Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial.

BACKGROUND: The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. METHODS: We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. FINDINGS: 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort). INTERPRETATION: Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. FUNDING: Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.