Estimated Effectiveness of 2024-2025 COVID-19 Vaccination Against Severe COVID-19

Importance As SARS-CoV-2 JN.1 lineage descendants continue to evolve, evaluating COVID-19 vaccine effectiveness (VE) against severe COVID-19 remains important to guide vaccination strategies. Objective To estimate the VE of the 2024-2025 COVID-19 vaccines against COVID-19–associated hospitalization and severe in-hospital outcomes overall and by time since dose (7-89, 90-179, and ≥180 days), JN.1 descendant lineage (KP.3.1.1, XEC, LP.8.1), and spike protein mutations associated with immune evasion. Design, Setting, and Participants This multicenter, test-negative, case-control study conducted by the Investigating Respiratory Viruses in the Acutely Ill Network included adult patients (aged ≥18 years) hospitalized between September 1, 2024, and April 30, 2025, at 26 hospitals in 20 US states. Case patients presented with COVID-19–like illness and positive SARS-CoV-2 nucleic acid or antigen test results; control patients had COVID-19–like illness but tested negative for SARS-CoV-2. Exposure Receipt of a 2024-2025 COVID-19 vaccine at least 7 days before illness onset. Main Outcomes and Measures Main outcomes were COVID-19–associated hospitalization and severe in-hospital outcomes (supplemental oxygen therapy, acute respiratory failure, intensive care unit admission, and invasive mechanical ventilation or death). Logistic regression was used to estimate the odds of vaccination in case and control patients, adjusting for demographics, clinical characteristics, and enrollment region. The VE was estimated as (1-adjusted odds ratio) × 100%. Results A total of 8493 patients (median [IQR] age, 66 [54-76] years; 4338 female [51.1%]), including 1888 case patients with COVID-19 (among whom 951 [50.4%] had successful whole-genome sequencing, including 348 [36.6%] with KP.3.1.1, 218 [22.9%] with XEC, and 134 [14.1%] with LP.8.1 infections) and 6605 control patients were enrolled. Vaccine effectiveness against COVID-19–associated hospitalization was 40% (95% CI, 27%-51%), and protection was sustained through 90 to 179 days after vaccination. Vaccine effectiveness was higher against the most severe outcome of invasive mechanical ventilation or death at 79% (95% CI, 55%-92%). It was 49% (95% CI, 25%-67%) against hospitalization with KP.3.1.1, 34% (95% CI, 4%-56%) against XEC, and 24% (95% CI, −19% to 53%) against LP.8.1, with increasing median time since dose receipt among vaccinated case patients due to sequential circulation patterns (60, 89, and 141 days, respectively). The VE was similar against lineages with spike protein S31 deletion (41% [95% CI, 22%-56%]) and T22N and F59S substitutions (37% [95% CI, 9%-57%]). Conclusions and Relevance In this multicenter, case-control analysis of VE, 2024-2025 COVID-19 vaccines may have provided protection against hospitalizations and severe in-hospital outcomes as multiple JN.1 descendant lineages circulated. Monitoring COVID-19 VE, including stratifying by SARS-CoV-2 lineage and spike protein mutations, remains important to guide COVID-19 vaccine composition and recommendations.