Abstract Rationale Respiratory syncytial virus (RSV) remains a leading cause of hospitalization in infants despite new immunoprophylaxis strategies, including the monoclonal antibody nirsevimab and maternal preF vaccination. While both interventions have markedly reduced RSV-related hospitalizations, breakthrough infections still occur. This study aimed to characterize the clinical and virological features of RSV infections in infants with and without current-season immunoprophylaxis. Methods We conducted a prospective observational study of 245 infants under 2 years of age with RT-PCR-confirmed RSV infection during the 2024-2025 season. Clinical data and nasopharyngeal swabs were collected across outpatient, emergency, and inpatient settings. Infants were classified by RSV immunoprophylaxis status (current-season, prior-season, or none). Viral load was quantified by RT-qPCR, and RSV subtyping and whole-genome sequencing were performed. Comparative analyses included t-tests, Fisher exact tests and multivariate logistic regression. Results Among 245 RSV-infected infants, 28 (11%) represented breakthrough infections despite current-season immunoprophylaxis. These infants exhibited significantly higher Ct values (mean 22.4 vs. 19.8; p = 0.003), indicating lower viral burden, and were less likely to present with fever (46% vs. 72%; p = 0.007) or lower respiratory tract infection (LRTI) (p = 0.02). In multivariate analysis, current-season immunoprophylaxis was independently associated with lower odds of LRTI (p = 0.004). All nirsevimab breakthrough cases were RSV A, while most maternal preF breakthrough cases were RSV B (p = 0.005). No known resistance mutations were detected in the nirsevimab F-binding region. Infants with prior-season prophylaxis exhibited viral loads and clinical severity comparable to those never immunized, underscoring the limited duration of passive protection Conclusions Current-season RSV immunoprophylaxis not only reduces infection risk but attenuates viral replication and disease severity in breakthrough cases. Subtype-specific patterns highlight the need for continued genomic surveillance and refinement of prophylaxis strategies to sustain population-level protection in infants. This abstract is funded by: NIH/NHLBI 1R01HL173059-02 (LMY); Center for Disease Control U01-IP001257-01 (WIG, KES, JEL, LMY).
Ortiz et al. (Fri,) studied this question.