Clinical efficacy, immunogenicity and safety of RTS,S/AS01, R21/Matrix-M and candidate malaria vaccines in children: A systematic review and meta-analysis.

BACKGROUND: Malaria remains a global public health emergency with high mortality especially among children under 5 years. Despite increased research on pediatric malaria vaccines, comprehensive evidence syntheses are limited. We aimed to assess the efficacy and safety of currently available malaria vaccines in children. METHODS: Following PRISMA we included Phase IIb-IV and post-marketing studies from PubMed, SCOPUS, WoS, ClinicalTrials.gov, ISRCTN, EUCTR, CTIS and PACTR. Licensed and candidate vaccines used to individuals < 18 years were compared with controls or seasonal malaria chemoprevention (SMC). Outcomes were seroconversion, incidence of clinical malaria and serious adverse events (SAE). Meta-analyses were performed for the intention-to-treat cohorts with subgroup analyses by vaccine type and follow-up (PROSPERO: CRD420251032609). RESULTS: 56 trials were included (134424 participants). The proportional meta-analysis revealed an overall SAE rate of 16% (95% CI 12% -19%), higher for RTS,S/AS02 (29%; 95% CI 14%-44%) and lower for R21-MM (3%; 95% CI 2%-3%). In comparative analyses vaccination reduced SAE risk by 9% vs controls (RR=0·91; 95% CI 0·86-0·96). Overall vaccine efficacy (VE) was 31% (IRR=0·69; 95% CI 0.57-0.84), higher for RTS,S/AS02 (47%; IRR=0·53; 95% CI 0.36-0.80) and RTS,S/AS01 (32%; IRR=0·68; 95% CI 0.57-0.81). R21-MM showed a VE of 72% (IRR=0·28; 95% CI 0.22-0.34, single trial Phase 2b). Efficacy declined with time: 33% (IRR=0·67; 95% CI 0.43-1.02) within 12 months, 35% (IRR=0·65; 95% CI 0.50-0.82) at 12-36 and 11% (IRR=0·89; 95% CI 0.81-0.99) beyond 36 months. The combination of vaccination and SMC showed 65% (IRR=0·35; 95% CI 0.23-0-51) efficacy. Cumulative seroconversion rate was 0·99 (95% CI 0·98-1·00). Comparative seroconversion analysis was not feasible due to absent control data. No study was rated as low quality by RoB2. CONCLUSIONS: Malaria vaccines in children show a favorable safety profile and provide meaningful although time-limited protection against clinical malaria. RTS,S and R21 vaccines achieve the highest efficacy particularly in combination with SMC. Malaria vaccination should be integrated into childhood malaria control strategies emphasizing the need for booster strategies and long-term effectiveness monitoring in endemic settings.