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

WRP-Kisumu 2

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

Why is malaria so important? Severe disease burden 300 - 500 million cases 575 000 CM (19% mortality) 1.42–5.66 million Anemia (13% mortality) 1.12–1.99 million RDS (18% mortality) In Kombewa 62% of admissions in children due to malaria

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)

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

RTS,S Program History

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

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

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.

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

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

DEVELOPMENT OF RTS,S MALARIA VACCINE HEP-B VIRUS SPOROZOITE + S (HEP-B) R (REPEAT) T (T-CELL) + Explain the slide R T S S

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

DEVELOPMENT OF RTS,S MALARIA VACCINE SPOROZOITES – ARE COATED WITH A SURFACE PROTEIN – CIRCUMSPOROZOITE PROTEIN (CSP) A SEGMENT OF THE CIRCUMSPOROZOITE PROTEIN CONTAINING 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

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

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

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

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

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.

DESIGN OF THE TRIAL Vaccination at 0, 1, 2 months Boost at month 20 Children 5-17 months of age Vaccination at 0, 1, 2 months Boost at month 20 RTS,S Control Vaccine Control vaccine Children 6-12 weeks of age Vaccination at 0, 1, 2 months Boost at month 20 RTS,S + EPI VACCINE RTS,S RTS,S/AS01E + EPI VACCINE CONTROL VACCINE CONTROL VACCINE + EPI VACCINE

Thank you