Effectiveness of 2024–2025 COVID-19 Vaccination Against COVID-19 Hospitalization and Severe In-Hospital Outcomes — IVY Network, 26 Hospitals, September 1, 2024–April 30, 2025

Importance: As SARS-CoV-2 JN.1 lineage descendants continue to evolve, evaluating COVID-19 vaccine effectiveness (VE) against severe COVID-19 is necessary to inform vaccine composition updates. Objective: To estimate effectiveness of 2024–2025 COVID-19 vaccines against COVID-19–associated hospitalizations 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 mutations potentially associated with immune evasion. Design, setting, and participants: This test-negative, case-control analysis included adult patients hospitalized during September 1, 2024–April 30, 2025 at 26 hospitals in 20 U.S. states. Cases presented with COVID-19–like illness and a positive SARS-CoV-2 nucleic acid or antigen test; controls had COVID-19–like illness but tested negative. Exposure: Receipt of 2024–2025 COVID-19 vaccine ≥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, invasive mechanical ventilation [IMV] or death). Logistic regression was used to estimate the odds of vaccination in cases and controls adjusting for demographics, clinical characteristics, and enrollment region. VE was estimated as (1 – adjusted odds ratio) x 100%. Results: 1,888 COVID-19 cases (including 348 with KP.3.1.1, 218 with XEC, and 134 with LP.8.1 infections) and 6,605 controls were enrolled (median [IQR] age, 66 [54–76] years; 4,338 [51%] female). VE against COVID-19–associated hospitalization was 40% (95% CI, 27%–51%) and protection was sustained through 90–179 days after vaccination. VE was higher against the most severe outcome of IMV or death at 79% (95% CI, 55%–92%). VE 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 due to sequential circulation patterns (60, 89, and 141 days, respectively). 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%]). Conclusion and Relevance: 2024–2025 COVID-19 vaccines provided additional protection against severe disease as multiple JN.1 descendant lineages circulated.