1. Research: Malaria Vaccine and Development Baraka Amuri Ifakara Health Institute (IHI)

2. Presentation Outline Research and Development Clinical phases Target sites for malaria vaccines Challenges

3. Research & Development Identify Antigen s Produce Antigens Test in Animal s Proof of Concept Phase IIIIFile x Registration /Post marktng x up to 10- 20M$ up to 50-100M$ up to 500-1B$ x x 1-10 yrs 2-3yrs 2-4 yrs  1 yr x Transfer Process to Manufacturing Build Facility II Research (Inc. Immunology) Preclinical Development (Inc. Formulation Science) Clinical Development (Inc Post Marketing Surveillance

4. Vaccine/Drug Development Model Stage 1a Discovery per se Stage 1b Transitional research Stage 1c Non-regulated Non-clinical research Stage of Development: A.Discovery and Pre-clinical Stages B.Clinical Phases/stages i.Phase I ii.Phase II iii.Phase II iv.Phase IV

5. Stage 1a: Discovery per se Researcher/scientist identifies a possible new vaccine/drug candidate Identifying signs that a compound may have a therapeutic potential Idea come from: Direct observation Scientific literature Knowledge of traditional practices Systematic screening Unlikely the research progress smoothly; researcher meet many dead ends and may collect inconclusive results

6. Stage 1b: Transitional research Researcher tries to characterize the active pharmaceutical ingredient (API) Investigate on how to produce and analyze the API Biological experimentation to investigate its actions in cells, tissues or the whole body

7. Stage 1c: Non-regulated, non-clinical research Biological tests on subcellular systems, tissues and/or animals provide evidence for efficacy – i.e. ‘proof of principle’ (POP) Rigorously controlled studies with biological models Indicates whether the compound is biologically active Whether it is likely to be efficacious in man A sufficient supply of well-characterized test compound has to be ensured

8. Example Stage 1a Discovery per se Stage 1b Transitional research Stage 1c Non-regulated Non-clinical research A researcher knows that a population traditionally uses a local herb to alleviate an affective disorder. But the herb contains dozens of interesting compounds of which several might be the active principle Isolation of the most promising API, further exploration of the biological activity in cell, tissues and/or animal model. Methods of producing and analyzing the compound Receptor binding studies and animal behavioral models are most useful for establishing potential for efficacy

9. Clinical trial of Malaria vaccine Animal models Safety, immunogenicity, tolerability, efficacy Safety, immunogenicity, tolerability Non-immune human volunteers in non-malarious areas. Clinical setting Human volunteers. Experimental challenge with infected mosquitos. Clinical setting Phase IIa: non-immune volunteers Phase IIb: Immune volunteers Vaccine efficacy, safety, tolerability, acceptance Semi-immune residents of malarious areas (all endemicities). Small target population, special groups. Natural challenge Semi-immune residents of malarious areas.Large target population, whole communities Natural Challenge Vaccine efficacy, safety, tolerability, acceptance Vaccine efficacy, safety, tolerability, acceptance, vaccination strategy, effectiveness PHASE 0 Preclinical PHASE 1 Clinical PHASE II Clinical PHASE III PHASE IV

10. Developing any vaccine is hard Can take 10-20 years to develop a product. Cost hundreds of millions of dollars Phase 3 Phase 2 Phase 1a Pre-clinical Laboratory Phase 1b

11. Malaria: Plasmodium Life Cycle Liver Stage Blood Stage Sporozoites Merozoites Gametocyte s

12. Malaria: Plasmodium Life Cycle Liver Stage Sporozoites Pre-erythrocytic Stage Pre-erythrocytic stage, that is the stage that takes place shortly after being bitten by an infected mosquito up to and including the liver stage. Pre-erythrocytic stage, that is the stage that takes place shortly after being bitten by an infected mosquito up to and including the liver stage.

13. Pre-erythrocytic Stage Vaccines How they work: Generates Ab response against sporozoites and prevents them from invading the liver Prevents intra-hepatic multiplication by killing parasite-infected hepatocytes Intended Use: Ideal for travelers - protects against malaria infection

14. Malaria: Plasmodium Life Cycle Blood Stage Merozoites Asexual Erythrocytic Stage

15. Asexual Erythrocytic Stage Vaccines How they work: Elicit antibodies that will inactivate merozoites and/or target malarial Ag expressed on RBC surface Inhibit development of parasite in RBCs Intended Use: Morbidity reduction in endemic countries

16. Malaria: Plasmodium Life Cycle Gametocytes Sexual Stage

17. Sexual Stage Vaccines How they work: Induces Ab against sexual stage Ag Prevents development of infectious sporozoites in salivary glands of mosquitoes Prevent or decrease transmission of parasite to new hosts Intended Use: Decreased malaria transmission

18. Vaccine Portfolio Ad5 CSP/ LSA/TRAP Development Manufacture Pre-Clinical Evaluation Phase 1 +/- Challenge Phase 1b endemic Phase 2b endemic Phase 3 AMA-1C in ISA 720 MSP-2 in ISCOM PvR II in AlOH PvR II in ASO2 MSP-2 in ISA 720 RTS,S in ASO1 RTS,S in ASO2 Pfs-16 MSP-5 Ad5 MSP- AMA 1 MSP-4 LSA-1 in ASO1 LSA-1 in ASO 2 MSP-1C in Alum-CPG CP2.9 in ISA 720 AMA-1 in ASO1 AMA-1 in ASO2 RTS,S in ASO2

19. RTS,S vaccine - Pre erythrocytic vaccine Hybrid containing the central repeats and most of the C-terminal of the CSP fused with hepatitis B surface antigen Complex adjuvant mixture AS02 Completely protected six out of seven volunteers Field study in The Gambia showed good short-term protection A clinical trial in Mozambique and Tanzania showed delay of infection and reduction in incidence of severe malaria in young children The vaccine advanced to Phase III trial.

22. Efficacy in Double Blind Phase 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 29.9% 95% CI 11-45 p = 0.004 ATP analyses Proportion Cohort 1 0.00 0.01 0.08 0.07 0.06 0.05 0.04 0.03 0.02 Severe malaria Hospitalized malaria 57.7% 95% CI 15-79 p = 0.019 32.3% 95% CI 1- 54 p = 0.053 Rate Exploratory cohort 1 0 1 2 3 4 5 6 7 Infection 44.9% 95% CI 31-56 p < 0.001 Events Cohort 2 Control RTS,S/AS02 Clinical Malaria

23. Challenges for Malaria Vaccine Four antigenetically distinct malaria species Each has ~6,000 genes First gene only identified in 1983 Immunity in malaria is complex and immunological responses and correlates of protection are incompletely understood. Identifying and assessing vaccine candidates takes time and is expensive There is no clear ‘best approach’ for designing a malaria vaccine

24. Asante Sana