Sustained efficacy of the RTS,S/AS01E malaria vaccine over 50 months of follow-up when used in full-dose or fractional-dose regimens in young children in Ghana and Kenya: final results from an open-label, phase 2b, randomised controlled trial

Abstract

Background: We conducted a phase 2b trial evaluating fractional-dose and full-dose regimens of the RTS,S/AS01_E vaccine (RTS,S). All regimens provided substantial protection against clinical malaria in natural exposure settings, over 21 and 32 months of follow-up. Here, we present end-of-study results, after 50 months of follow-up.

Methods: This open-label, randomised controlled trial was conducted at two research centres in Agogo (Ghana) and Siaya County (Kenya) between Sept 28, 2017, and Nov 14, 2022. Children aged 5-17 months were randomly assigned (1:1:1:1:1) to one of five groups to receive rabies vaccine (the control group) at months 0, 1, and 2; or full doses of RTS,S at months 0, 1, and 2, followed by either full doses (R) at month 20 (group R012-20) or months 14, 26, and 38 (R012-14-26-38); or full doses at months 0 and 1, followed by fractional doses (Fx; one-fifth of full dose) at months 2, 14, 26, and 38 (Fx012-14-26-38) or months 7, 20, and 32 (Fx017-20-32). We present results of secondary objectives, evaluating vaccine efficacy, impact, immunogenicity, and harms up to month 50. Endpoints were the occurrence of clinical malaria meeting the primary and secondary case definitions and antibody responses at predefined timepoints, and the occurrence of solicited adverse events within 7 days from vaccination and serious adverse events and adverse events of special interest up to study end. This trial is registered at ClinicalTrials.gov (NCT03276962) and is complete.

Findings: Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned (322 to each RTS,S group and 321 to the control group). Of these 1609 children, 1500 received at least one study vaccine dose (exposed set), and 1333 were included in the per-protocol set for efficacy. Among children in the exposed set, to month 50, vaccine efficacy against all episodes of clinical malaria was 36% (95% CI 19-50), 51% (37-61), 43% (28-55), and 41% (26-53) in groups R012-20, R012-14-26-38, Fx012-14-26-38, and Fx017-20-32, respectively (p<0·001 for all). The numbers of cases averted per 1000 RTS,S full-dose equivalents were 353 (R012-20 group), 544 (R012-14-26-38 group), 1151 (Fx012-14-26-38 group), and 1134 (Fx017-20-32 group). Vaccine efficacy and impact and immune responses were maintained over 50 months of follow-up in groups who received additional vaccine doses after the fourth dose. The vaccine was well tolerated; only five serious adverse events were considered to be related to vaccination. There were no deaths considered to be related to vaccination.

Interpretation: All RTS,S regimens provided substantial protection against clinical malaria, with additional yearly doses maintaining vaccine efficacy and impact up to 50 months. Using fractional-dose regimens could increase the availability of RTS,S and reduce vaccination cost.

Funding: GSK; PATH (through the Bill & Melinda Gates Foundation and the German Federal Ministry of Education and Research).