Maternal RSV vaccination for infant protection: A systematic review and meta-analysis of phase 3 trials with an integrated economic evaluation

Background: Respiratory syncytial virus (RSV) is a leading cause of hospitalization and mortality in early infancy. Maternal immunization offers a preventive strategy, but uncertainties regarding safety and economic value have limited its implementation. Objective(s): To synthesize phase 3 randomized trial evidence on the efficacy and safety of maternal RSV vaccination and to estimate its potential population and economic impact. By integrating a scenario-based modeling framework derived from pooled meta-analytic estimates, this review provides high-certainty, policy-relevant evidence to guide maternal immunization strategies in diverse settings. Search Strategy: PubMed, MEDLINE, Scopus, and Google Scholar were searched up to April 2025 using predefined terms for RSV vaccination, pregnancy, and randomized controlled trials (RCTs). Selection Criteria: Phase 3 RCTs comparing maternal RSV vaccination with placebo and reporting neonatal or maternal outcomes were included. Non-randomized studies, monoclonal antibody trials, or reports lacking extractable data were excluded. Data Collection and Analysis: Two reviewers independently screened studies, extracted data, and assessed risk of bias (RoB-2). Pooled risk ratios (RR) and absolute risk differences were calculated with random-effects models. Certainty of evidence was graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A scenario-based cost-effectiveness model was applied to the Mexican birth cohort. Main Result(s): Four phase 3 RCTs (17 391 women) were included. Maternal RSV vaccination halved the risk of infant RSV infection (risk ratio [RR] 0.47, 95% confidence interval [CI]: 0.29-0.76; number needed to vaccinate [NNV] 85) and reduced severe disease by 64% (RR 0.36, 95% CI: 0.21-0.60; NNV 127). No increased risks were observed for preterm birth, pre-eclampsia, or stillbirth. Certainty was moderate (any RSV) to high (severe RSV). In Mexico, universal vaccination at list price (US$295 per dose) would prevent approximately 20 769 infections and 228 neonatal deaths annually, though with high costs per case averted. At public-sector pricing (US$50 per dose), cost-effectiveness improved substantially. Conclusion(s): Maternal RSV vaccination is effective, safe, and potentially cost-justifiable in high-burden settings, supporting its integration into national immunization programs. PROSPERO registration: CRD420251014636 (March 2025). Copyright © 2025 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.