Durability and Seasonal Variation in the Effectiveness of Nirsevimab over Three Seasons in Connecticut

Technical Summary: Durability and Seasonal Variation in the Effectiveness of Nirsevimab over Three Seasons in Connecticut

Problem Statement
Nirsevimab, a long-acting monoclonal antibody approved in 2023, is widely used to prevent severe Respiratory Syncytial Virus (RSV) disease in infants. While early post-licensure studies demonstrated high initial effectiveness, significant knowledge gaps remain regarding the durability of protection beyond the first RSV season and the impact of variable RSV seasonality on real-world effectiveness. Specifically, it is unclear how the fixed seasonal administration schedule (typically October–November) interacts with years of delayed RSV activity, potentially leading to waning immunity before peak viral circulation. Furthermore, the extent of protection during an infant's second RSV season remains uncertain.

Methodology
The authors conducted a test-negative case-control study utilizing electronic health records (EHR) from the Yale New Haven Health System in Connecticut. The study population comprised 17,755 infants and young children (aged ≤36 months) tested for RSV via polymerase chain reaction (PCR) between October 1, 2023, and March 1, 2026, covering three consecutive RSV seasons (2023/24, 2024/25, and 2025/26).

• Study Design: Cases were defined as RSV-positive patients with medically attended acute respiratory infections (ARI); controls were RSV-negative patients with ARI.
• Exposure: Immunization status was determined via Connecticut's statewide immunization information system (CT WiZ).
• Statistical Analysis:
  • Primary Analysis: Multivariable logistic regression was used to estimate overall effectiveness by surveillance year, adjusting for age, weekly RSV activity, risk factors for severe disease, and maternal RSV vaccination status.
  • Waning Analysis: A Bayesian logistic regression framework with spline structures was employed to model effectiveness as a function of time since immunization (up to 24 months).
  • Sensitivity Analyses: Six sensitivity analyses were conducted to address potential confounders, including exclusions for co-infections, restrictions to specific control groups, and adjustments for maternal vaccination status.

Key Results

• Overall Effectiveness: Across all three seasons, nirsevimab demonstrated an overall effectiveness of 67.3% (95% CI: 59.8–73.3%) against medically attended RSV infection. Effectiveness was 60.2% against outpatient visits and 88.9% against hospitalization.
• Seasonal Variation: Effectiveness declined in later seasons, corresponding to progressively delayed RSV activity. Effectiveness against medically attended infection dropped from 76.7% in 2023/24 to 54.4% in 2025/26. Similarly, protection against hospitalization decreased from 93.4% to 84.7% over the same period.
• Durability and Waning:
  • Protection waned over the first 12 months post-immunization. Against hospitalization, effectiveness declined from 92.5% at 1 month to 77.2% at 6 months, and 39.9% at 12 months.
  • After 12 months, effectiveness appeared to plateau at a low level with high uncertainty, suggesting limited protection into the second RSV season.
  • Crucially, the initial effectiveness (within the first 2 months post-immunization) did not differ significantly across the three years (p=0.63), indicating that the observed decline in later seasons was driven by the timing of exposure relative to immunization rather than a fundamental loss of efficacy or viral escape.
• Timing Correlation: The study observed a progressively delayed RSV peak from 2023/24 to 2025/26. In 2025/26, the median interval between immunization and RSV testing increased to 87 days, compared to 43 days in 2023/24. This extended interval allowed immunity to wane further before peak exposure.

Key Contributions

1. Extended Durability Assessment: This is the first study to characterize the temporal dynamics of nirsevimab effectiveness over an extended period (>12 months), providing data on protection during an infant's second RSV season.
2. Seasonal Timing Impact: The study is the first to empirically evaluate how shifts in RSV epidemic timing influence nirsevimab effectiveness. It demonstrates that delayed RSV activity, when combined with a fixed administration schedule, results in lower observed effectiveness due to the waning of antibody levels before peak exposure.
3. Differentiation of Waning vs. Escape: By showing that initial effectiveness remained stable across years despite declining overall effectiveness, the authors provide evidence that the reduced protection in 2025/26 was likely due to the duration of immunity relative to exposure timing, rather than the emergence of viral variants with reduced susceptibility.

Significance and Claims
The paper claims that nirsevimab provides sustained protection against RSV-associated hospitalization for 6 to 12 months post-immunization, though protection beyond 12 months is limited and uncertain. The study highlights that the effectiveness of nirsevimab is highly dependent on the alignment between the administration schedule and local RSV circulation patterns. The authors conclude that the lower effectiveness observed in the 2025/26 season was a consequence of delayed RSV activity allowing immunity to wane prior to peak exposure. Consequently, the paper suggests that aligning administration schedules more flexibly with predicted local RSV peaks could enhance overall protection, rather than attributing reduced efficacy to viral evolution or intrinsic drug failure.