IMPORTANCE: Vaccine effectiveness (VE) estimates are needed to monitor the effect of updated COVID-19 vaccinations.
OBJECTIVE: To assess the effectiveness of 2024-2025 COVID-19 vaccines against medically attended COVID-19 among adults 18 years and older in the US.
DESIGN, SETTING, AND PARTICIPANTS: This case-control study with a test-negative design included patient encounters with a COVID-19-like illness discharge diagnosis code and a molecular or antigen SARS-CoV-2 test within 10 days before to 3 days after the encounter date, from September 5, 2024, to September 2, 2025. Encounters were captured in VISION (Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network), a multisite, electronic medical record-based network of health care systems, including 381 emergency department/urgent care (ED/UC) departments and 246 hospitals in 6 states.
EXPOSURE: Vaccination with a 2024-2025 COVID-19 vaccine formulation (approved by the US Food and Drug Administration in August 2024) in the previous 7 to 299 days.
MAIN OUTCOMES AND MEASURES: Outcomes were COVID-19-associated ED/UC encounters, COVID-19-associated hospitalization, and COVID-19-associated critical illness (hospitalization with an intensive care unit admission or in-hospital death). Encounters with a positive molecular or antigen SARS-CoV-2 test result were classified as cases, and encounters with a negative molecular SARS-CoV-2 test result were classified as controls. The odds of 2024-2025 COVID-19 vaccination were compared among cases and controls, adjusting for confounders, with estimated VE calculated as (1 - adjusted odds ratio) × 100%.
RESULTS: In 333 262 eligible ED/UC encounters (median [IQR] age of patients, 54 [35-72] years; 60% female) and 97 663 eligible hospitalizations among immunocompetent adults 18 years and older (median [IQR] age of patients, 72 [59-81] years; 53% female), estimated VE was 26% (95% CI, 23%-29%) against COVID-19-associated ED/UC encounters, 35% (95% CI, 30%-40%) against COVID-19-associated hospitalization, and 41% (95% CI, 28%-51%) against COVID-19-associated critical illness 7 to 299 days after vaccination. Among immunocompetent adults 65 years and older (122 663 ED/UC encounters and 63 958 hospitalizations), estimated VE was 26% (95% CI, 22%-30%) against COVID-19-associated ED/UC encounters, 35% (95% CI, 29%-40%) against COVID-19-associated hospitalization, and 41% (95% CI, 28%-52%) against COVID-19-associated critical illness 7 to 299 days after vaccination. Among 32 629 hospitalizations in immunocompromised adults 18 years and older, estimated VE against COVID-19-associated hospitalization was 24% (95% CI, 13%-34%). VE estimates waned with more time since vaccination.
CONCLUSIONS AND RELEVANCE: In this test-negative case-control study, 2024-2025 COVID-19 vaccination was associated with reduced likelihood of medically attended COVID-19-associated outcomes among immunocompetent and immunocompromised adults, highlighting the importance of adults receiving recommended COVID-19 vaccinations.