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Up date on malaria vaccine

Dr Walter Otieno MBChB, M. Med (Paeds), PhD Walter Reed Project-Centre for Clinical Research Kenya Medical Research Institute. Up date on malaria vaccine. Mark R. Withers, M.D., MPH, Director, WRP Kombewa Clinic. WRP-Kisumu. 2. WRP-Kisumu: 4 main campuses. Kisumu HQ (“Kondele”)

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Up date on malaria vaccine

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  1. Dr Walter OtienoMBChB, M. Med (Paeds), PhD Walter Reed Project-Centre for Clinical Research Kenya Medical Research Institute Up date on malaria vaccine Mark R. Withers, M.D., MPH, Director, WRP Kombewa Clinic

  2. WRP-Kisumu 2

  3. WRP-Kisumu: 4 main campuses • Kisumu HQ (“Kondele”) • Administration • Basic science: ELISA, PCR, flow cyt, RDTs • New Nyanza Provincial General Hospital (PGH, Russian) • Children’s Hospital: 65 bed facility • Ward 8: dedicated in-out patient clinical research center • “Center of Excellence” for malaria microscopy • KEMRI “Center for Global Health” (Kisian town) • Entomology • malaria culture lab (monitors drug resistance patterns) • Kombewa Clinical Research Center • Dedicated unit for large clinical trials

  4. Malaria Vaccine Development • Ongoing for P. falciparum & P. vivax • Theoretical Concepts: • Pregnant women protect newborns • Living in endemic areas develop immunity • Malaria vaccines target the life cycle: • Pre-erythrocytic stage(sporozoite/hepatic) • Erythrocytic (asexual) stage • Sexual stage (transmission blocking)

  5. TARGETS OF MALARIA VACCINES • Pre-erythrocytic -Prevent infection -Reduce disease • Blood-stage -Prevent disease • Transmission blocking -Prevent transmission

  6. RTS,S Program History

  7. Circumsporozoite protein • Most abundant protein covering entire sporozoite surface • Also expressed by malaria liver stages • Structure of CS protein: • Of all malaria species has a central domain with several amino acid repetitions • Amino acid sequence that composes each repetition is completely different for each plasmodium species

  8. Circumsporozoite protein • Structure of CS protein: • P. falciparum CS protein has limited variability therefore ideal for vaccines • P. vivax isolates display enormous variation-therefore not ideal for malaria vaccines • Amino acid repetitions targets for antibodies • N- & C-terminals contain epitopes recognized by CD4 & CD8 T cells • T cells specific for epitopes of CS protein confer protective immunity against liver stages

  9. RTS,S Malaria Vaccine Development • Pre-erythrocytic stage vaccine • Composition of vaccine antigen: • Sequence of circumsporozoite protein • Hepatitis B surface antigen (HBsAg) • Adjuvants: ASO2 & ASO1 • HBsAg is encoded with hepatitis B virus S protein gene, therefore protects against hepatitis B.

  10. RTS,S Malaria Vaccine Development… • Goal: develop 80% efficacious vaccine by 2025 with ≥4 year protection • Characteristics of an ideal vaccine: • Safe • Effective • Affordable • Easy to deliver (EPI delivery system) • Will not interfere with other EPI vaccines

  11. DEVELOPMENT OF THE RTS,S MALARIA VACCINE SPOROZOITE STAGE OF MALARIA PARASITE

  12. DEVELOPMENT OF RTS,S MALARIA VACCINE HEP-B VIRUS SPOROZOITE + S (HEP-B) R (REPEAT) T (T-CELL) + S R T S

  13. STRUCTURE OF THE CIRCUMSPOROZOITE PROTEIN (CSP) N -TERMINAL C -TERMINAL T-CELL EPITOPES CENTRAL REPEAT REGION

  14. DEVELOPMENT OF RTS,S MALARIA VACCINE SPOROZOITES – ARE COATED WITH A SURFACE PROTEIN – CIRCUMSPOROZOITE PROTEIN (CSP) A SEGMENT OF THE CIRCUMSPOROZOITE PROTEINCONTAINING REPEAT (R) AND T-CELL EPITOPES (T) IS FUSED TO HEPATITIS B SURFACE ANTIGEN (S) TO PRODUCE FUSION PROTEIN, RTS RTS IS COMBINED WITH A SECOND UNFUSED HEPATITIS B SEGMENT (S) TO FORM A STABLE RTS,S ANTIGEN

  15. RESULTS OF RTS,S MALARIA VACCINE TRIALS • Many trials have shown that RTS,S malaria vaccine is safe and immunogenic • RTS,S efficacy trial in Mozambique – enrolled 2022 children aged 1-4 years • 50% protection against severe malaria and severe anemia at 42 months post vaccination

  16. RESULTS OF RTS,S MALARIA VACCINE TRIALS • Many trials have shown that RTS,S malaria vaccine is safe and stimulates the immune system • RTS,S efficacy trial in Mozambique – enrolled 2022 children aged 1-4 years • 50% protection against severe malaria and severe anemia • Malaria causes 1 million childhood deaths per year in Africa • If this vaccine could reduce by half the cases of severe disease, we would be saving thousands of lives

  17. MAIN OBJECTIVES • To investigate efficacy against clinical disease in children 5-17 months of age and • Infants 6-12 weeks of age who receive the vaccine co-administered with EPI vaccines

  18. ON GOING RTS,S VACCINE TRIAL • A multi-center, Phase III trial of the candidate malaria vaccine RTS,S • The trial has been designed to address key safety and efficacy information required before a vaccine can be licensed • Across 11 sites in Africa with different levels of malaria transmission; Kenya, Tanzania, Mozambique, Gabon, Ghana, Burkina Faso

  19. How does RTS, S work? • RTS,S induces the production of antibodies and T cells that are believed to diminish the malaria parasite’s ability to infect, develop, and survive in the human liver.

  20. DESIGN OF THE TRIAL Children 5-17 months of age Children 6-12 weeks of age

  21. Thank you

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