1. 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

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. Why is malaria so important? Severe disease burden
million cases
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

5. 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)

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

9. RTS,S Program History

10. 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

11. 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

12. 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.

13. 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

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

15. 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

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

17. 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

18. 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

19. 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

21. 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

22. 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

23. 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.

24. 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

25. Thank you