The Lancet – Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial

The Lancet
Online First
Comment
Final results from a pivotal phase 3 malaria vaccine trial
Vasee S Moorthy, Jean-Marie Okwo-Bele
Published Online: 23 April 2015
DOI: http://dx.doi.org/10.1016/S0140-6736(15)60767-X
Summary
In The Lancet, the RTS,S Clinical Trials Partnership1 report the most recent results from the pivotal phase 3 trial of RTS,S/AS01 malaria vaccine, the fourth major publication from this randomised controlled trial.2–4 The trial enrolled 15,459 infants and young children at 11 centres in seven sub-Saharan African countries: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and Tanzania. Two age groups were included: 6–12 weeks and 5–17 months at first dose. The schedule involved a primary series of three monthly doses, with a booster dose given 18 months later in one of the three trial groups.

.
Articles
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial
RTS,S Clinical Trials Partnership – Members listed at end of paper
Published Online: 23 April 2015
DOI: http://dx.doi.org/10.1016/S0140-6736(15)60721-8
Summary
Background
The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose.
Methods
From March 27, 2009, until Jan 31, 2011, children (age 5–17 months) and young infants (age 6–12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619.
Findings
8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39–50) and young infants for 38 months (34–41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36•3%, 95% CI 31•8–40•5) and 7396 occurred in the R3C group (28•3%, 23•3–32•9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32•2%, 13•7 to 46•9) and 169 in the R3C group (1•1%, −23•0 to 20•5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25•9%, 95% CI 19•9–31•5) and 5444 occurred in the R3C group (18•3%, 11•7–24•4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17•3%, 95% CI −9•4 to 37•5) and 104 in the R3C group (10•3%, −17•9 to 31•8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387–2186) in the R3R group and 1363 per 1000 children (995–1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592–1337) in the R3R group and 558 (158–926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2•2 per 1000 doses in young infants and 2•5 per 1000 doses in children.
Interpretation
RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3–4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.
Funding
GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.