Abstract
SummaryBackgroundThe efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data.MethodsWe analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2–10 years (PrP2–10), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02.FindingsVaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP2–10 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP2–10 20%) it was 41% (21 to 57), and at high transmission (PrP2–10 70%) the efficacy was 4% (−10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)—eg, at low transmission (PrP2–10 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (−38 to 38) after 3 years.InterpretationVaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination.FundingMedical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust.
Highlights
The increasing application of interventions for malaria control over the past 10 years has been linked to reductions in morbidity and mortality associated with malaria infection.[1,2] A vaccine for malaria could have an important role in further reduction of the burden of disease
In our analysis here we use active case detection for Plasmodium falciparum infection (ACDi) to refer to the combination of ACDi and passive case detection (PCD), active case detection for clinical malaria (ACDc) to refer to combined ACDc and PCD, and PCD to refer to exclusive use of PCD
We analysed pooled data for 4453 participants in seven trials. 1376 participants received all three vaccinations, were given curative antimalarial treatment, and underwent ACDi. 3184 participants received all three vaccinations and were monitored for episodes of clinical malaria, either by ACDc or PCD. 465 adults received one or more vaccination; these data were excluded from the analysis for severe malaria or death. 3988 children received one or more vaccination and were included in intention-to-treat analyses for severe malaria or death
Summary
The increasing application of interventions for malaria control over the past 10 years has been linked to reductions in morbidity and mortality associated with malaria infection.[1,2] A vaccine for malaria could have an important role in further reduction of the burden of disease. The candidate malaria vaccine RTS,S/AS01 is in phase 3 clinical trials, for which preliminary data for the first 12 months of follow-up are available.[3] Efficacy against clinical malaria was 55·8% (97·5% CI 50·6–60·4) among children age 5–17 months. Combined efficacy against severe malaria for children aged 5–17 months and 6–12 weeks was 34·8% (95% CI 16·2–49·2). RTS,S protects at pre-erythrocytic stages of the parasite’s lifecycle. It is partly effective and has been described as a leaky vaccine4—ie, no individual is protected consistently against every episode of exposure, but the risk of acquiring infection after any single episode of exposure is reduced. RTS,S has been given with either of two different adjuvant systems: AS01 or AS02. RTS,S/AS01 seems to be more immunogenic than RTS,S/AS02, efficacy trials of RTS,S/ AS01 and RTS,S/AS02 have not resulted in definitively powered comparisons.[5,6] the variation in vaccine efficacy over time remains unknown, with conflicting evidence from individual trials
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