Impact of Universal Nirsevimab Immunoprophylaxis on Bronchiolitis Hospitalizations and Disease Severity in Neonates: A Real-World Single-Centre Study

(1) Background: Respiratory syncytial virus (RSV) is the leading cause of neonatal lower respiratory tract infection. We described changes in neonatal bronchiolitis hospitalizations, RSV detection and disease severity across the transition from two seasons without systematic RSV prophylaxis to two seasons following the introduction of universal nirsevimab immunoprophylaxis (Lazio region, December 2024) in a tertiary pediatric center. (2) Methods: A retrospective, observational study was conducted at “Bambino Gesù” Children’s Hospital IRCCS (Rome, Italy) comparing four consecutive RSV seasons: pre-universal prophylaxis (2022–2024, n = 256) versus post-universal prophylaxis (2024–2026, n = 122). Term infants ≤30 days and preterm infants under term-corrected age hospitalized for acute bronchiolitis were included. RSV status was confirmed by viral testing within 72 h of admission. (3) Results: Total bronchiolitis admissions dropped by 52% (256 to 122), with RSV-positive cases decreasing from 66.8% to 43.4% (RR 0.65, 95% CI 0.52–0.81; p < 0.001). Monthly peak RSV admissions fell progressively from 56 (December 2022) to 6 (January 2026). Among all admissions, ICU rates dropped from 18.4% to 4.1% (RR 0.22, 95% CI 0.09–0.55; p < 0.001). Within RSV-positive neonates, respiratory support requirements decreased from 93.0% to 71.7% (RR 0.77, 95% CI 0.65–0.92; p < 0.001), and ICU admissions declined from 24.0% to 5.7% (RR 0.24, 95% CI 0.08–0.73; p = 0.003). Non-RSV pathogens dominated the post-campaign viral profile, with the relative prevalence of human metapneumovirus (hMPV) increasing from 3.9% to 11.5% (RR 2.94, 95% CI 1.34–6.42; p = 0.006) without increasing overall severity. In the post-campaign period, 22 of 53 RSV-positive admissions occurred in nirsevimab-immunized neonates (breakthrough infections): 7/35 in 2024–25 and 15/18 in 2025–26 (p < 0.001), reflecting higher population coverage. (4) Conclusions: Universal nirsevimab prophylaxis was associated with marked reductions in neonatal bronchiolitis hospitalizations, RSV positivity, respiratory support needs, and ICU admissions. Early, high-coverage implementation prior to seasonal RSV peaks maximizes population-level protection in highly vulnerable newborns.