Peer-reviewed article
Feasibility, safety, and impact of the RTS,S/AS01<sub>E</sub> malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.
Asante KP, Mathanga DP, Milligan P, Akech S, Oduro A et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This study evaluated the introduction of the RTS,S malaria vaccine through national immunisation programmes in Ghana, Kenya, and Malawi starting in 2019. The vaccine was given in four doses to children aged 5 months to 2 years across 158 geographical clusters randomly assigned to early or delayed introduction. The vaccine achieved high coverage (73-79% for first dose) and was associated with a 32% reduction in hospital admissions for severe malaria and a 9% reduction in all-cause child mortality, with no evidence of previously observed safety concerns.
Key points
- Coverage of the first RTS,S dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi within 18 months
- No excess cases of meningitis or cerebral malaria were found in vaccine recipients compared to comparison areas, contrary to concerns from phase 3 trials
- RTS,S introduction was associated with a 32% reduction in hospital admissions with severe malaria among children eligible for three vaccine doses
- All-cause mortality (excluding injury) was reduced by 9% in vaccinated children
- Mortality impact was similar for girls and boys, addressing concerns about differential safety between sexes
Limitations
The evaluation was planned for 4 years, and this report covers only the first 2 years of implementation, so longer-term impacts and the effect of the fourth dose remain unknown. The study design compares early versus delayed introduction areas rather than vaccinated versus unvaccinated individuals, which may not fully capture individual-level vaccine efficacy.
Abstract
Background The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. Methods In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. Findings By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1-59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). Interpretation In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. Funding Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.