Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial

Background Seasonal vaccination with the RTS,S/AS01E vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period. The objective of this study was to establish whether the added protection provided by the combination could be sustained for a further 2 years.Methods This was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Hounde district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5-17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01E plus placebo SMC, or SMC plus RTS,S/AS01E. They continued to receive the same interventions until the age of 5 years. The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01E-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups. The study is registered with ClinicalTrials.gov, NCT04319380, and is complete.Findings In April, 2020, of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study. Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01E-alone group, and 133 in the combined group. The combination of RTS,S/AS01E and SMC was superior to SMC (protective efficacy 57 center dot 7%, 95% CI 53 center dot 3 to 61 center dot 7) and to RTS,S/AS01E (protective efficacy 59 center dot 0%, 54 center dot 7 to 62 center dot 8) in preventing clinical malaria. RTS,S/AS01E was non-inferior to SMC (hazard ratio 1 center dot 03 [95% CI 0 center dot 95 to 1 center dot 12]). The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57 center dot 7% (53 center dot 3 to 61 center dot 7) and versus RTS/AS01E-alone being 59 center dot 0% (54 center dot 7 to 62 center dot 8). The comparable figures for the first 3 years of the study were 62 center dot 8% (58 center dot 4 to 66 center dot 8) and 59 center dot 6% (54 center dot 7 to 64 center dot 0%), respectively. Hospital admissions for WHO-defined severe malaria were reduced by 66 center dot 8% (95% CI 40 center dot 3 to 81 center dot 5), for malarial anaemia by 65 center dot 9% (34 center dot 1 to 82 center dot 4), for blood transfusion by 68 center dot 1% (32 center dot 6 to 84 center dot 9), for all-cause deaths by 44 center dot 5% (2 center dot 8 to 68 center dot 3), for deaths excluding external causes or surgery by 41 center dot 1% (-9 center dot 2 to 68 center dot 3), and for deaths from malaria by 66 center dot 8% (-2 center dot 7 to 89 center dot 3) in the combined group compared with the SMC alone group. No safety signals were detected. Interpretation Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission.Funding UK Joint Global Health Trials and PATH's Malaria Vaccine Initiative (through a grant from the Bill & Melinda Gates Foundation).Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.