Adjuvanted vs High-Dose Influenza Vaccines in Older US Adults

Importance: In the US, adjuvanted or higher-dose influenza vaccines are preferentially recommended for annual use among adults aged 65 years or older. Adjuvanted and high-dose influenza vaccines have not been compared in a pragmatic randomized study. Objective: To assess the relative vaccine effectiveness (rVE) of adjuvanted vs high-dose inactivated influenza vaccine against polymerase chain reaction (PCR)-confirmed influenza in older adults at Kaiser Permanente Northern California (KPNC). Design, Setting, and Participants: In this cluster randomized crossover study, during the 2023 to 2024 influenza season, 65 KPNC facilities were cluster randomized such that approximately half of facilities administered adjuvanted and half high-dose influenza vaccine on the first week of the vaccination season (and thereafter every facility crossed over and alternated formulations weekly). Using Cox proportional hazards regression on a calendar time scale, the rVE of adjuvanted vs high-dose vaccine was estimated for each outcome as 1 minus the hazard ratio, adjusted for age, sex, race and ethnicity, comorbidities, and health care utilization. Study participants included all adults 65 years or older who were vaccinated with adjuvanted or high-dose inactivated influenza vaccine during routine care at a KPNC facility between August 17, 2023, and April 16, 2024. Exposures: Adjuvanted or high-dose inactivated influenza vaccine receipt during the 2023 to 2024 influenza season. Individuals were considered vaccinated 14 days after immunization. Main Outcomes and Measures: The primary outcome was PCR-confirmed influenza in any clinical setting. Secondary outcomes were PCR-confirmed influenza with hospitalization or emergency department visits and hospitalization for community-acquired pneumonia. Outcomes were assessed starting October 1, 2023, or 14 days after vaccination, whichever came later. Results: This study included 429 595 individuals from the 2023 to 2024 influenza season (mean [SD] age, 75 [7] years; 236 857 [55.1%] female; 86 287 [20.1%] Asian, 22 910 [5.3%] Black, 53 820 [12.5%] Hispanic, 1123 [0.3%] American Indian or Alaska Native, 2562 [0.6%] Pacific Islander, 252 709 [58.8%] White, 1638 [0.4%] multiracial, and 8546 [2.0%] unknown race), of whom 212 875 (49.6%) received adjuvanted and 216 720 (50.4%) received high-dose influenza vaccine. There were 836 cases of PCR-confirmed influenza (3.9 per 1000 persons) identified after adjuvanted and 867 cases (4.0 per 1000 persons) after high-dose vaccine. The rVE of adjuvanted compared with high-dose influenza vaccine was 1.5% (95% CI, -8.4% to 10.5%) against influenza, 9.1% (95% CI, -4.0% to 20.4%) against influenza with hospitalization or emergency department visits, and 1.0% (95% CI, -11.4% to 12.0%) against hospitalizations for community-acquired pneumonia. Conclusion and Relevance: In the first season of a large, ongoing study in adults 65 years or older, adjuvanted and high-dose influenza vaccines did not differ in effectiveness against laboratory-confirmed influenza during the 2023 to 2024 influenza season. Consistent with Advisory Committee on Immunization Practices recommendations, these results support the equivalency of adjuvanted and high-dose influenza vaccines for adults 65 years or older. Trial Registration: ClinicalTrials.gov Identifier: NCT06029933.