Frequency of serious adverse events and death in 5-17 months children receiving RTS,S/AS01E vaccine - a systematic review and meta-analysis of RCTs.

Background The RTS,S/AS01E vaccine has been authorized for use in children in sub-Saharan Africa from the age of 5 months. Nevertheless, there is a limited number of clinical studies documenting serious adverse events (SAEs) and their correlation with the vaccine. This systematic review and meta-analysis aimed to analyze and summarize the data published to date on the primary serious adverse events (SAEs) associated with the RTS,S/AS01E malaria vaccine in children aged 5–17 months. Methods The systematic review adhered to the PRISMA 2020 guidelines. An extensive search was conducted across multiple databases, including PubMed, Cochrane Library, Wiley Online Library, and Web of Science, without any restrictions on publication year and language. The final search of databases and registries was completed on January 23, 2024. Randomized clinical trials (RCTs) related to SAEs of RTS,S/AS01E in children aged 5–17 months, for 0, 1, 2-schedule, were included in the study. The primary outcomes focused on the proportions of SAEs and deaths in RTS,S/AS01E vaccine recipients. Pooled effect size estimates and their 95% confidence intervals were obtained through random-effect models meta-analysis. Publication bias among included studies was evaluated using the "risk of bias assessment" tool from the Cochrane systematic review. Outcomes were tested for significance using Z tests. Results This meta-analysis comprised 10 studies and 30,573 children (19,769 recipients of RTS,S/AS01E and 10,804 control recipients). The combined frequency of all SAEs was 17.6% (95% CI: [15.3, 20.2]) among RTS,S/AS01E recipients, which was significantly lower than the combined frequency of 22% (95% CI: [0.204, 0.237]) observed in the control group, with a combined risk ratio (RR) of 0.80 (95% CI: [0.72, 0.90], P  = 0.0002). The combined frequency of all deaths was 1% (95% CI: [08, 1.2], P  < 0.0001) among RTS,S/AS01E recipients, which was not significantly higher than the combined frequency of 0.7% (95% CI: [0.3, 1.7]) observed in the control group, with a combined RR of 1.04 (95% CI: [0.77, 1.41], P  = 0.79. Throughout the follow-up period, the frequently reported SAEs were as follows: severe malaria (25.9% and 44.6%), pneumonia (31.5% and 27.5%), gastroenteritis (14.8% and 15.1%), anemia (16.7% and 19.4%), and febrile convulsions (26.5% and 23.3%) in the RTS,S/AS01E and control groups, respectively. The corresponding odds ratios (ORs) were as follows: severe malaria 0.47 (95% CI: [0.29, 0.76], P  = 0.002), pneumonia 1.19 (95% CI: [0.98, 1.45], P  = 0.07), gastroenteritis 0.99 (95% CI: [0.65, 152], P  = 0.97), anemia 0.70 (95% CI: [0.33–1.47], P  = 0.34), and febrile convulsions 1.26 (95% CI: [1.00, 1.59], P  = 0.005). Conclusions The occurrence of major serious adverse events (SAEs) with the RTS vaccine is rare, and their frequency does not seem to differ from that in unvaccinated children. As a result, there were no significant major side effects associated with the vaccine. However, additional long-term data is required. Trial registration CRD42024321008 / PROSPERO.