Does the Effectiveness of the Nirsevimab Immunization Programs Decline from One RSV Season to the Next? Real-World Evidence from Northeastern Italy

Background: Nirsevimab has demonstrated high effectiveness in preventing severe respiratory syncytial virus (RSV) disease in infants. However, real-world evidence from subsequent seasonal immunization campaigns remains limited. We evaluated the effectiveness of universal infant immunization during a second RSV season and assessed protection during the following season after immunization in the previous year. Methods: We conducted a population-based retrospective cohort study in the Province of Udine, Italy, using linked anonymized regional healthcare databases. All infants born between 1 April 2025 and 31 March 2026 were included in the analysis of the 2025–2026 RSV season. RSV-related hospitalizations were identified from hospital discharge diagnoses. Effectiveness was estimated using multivariable logistic regression and a Cox proportional hazards model with time-varying immunization status. We also assessed RSV-related hospitalizations during the subsequent season among infants who had received nirsevimab during the previous campaign. Seasonal hospitalization risks for RSV and other respiratory viral infections were compared across pre- and post-implementation seasons. Results: Of 2620 infants born during the second campaign, 2293 (87.5%) received nirsevimab. Twenty infants were hospitalized for RSV-related conditions, including 13/2293 (5.67 per 1000) immunized and 7/327 (21.41 per 1000) non-immunized infants (p = 0.008). Adjusted analyses showed significantly lower odds and hazard of RSV-related hospitalization among immunized infants (OR 0.22, 95% CI 0.09–0.57; HR 0.27, 95% CI 0.11–0.69), corresponding to estimated effectiveness of 78% and 73%, respectively. During the following RSV season, six infants from the previous birth cohort were hospitalized with RSV-related conditions, all of whom had received nirsevimab during the preceding campaign (cohort coverage: 78.5%). Hospitalization rates for non-RSV respiratory viruses were lower in the two post-implementation seasons than in the preceding seasons, although this ecological analysis was not designed to establish causality. Conclusions: Universal infant immunization with nirsevimab remained highly effective in preventing RSV-related hospitalization during the second seasonal campaign, achieving high population coverage. No evidence of residual protection was observed during the subsequent RSV season after immunization in the previous year. Continued real-world surveillance is warranted to monitor nirsevimab effectiveness and the broader epidemiology of respiratory viral infections following widespread implementation.