Safety of RTS,S/AS01E vaccine for malaria in African children aged 5 to 17 months: A systematic review and meta-analysis of randomized controlled trials.

backgroundNumerous randomized controlled trials (RCTs) have demonstrated the safety of the RTS,S/AS01E vaccine in African children aged 5-17 months. However, conflicting evidence surrounding serious adverse events (SAEs) has prompted calls for further research to determine whether the benefits of the vaccine outweigh its risks, particularly in high-risk populations such as young children in malaria-endemic regions.

methodsOn February 12, 2025, a comprehensive literature search was performed across PubMed, Wiley Online Library, and Web of Science. The Patient/Population, Intervention, Comparison, Outcomes, and Study Design (PICOS) framework was employed to screen and select relevant studies. Following initial screening, titles, abstracts, and full texts were filtered using EndNote software. Data were systematically extracted from each included study. SAEs were categorized according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The analysis focused on calculating proportions (%), risk ratios (RRs), and odds ratios (ORs) of SAEs. Pooled effect sizes and 95% confidence intervals (CIs) were derived using random-effects models from aggregated data meta-analysis. Publication bias was evaluated using the Begg's test, and Egger's test, with statistical significance assessed via Z tests.

resultsThis systematic review and meta-analysis included 11 studies involving 27949 children (16976 vaccinated with RTS,S/AS01E and 10973 vaccinated with rabies vaccine). The overall proportion of SAEs was 21.4% [95% CI: 17.5-25.5] in the RTS,S/AS01E group, compared to 26.2% [95% CI: 22.4-30.2] in the control group (rabies vaccine), yielding a pooled RR of 0.80 [95% CI: 0.72-0.88, P < 0.0001]. The pooled frequency of death was 1.37% [95% CI: 0.53-2.61] in the RTS,S/AS01E group and 1,31% [95% CI: 0.49-2.52] in the control group, with a non-significant odds ratio (OR) of 1.08% [95% CI: 0.83-1.41, P = 0.56]. Common SAEs included febrile convulsions, pneumonia, and severe malaria, with severe malaria being significantly more prevalent in children who received the rabies vaccine [OR = 0.61, 95% CI: 0.53-1.26, P < 0.00001]. The overall methodological quality of the included studies was high, with a low probability of bias.

conclusionsThe risk of SAEs is comparable between children who received the RTS,S/AS01E vaccine and those who received the rabies vaccine, except for severe malaria, which is significantly more frequent in the rabies vaccine group. This suggests that the RTS,S/AS01E vaccine may provide meaningful protection against severe forms of malaria, a critical outcome in high-burden regions. However, further long-term data are needed to confirm these findings and address several unresolved questions. PROSPERO REGISTRATION NUMBER: CRD42024321008.