Efficacy and safety of maternal RSV vaccination against infant lower respiratory tract infections: a systematic review and meta-analysis

Background Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract infection (LRTI) and hospitalisation worldwide. Maternal RSV prefusion F (RSVpreF) vaccination protects infants through transplacental antibody transfer. We aimed to synthesise the efficacy, real-world effectiveness, and safety of maternal RSV vaccination for preventing infant LRTI, integrating randomised and observational evidence. Methods We searched PubMed, Embase, Scopus, and Cochrane CENTRAL (to June 2026) for randomised controlled trials (RCTs) and observational studies of maternal RSV vaccination reporting infant LRTI, hospitalisation, or maternal–infant safety. A single reviewer, with large language model-assisted verification, screened records, extracted data, and assessed risk of bias (RoB 2; Newcastle–Ottawa Scale). Randomised and observational evidence were pooled separately using random-effects models; overlapping populations were resolved based on study periods and named participating sites. Certainty was rated with GRADE (PROSPERO CRD420261400053). Results Twenty-four studies (9 RCTs enrolling approximately 18,600 pregnant women, 15 observational) were included; all 15 observational studies evaluated the licensed Pfizer vaccine (Abrysvo). Pooled vaccine effectiveness against infant RSV-associated hospitalisation was 79.7% (95% CI 73.9–84.2) within 3 months and 68.1% (57.1–76.3) through 6 months. Randomised efficacy against severe RSV-LRTI was 70% for the licensed Pfizer vaccine, closely concordant with the real-world effectiveness; efficacy against medically attended RSV-LRTI was 51.5% (36.3–63.1). Preterm birth was modestly increased in the randomised trials (Mantel–Haenszel RR 1.17, 95% CI 1.03–1.32), but the signal was not robust: it became non-significant after excluding the GSK trial (GRACE; 1.10, 0.95–1.27), and for the licensed Pfizer vaccine, the increase was small and not robustly significant (pivotal MATISSE trial 1.20, 0.98–1.46; three-trial Pfizer pool 1.21, 1.00–1.46), while observational data showed a biologically implausible protective association (0.90, 0.82–0.99), consistent with healthy vaccinee confounding. No other maternal or neonatal safety signal was identified. Certainty of evidence was moderate for effectiveness and efficacy. Conclusion Maternal RSVpreF vaccination confers substantial, generalisable protection against infant RSV disease, with randomised and real-world evidence in close agreement. For the licensed Pfizer vaccine administered within its approved 32–36-week window, no robustly significant increase in preterm birth is established, supporting its continued programmatic use alongside ongoing post-marketing surveillance. Systematic review registration Unique Identifier: CRD420261400053 https://www.crd.york.ac.uk/PROSPERO/view/CRD420261400053