A Systematic Review of the Immunogenicity, Safety and Efficacy of the RTS,S/AS01 Malaria Vaccine

Abstract

Malaria remains a major global health challenge, with Plasmodium falciparum causing high morbidity and mortality, especially in sub-Saharan Africa. The RTS,S/AS01 vaccine, endorsed by the WHO, represents a significant advancement in malaria prevention, though questions persist regarding its long-term efficacy, immune durability and safety across populations. To address these gaps, this systematic review and meta-analysis evaluated available evidence on the immunogenicity, efficacy and safety of RTS,S/AS01. Following PRISMA 2020 guidelines and registered in PROSPERO (CRD42023374259), studies published between 2012 and 2024 were identified through PubMed, Cochrane Library, Scopus and ClinicalTrials.gov. Risk of bias was evaluated using ROB-2 and ROBINS-I tools. Data were synthesized using fixed- and random-effects models, with subgroup and heterogeneity analyses. From 12,427 records, 51 studies were included qualitatively, and 12 in the meta-analysis. Immunogenicity was higher in children aged 5-17 months (GMT 621 EU/mL) than in infants (GMT 209 EU/mL), with stronger responses in Phase II trials. Booster doses enhanced antibody levels initially, but titres declined over time. Combining RTS,S/AS01 with seasonal malaria chemoprevention (SMC) improved immune responses, with regional variation. Safety analysis showed no significant difference in adverse events between vaccinated and control groups. Slight increases were noted in children aged 5-17 months and after booster doses but were not statistically significant. RTS,S/AS01 combined with SMC significantly reduced adverse events. Vaccine efficacy was highest in children aged 5-17 months (log OR -0.42), with improved protection from booster doses (log OR -0.34) and the RTS,S-SMC combination (log OR -0.92). Regional heterogeneity was observed, with moderate reductions in malaria cases in Ghana, Kenya, Malawi, Mozambique and Tanzania. RTS,S/AS01 offers moderate, time-limited protection with an acceptable safety profile. These findings support targeted vaccination in children aged 5-17 months and integration with existing interventions like SMC.