Malawi CISM, Manhiça Mozambique RTS,S project is MVI’s largest collaboration

12. Where are we today? A second vaccine approach approved for first-in-human trial in the United States Sanaria Inc. seeks to replicate original experiment with irradiated mosquitoes

13. How MVI works MVI partners to achieve its mission; success depends on the strength of its collaborations MVI is a non-profit vaccine investor. Partners include academia, government agencies, biotechs, pharmaceutical companies MVI identifies potentially promising malaria vaccine candidates and approaches, then… MVI systematically move candidates and approaches through the development process.

14. 14 Preclinical Feasibility*Translational Project Candidate Vaccines AntigensDeliveryPreclinicalPhase 1Phase 2aPhase 2bPhase 3 SBRI (antigen selection) Aeras (rBCG) Crucell (Ad26/35- CSP) Sanaria (whole irradiated sporozoite) GSK (RTS,S/AS01) WEHI (AMA1) GenVec (Ad28) ICGEB (PvRII) LaTrobe/QIMR (MSP2) LaTrobe/WRAIR (AMA1) VGX/U Penn (pDNA/EP) NIH/QIMR (AMA1) WEHI/NIH (EBA/Rh Lipoxen/NIH (Imu/Xen) Juvaris/NIH (JVRS-100) USMMVP/NIH/ GenVec (Ad5/Protein+Adj) NIH (conjugates) Pre-erythrocytic Blood-stage Transmission- blocking MVI Portfolio *Selected projects

15. 15 MVI collaborators include…

16. Goals in sight? Vaccine goal for 2015 in sight –50% efficacy against severe disease –Lasts more than one year –Another tool to achieve malaria control Next-generation vaccine could be in the pipeline now –Higher efficacy, lasts longer than 4 years –Transmission blocking? –Key to malaria elimination, eradication

17. 17 Malaria vaccine community goal By 2025, to develop and license a malaria vaccine that has a protective efficacy of more than 80% against clinical disease and lasts longer than four years BUT, Could we do more?

18. 18 Goal: Malaria eradication

19. What comes next? Focus on questions to be answered

20. 20 Different types of vaccine target different stages of the lifecycle Pre-erythrocytic vaccines Blood-stage vaccines Transmission-blocking vaccines

21. Pre-erythrocytic Stage Prevent infection Blood-stageReduce clinical disease Transmission- blocking Prevent the spread of parasites by mosquitoes Different types of vaccine target different stages of the lifecycle

22. 22 Transmission-blocking vaccines target the parasite in the mosquito—and mosquito itself

23. 23 Transmission-blocking vaccines Goal: Interrupt lifecycle to reduce transmission Strategies: 1. Block production of gametocytes (highly effective PE vaccine) 2. Block oocyst formation in mosquito (prevent transmission of the disease) TBVs target transmission: –No direct, immediate benefit to vaccinee –Infections reduced due to reduced transmission (herd effect) 2 1

24. 24 MFA with sera (1:2) from baboons immunized with CH-rPfs48/45 in Montanide ISA-51 # Doses % Blocking (MFA) Primary93 + 3 (88–94) Boost 197 + 1 (95–98) Boost 2 (15d)97 + 1 (95–99) Boost 2 (30 d)97 + 1 (96–98) Boost 2 (3 mo)97 + 1 (95–99) Chowdhury, DR. et al. PLoS One July 2009. 4(7):1–10 Nov 10 Dec 10 Jan 10 Feb 5 Feb 21 Mar 6 May 5 Primary 1 st boost 2 nd boost Time points of various bleeds from animals A

25. 25 MFA to evaluate transmission blocking antibodies Cultured serum + gametocytes fed to starved mosquitoes through membrane Count oocysts in midgut 1 week later. Result: % oocyst reduction

26. 26 Vaccines: Critical component of coordinated eradication effort Vector control –Insecticide treated bednets –Indoor residual spraying –Integrated vector management Drug therapy Vaccines

27. Final thoughts… Malaria eradication will not happen without vaccines Funding for R&D — and introduction — is needed Collaboration Coordination Commitment

28. 28 Tomorrow…

29. Thank You www.path.org www.malariavaccine.org