Abstract
Effectiveness of nirsevimab against respiratory syncytial virus (RSV) hospitalization during the 2024/2025 season in Spain was estimated using a test-negative design (TND) and hospital-based respiratory infections surveillance data. Children born between 1 April 2024 and 31 March 2025 and hospitalized with severe respiratory infection between the start of the 2024 immunization campaign (regionally variable, between 16 September and 1 October 2024) and 31 March 2025 were systematically RT-PCR RSV-tested within 10 days of symptom onset and classified as cases if positive or controls if negative. Nirsevimab effectiveness ((1 - odds ratio) × 100) was estimated using logistic regression, adjusted for admission week, age, sex, high-risk factors, and regional RSV hospitalization rate. We included 199 cases (68.8% immunized) and 360 controls (86.4% immunized). Overall effectiveness was 65.5% (95% confidence interval: 45.2 to 78.3). Effectiveness was similar among infants born before and after the campaign start (63.6% vs. 70.4%, respectively). We found an unexpected early decrease in effectiveness with increasing time since immunization and age, albeit with wide confidence intervals for some groups. Strong age-period-cohort effects and potential sources of bias were identified, highlighting the need to further explore methodological challenges of implementing the TND in the dynamic population of newborns.