{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T15:54:17Z","timestamp":1783698857276,"version":"3.55.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosglobalpublichealth.org"],"crossmark-restriction":false},"short-container-title":["PLOS Glob Public Health"],"abstract":"<jats:sec id=\"sec021\">\n<jats:title>Background<\/jats:title>\n<jats:p>Numerous randomized controlled trials (RCTs) have demonstrated the safety of the RTS,S\/AS01E vaccine in African children aged 5\u201317 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec022\">\n<jats:title>Methods<\/jats:title>\n<jats:p>On 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\u2019s test, and Egger\u2019s test, with statistical significance assessed via Z tests.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec023\">\n<jats:title>Results<\/jats:title>\n<jats:p>This 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\u201325.5] in the RTS,S\/AS01E group, compared to 26.2% [95% CI: 22.4\u201330.2] in the control group (rabies vaccine), yielding a pooled RR of 0.80 [95% CI: 0.72\u20130.88, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001]. 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, <jats:italic>P<\/jats:italic>\u2009=\u20090.56]. 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, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.00001]. The overall methodological quality of the included studies was high, with a low probability of bias.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec024\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec025\">\n<jats:title>PROSPERO registration number<\/jats:title>\n<jats:p>CRD42024321008.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pgph.0004387","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T17:27:47Z","timestamp":1750094867000},"page":"e0004387","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgph.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["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"],"prefix":"10.1371","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3051-5772","authenticated-orcid":true,"given":"Joseph Alexis","family":"Zoa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahi-metou","family":"Njemguie Linjouom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Nyangono Ndongo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-2352","authenticated-orcid":true,"given":"Jan Rene","family":"Nkeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"pgph.0004387.ref001","volume-title":"World malaria report 2023 - spread view","author":"WHO","year":"2023"},{"key":"pgph.0004387.ref002","volume-title":"World malaria report 2024","author":"WHO","year":"2024"},{"key":"pgph.0004387.ref003","first-page":"322","volume-title":"World malaria report 2021","author":"WHO","year":"2021"},{"issue":"3","key":"pgph.0004387.ref004","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s15010-022-01952-2","article-title":"Plasmodium cynomolgi in humans: current knowledge and future directions of an emerging zoonotic malaria parasite","volume":"51","author":"LP Kojom Foko","year":"2023","journal-title":"Infection"},{"issue":"2","key":"pgph.0004387.ref005","first-page":"215","article-title":"Antimalarial drugs resistance genes of Plasmodium falciparum: a review","volume":"68","author":"C Tchekounou","year":"2022","journal-title":"Ann Parasitol"},{"issue":"6","key":"pgph.0004387.ref006","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/s41591-021-01365-y","article-title":"Author correction: emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda","volume":"27","author":"A Uwimana","year":"2021","journal-title":"Nat Med"},{"issue":"14","key":"pgph.0004387.ref007","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1056\/NEJMc2117480","article-title":"Evidence of artemisinin-resistant malaria in Africa","volume":"386","author":"BH Stokes","year":"2022","journal-title":"N Engl J Med"},{"issue":"10","key":"pgph.0004387.ref008","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1038\/s41564-023-01461-4","article-title":"Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia","volume":"8","author":"AA Fola","year":"2023","journal-title":"Nat Microbiol"},{"issue":"9","key":"pgph.0004387.ref009","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/S1473-3099(02)00372-9","article-title":"Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development","volume":"2","author":"PJ Guerin","year":"2002","journal-title":"Lancet Infect Dis"},{"key":"pgph.0004387.ref010","first-page":"40","volume-title":"Full evidence report on the RTS,S\/AS01 Malaria Vaccine","author":"WHO","year":"2021"},{"issue":"10287","key":"pgph.0004387.ref011","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(21)00943-0","article-title":"Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial","volume":"397","author":"MS Datoo","year":"2021","journal-title":"Lancet"},{"key":"pgph.0004387.ref012","unstructured":"Gavi. 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