Maternal RSVpreF Vaccine Effectiveness Against Respiratory Syncytial Virus in Hospitalized Infants

Importance: In February 2025, Australia introduced maternal vaccination with bivalent respiratory syncytial virus prefusion F protein-based vaccine (RSVpreF) in the National Immunization Program for pregnant individuals from 28 weeks' gestation as the primary, year-round strategy to prevent RSV disease in infants 6 months of age or younger. Objective: To estimate effectiveness of RSVpreF vaccination during pregnancy against infant RSV hospitalization in Australia. Design, Setting, and Participants: This retrospective case-control study with a test-negative design was conducted in 9 hospitals across Australia with year-round respiratory testing for acute respiratory illness (ARI) among infants born from 28 weeks' gestation and hospitalized with ARI at 6 months of age or younger, March 1, 2025, through February 28, 2026. Data were analyzed March 2026 through May 2026. Exposure: Maternal RSVpreF vaccination administered from 28 weeks' gestation and 14 days or more before delivery. Main Outcomes and Measures: Maternal RSVpreF effectiveness was evaluated against hospitalization for RSV lower respiratory tract disease (RSV-LRTD, primary objective), severe RSV-LRTD, and RSV-ARI. Logistic regression with confounder adjustment was used to calculate vaccine effectiveness (VE) as (1 - adjusted odds ratio) × 100%. Results: Of 1012 infants hospitalized with ARI, 655 had LRTD, with 114 of 386 case infants (30%) and 171 of 269 control infants (64%) born to RSVpreF-vaccinated mothers (median [IQR] gestational age at vaccination, 31 weeks [29-33]). Median (IQR) maternal age at delivery was 32 years (29-35). Median (IQR) age of infants hospitalized for LRTD was 52 days (30-89); 495 of 655 (76%) were aged 3 months or younger. VE against RSV-LRTD hospitalization was 77.8% (95% CI, 66.4%-85.3%) among infants from birth through 6 months of age, 80.2% (95% CI, 71.1%-86.5%) among infants from birth through 3 months of age, 86.3% (95% CI, 79.0%-91.1%) among infants from birth through 2 months of age, and 68.2% (95% CI, 42.2%-82.5%) among infants older than 2 months through 4 months of age. Comparable VE among infants aged 6 months or younger was observed for severe RSV-LRTD (80.4%; 95% CI, 54.4%-91.6%) and RSV-ARI (80.8%; 95% CI, 70.4%-87.6%) hospitalization, with similar age-specific trends. VE was consistent across stratifications by gestational age at vaccination, vaccination to delivery time interval, and proximal administration with other vaccines during pregnancy. Descriptively, among all infants hospitalized with ARI, 161 of 499 (32%) born to RSVpreF-unvaccinated mothers had severe LRTD, while 87 of 513 (17%) born to RSVpreF-vaccinated mothers had severe LRTD. Conclusions and Relevance: Findings in this case-control study demonstrate high year-round effectiveness of RSVpreF vaccination against RSV-associated hospitalization in infants 6 months of age or younger in the first year following introduction in Australia, with the highest VE observed in the earliest age intervals. Future analyses with larger sample sizes will evaluate VE among additional subgroups.