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.

Question What 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?

Findings Among 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).

Meaning COVID-19 vaccines protected against severe disease during the 2024–2025 season when multiple JN.1 lineages evolved and circulated.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonathan D. Casey reports receiving personal fees from Reprieve Cardiovascular, Inc., outside the submitted work. James D. Chappell received support from Merck for studies of RSV epidemiology among hospitalized children in Jordan and from QuidelOrtho for diagnostic detection of RSV among hospitalized children in Jordan, outside the submitted work. Michelle Ng Gong reports grant funding from NIH and CDC for research, receives fees for serving on the DSMB for clinical trials from NIH, Regeneron, Emory, fees for serving as scientific advisor or consultant for Philips Healthcare, Novartis, Radiometer, receives travel expenses and payment as President Elect of American Thoracic Society, payment as Section Editor for UpToDate from Wolters Kluwer, and travel expenses and honorarium as faculty for ISICEM international conference, outside the submitted work. Carlos G. Grijalva has received consultant fees from GSK and Merck, and has received research support from CDC, NIH, FDA, AHRQ and SyneosHealth, outside the submitted work. Natasha Halasa reports a grant from Merck that ended December 31, 2025, outside the submitted work. Akram Khan reports that his institution has received grant funding from Dompe Pharmaceuticals, 4D Medical, Direct Biologics, BARDA and NIH for patient enrollment in clinical trials, outside the submitted work. Adam S. Lauring reports research support from Roche related to Baloxavir and influenza, outside the submitted work. Christopher Mallow reports ROMTech Investments, outside the submitted work. Ithan D. Peltan receives funding from NIGMS (R35GM151147), funding from NHLBI, and payments to his institution from Regeneron, Novartis, and Bluejay Diagnostics, outside the submitted work. H. Keipp Talbot reports grant funding from CDC outside the submitted work.

This work was supported by the United States Centers Disease Control and Prevention [contract 75D30122C14944].

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