Effectiveness of the RTS,S/AS01E malaria vaccine in a real-world setting over 1 year of follow-up after the three-dose primary schedule: an interim analysis of a phase 4 study in Ghana, Kenya, and Malawi

Abstract

Background: RTS,S/AS01_E was first introduced within the Malaria Vaccine Implementation Programme in selected areas in Ghana, Kenya, and Malawi. A series of post-introduction observational studies were initiated in these areas to assess RTS,S/AS01_E safety and effectiveness in real-world settings. Here, we report the results of the interim analysis of the EPI-MAL-003 study secondary objectives related to vaccine effectiveness.

Methods: EPI-MAL-003 was a phase 4, disease surveillance study with prospective cohort event monitoring. The study was performed in routine medical practice settings at 12 sites (four per country) in Ghana, Kenya, and Malawi. Children younger than 18 months were enrolled in exposed clusters (sites where RTS,S/AS01_E was introduced) and unexposed clusters; data were collected via active surveillance. In an interim analysis, we estimated the effect of vaccination on the incidence of malaria, all-cause hospitalisations, and malaria-related hospitalisations, the prevalence of anaemia among hospitalised children, and mortality over 1 year of follow-up after primary vaccination with three RTS,S/AS01_E doses. These endpoints were analysed in the effectiveness analysis set. The primary endpoints are reported elsewhere, together with secondary safety endpoints. This study is registered with ClinicalTrials.gov, NCT03855995, and is completed.

Findings: The first child was enrolled on March 21, 2019, and the cutoff date for the current analysis was Nov 2, 2023. 45 000 children were enrolled (22 426 [49·8%] were female and 22 574 [50·25%] were male). 39 463 children were included in the analyses. When comparing vaccinated children from exposed clusters with unvaccinated children from unexposed clusters, country-adjusted incidence rate ratios were 0·70 (95% CI 0·67-0·73; p<0·001) for any malaria, 0·42 (0·30-0·60; p<0·001) for severe malaria, 0·64 (0·56-0·72; p<0·001) for malaria-related hospitalisations, 0·79 (0·74-0·84; p<0·001) for all-cause hospitalisations, and 0·83 (0·64-1·09; p=0·18) for all-cause mortality. The adjusted odds ratio for the prevalence of anaemia among children who were hospitalised (vaccinated children from exposed clusters vs unvaccinated children from unexposed clusters) was 0·81 (95% CI 0·73-0·90; p<0·001). Similar trends were observed in a before-after comparison with unvaccinated children enrolled in the EPI-MAL-002 study conducted before the RTS,S/AS01_E introduction.

Interpretation: Over 1 year of follow-up after the third vaccine dose, vaccination with RTS,S/AS01_E in real-world settings showed significant reductions in malaria burden. These findings reinforce the continued use of RTS,S/AS01_E vaccination in children as an effective public health measure to reduce malaria-related illness and mortality in endemic regions, and highlight its relevance for future malaria control strategies.

Funding: GSK.