Abstract
BackgroundThe 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.MethodsUsing 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.ResultsVaccine-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.ConclusionsVaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.
Highlights
The RTS,S malaria vaccine is currently undergoing phase 3 trials
Two potential reasons for the lower observed vaccine efficacy in the 6- to 12-week cohort have been proposed: (1) that co-administration with other expanded programme on immunisation (EPI) vaccines in the 6- to 12-week cohort may have interfered with the response to the RTS, S vaccine; and (2) that the 6- to 12-week cohort have reduced ability to mount a sustained and effective immune response [3], perhaps due to interference from maternal antibodies
Statistical methods We examined the effects of the following covariates on CSPpeak: adjuvant (AS01 versus AS02), age at vaccination, site-specific transmission intensity, dosing schedules (0, 1, 2 versus 0, 1, 7 months), number of doses received and coadministration of other vaccines
Summary
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. Efficacy against clinical malaria over one year of follow-up was 55.8% (97.5% confidence interval (CI): 50.6% to 60.4%) in children 5- to 17-months old [1] but was significantly lower in infants 6- to 12-weeks old (31.3%, 97.5% CI: 23.6% to 38.3%) [2]. Vaccine-induced geometric mean anti-circumsporozoite protein (CSP) antibody titres following the third dose in the 6- to 12-week cohort was 209 ELISA units/ml (EU/mL) (95% CI: 197 to 222) [2] significantly lower than in the 5- to 17-month cohort (621 EU/mL, 95% CI: 592 to 652) [1]. To date, the extent to which this variation can be explained by vaccine-induced anti-CSP antibody titres has not been explored
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