Influenza Vaccine and Associated Infection and Death in California, 2024 to 2025

IMPORTANCE Effectiveness of seasonal influenza vaccine must be assessed annually as influenza viruses evolve, requiring updated vaccine components. Evidence is limited for direct vaccine benefit in lowering risk of death following influenza virus infection. OBJECTIVE To evaluate the association between current-season influenza vaccination and laboratory-confirmed influenza virus infection and, among persons with laboratory-confirmed influenza, the association with influenza-associated death. DESIGN, SETTING, AND PARTICIPANTS A case-control analysis of California residents aged 6 months or older with influenza diagnostic testing ordered between October 1, 2024, and May 31, 2025, with data on diagnostic test result and 2024 to 2025 influenza vaccination. Influenza-associated deaths within 30 days of testing among persons with laboratory-confirmed influenza were identified from vital statistics records. EXPOSURES Influenza vaccination from October 1, 2024, to May 31, 2025. MAIN OUTCOMES AND MEASURES Associations were evaluated between 2024 to 2025 influenza vaccination and (1) laboratory-confirmed influenza, in which case individuals tested positive and control individuals tested negative for laboratory confirmed influenza; and (2) influenza-associated death, in which deaths were compared with surviving cases among persons with laboratory-confirmed influenza. Associations were assessed with mixed-effects logistic regression. RESULTS Among 1 106 628 persons tested for laboratory-confirmed influenza (610 093 female participants 55.1%), 234 715 were case individuals with laboratory-confirmed influenza (median IQR age, 28 10-52 years) and 871 913 were control individuals (median IQR age, 42 19-67 years); 45 441 influenza cases (19.4%) and 255 605 control individuals (29.3%) had received 2024 to 2025 influenza vaccination. Vaccination was significantly associated with decreased likelihood of laboratory-confirmed influenza (estimated vaccine effectiveness, 40%; 95% CI, 39%-41%). Among persons with laboratory confirmed influenza, there were 801 influenza-associated deaths. Influenza-associated death among persons aged 65 years or older was associated with lower likelihood of influenza vaccination (adjusted odds ratio, 0.71; 95% CI, 0.60-0.84) compared with persons with nonfatal infection. CONCLUSIONS AND RELEVANCE In this case-control study of estimated vaccine effectiveness, influenza vaccination was associated with decreased likelihood of laboratory-confirmed influenza and influenza-associated deaths among those with laboratory-confirmed influenza. Electronic laboratory reporting linked to immunization registry and vital statistics provide tools to assess vaccine effectiveness and risk of death, a rare influenza-associated outcome.