Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure.

A B S T R AC T Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% con- fidence interval (CI), 10.3 to 45.3; P = 0.005) and 32.1% (95% CI, 11.6 to 47.8; P = 0.004), respectively, calculated by Cox regression. Multiple episodes were com- mon, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, −8.6 to 36.3; P = 0.18) and 24.3% (95% CI, 1.9 to 41.6; P = 0.04), respectively, calculated by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P = 0.004) and with increasing exposure to malaria (P = 0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was −0.4% (95% CI, −32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine effi- cacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, −11.0 to 36.4). CONCLUSIONS The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.)