Effectiveness of the 2025–2026 seasonal influenza vaccine among U.S. veterans: an observational study

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Background Annual vaccination is the primary strategy for preventing adverse clinical outcomes associated with seasonal influenza, but vaccine effectiveness varies by season with the degree of antigenic match and the predominant circulating subtype. The 2025–2026 season has been dominated by a newly emerged, antigenically distinct influenza A(H3N2) subclade K that arose after the vaccine strain was selected, raising concern about a vaccine mismatch and reduced effectiveness. Contemporary, season-specific evidence on effectiveness against clinically important outcomes is needed. Methods We used U.S. Department of Veterans Affairs (VA) electronic health records to emulate a series of 24 sequential 7-day target trials among VA users with an in-person primary care visit between September 15, 2025, and February 28, 2026, comparing those who did and did not receive a seasonal influenza vaccine at the visit. The final analytic cohort comprised 1,401,492 participant-trials (526,350 vaccinated and 875,142 unvaccinated). Exposure was defined as receipt of the 2025–2026 seasonal influenza vaccine on the date of an eligible primary care visit, compared with no seasonal influenza vaccination at that visit or during follow-up. The primary outcome was a composite of seasonal influenza–associated emergency department visit or hospitalization. Individual components were also evaluated. Vaccine effectiveness (VE), defined as 1 minus the risk ratio, was estimated as the per-protocol effect among vaccinated participants using discrete-time survival models with inverse-probability-of-treatment and inverse-probability-of-censoring weighting. Marginal cumulative risks, and risk differences (RDs) per 10,000 persons, together with risk ratios, were estimated. Findings Compared with no vaccination, receipt of the 2025–2026 vaccine was associated with a lower risk of the composite outcome (VE, 21.95%; 95% CI, 16.08%–27.65%; RD per 10,000 persons, −4.94; 95% CI, −6.49 to −3.47), influenza-associated emergency department visits (VE, 22.25%; 95% CI, 16.38%–27.94%; RD, −5.01; 95% CI, −6.55 to −3.53), and influenza-associated hospitalizations (VE, 31.84%; 95% CI, 14.77%–46.27%; RD, −1.08; 95% CI, −1.82 to −0.44). Vaccination was associated with lower risk of the composite outcome across prespecified subgroups defined by age (≤65 and >65 years) and immunocompromised status. Results were consistent across multiple sensitivity analyses, and negative outcome controls (all-cause hospitalization and all-cause death within 14 days) showed no association with vaccination. In analyses applying the same design to the 2024–2025 season, vaccine effectiveness was lower in 2025–2026 than in 2024–2025 for every outcome (composite, 21.95% vs 32.15%; approximately 30% lower in relative terms). Interpretation The 2025–2026 seasonal influenza vaccine was associated with reductions in influenza-associated emergency department visits and hospitalizations, but its effectiveness was lower than in the immediately preceding season. These findings provide contemporary, season-specific evidence supporting the continued use of seasonal influenza vaccination to prevent clinically important influenza outcomes. Funding U.S. Department of Veterans Affairs.

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