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, RTS,S Clinical Trials Partnership
Abstract
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.
Conflict of interest statement
Declaration of interests
PAl’s institute has received grants from the Catalan Government, the Spanish Government, Medicines for Malaria Venture, and the Bill & Melinda Gates Foundation. PAl has received personal fees from Medicines for Malaria Venture. DCM, CMai, PN, and LO’s institutes have received grants from MVI for other malaria studies. AMo has received personal fees from Medicines for Malaria Venture and GlaxoSmithKline. CO and KO’s institutes have received grants from the Malaria Clinical Trial Alliance. LO has received financial support from GlaxoSmithKline to participate to scientific congresses and to set up the “Trust in Science” grant. MT is a board member of the Optimus Foundation, and his institution is reimbursed for his activities on the Scientific Advisory Board of the Novartis Institute for Tropical Diseases. MT has also received for his institution other grants from MVI and from the Bill & Melinda Gates Foundation, and travel reimbursements from MVI and Sanaria. WRB, JCoh, YG, DH, EJ, DLa, AL, MLi, OO-A, AOli, and JV are, or were at the time of the study, employed by the GlaxoSmithKline group of companies. JCoh is an independent consultant for GSK Vaccines. JCoh, EJ, DLa, and OO-A have shares or stock options in the GlaxoSmithKline group of companies. JCoh and WRB are named inventors on patents for which the rights have been assigned to GlaxoSmithKline group of companies. DK, DLe, CO, and BS are or were at the time of the study employees at PATH MVI. DSc is employed by the London School of Hygiene & Tropical Medicine, and his consultancy activities for the MVI are funded as a grant to the London School of Hygiene & Tropical Medicine by MVI. All other members of the RTS,S Clinical Trials Partnership declare no competing interests.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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Source: PubMed