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

ImportanceAs 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. ObjectiveTo 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 participantsThis 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. ExposureReceipt of 2024-2025 COVID-19 vaccine [≥]7 days before illness onset. Main Outcomes and MeasuresMain 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%. Results1,888 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 Relevance2024-2025 COVID-19 vaccines provided additional protection against severe disease as multiple JN.1 descendant lineages circulated. Key pointsO_ST_ABSQuestionC_ST_ABSWhat was estimated effectiveness of 2024-2025 COVID-19 vaccines against severe COVID-19 and did effectiveness vary by SARS-CoV-2 lineage or spike protein mutations? FindingsAmong 1,888 adult COVID-19 cases and 6,605 controls included in a test-negative, case-control analysis during September 2024-April 2025, vaccine effectiveness was 40% against hospitalization and 79% against invasive mechanical ventilation or death. Vaccine effectiveness was similar for KP.3.1.1 and XEC lineages and spike mutations potentially associated with immune evasion (S31 deletion, T22N and F59S substitutions). MeaningCOVID-19 vaccines protected against severe disease during the 2024-2025 season when multiple JN.1 lineages evolved and circulated.