Efficacy and Response of R21/Matrix-M in Malaria Vaccine: A Systematic Review and Meta-Analysis of Clinical Trials.

BACKGROUND: R21/Matrix-M is a pre-erythrocytic malaria vaccine supported by a growing body of field-efficacy, immunogenicity, safety, controlled-challenge, and implementation evidence. We synthesized the contemporary human evidence and quantified protection against naturally acquired clinical malaria. METHODS: This systematic review and meta-analysis was conducted and reported in accordance with PRISMA 2020. PubMed, Scopus, Embase, Web of Science, and Cochrane CENTRAL were searched for studies published from January 2021 to February 2026. The review was not prospectively registered, and no separate protocol was prepared. Eleven studies were retained for the systematic review. The primary quantitative synthesis pooled 12-month Cox proportional-hazards estimates for the first episode of clinical malaria from two independent randomized field trials using generic inverse variance methods. Robustness was examined using a fixed-effect model, a sensitivity analysis that disaggregated the phase III seasonal and standard/perennial transmission strata, and a phase III-only analysis. Booster follow-up and controlled human malaria infection (CHMI) studies were summarized descriptively to avoid double counting and mixing of incompatible endpoints. RESULTS: The primary trial-level meta-analysis yielded a pooled hazard ratio (HR) of 0.265 (95% CI 0.235-0.299), equivalent to vaccine efficacy (VE) of 73.5% (95% CI 70.1-76.5%), with no detected heterogeneity (I2 = 0%; Q = 0.67, p = 0.41; tau2 = 0). Disaggregating the phase III transmission strata produced a similar random-effects estimate (HR 0.270, 95% CI 0.223-0.326; VE 73.0%, 95% CI 67.4-77.7%; I2 = 53.8%). The fixed-effect estimate was HR 0.270 (95% CI 0.240-0.304), and the phase III-only sensitivity analysis remained strongly protective (HR 0.281, 95% CI 0.220-0.357; VE 71.9%). Booster follow-up supported maintained protection, including approximately 80% efficacy during the 12 months after boosting with the 50-microgram Matrix-M regimen. Across the broader evidence base, the vaccine was generally well tolerated and elicited strong anti-CSP/anti-NANP antibody responses. CONCLUSIONS: R21/Matrix-M provides substantial protection against naturally acquired clinical malaria, and the central efficacy estimate is robust to alternative analytic specifications. The quantitative evidence base remains small, however, and longer-term effectiveness, severe-malaria protection, booster timing, and post-deployment safety require continued evaluation.