Background: The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres
to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of
clinical malaria.
Methods: Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity
(anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes.
We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.
Results: Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001),
pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001).
Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095).
Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a
second slower decay over the next three to four years. Antibody titres were significantly associated with protection,
with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in
children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation
rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will
avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants
when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include
an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.
Conclusions: Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed
vaccine efficacy.