Influenza Vaccine Effectiveness Estimates among US Department of Defense Adult Beneficiaries over Four Consecutive Influenza Seasons: A Test-Negative Design Study with Different Control Groups.

A test-negative design study with different control groups (influenza test-negative controls, non-influenza virus positive controls, and pan-negative controls) was conducted to assess inactivated influenza vaccine effectiveness (VE) in adults aged ≥18 years, 2016-2017 through 2019-2020 influenza seasons. A database was developed from the US Department of Defense Global Respiratory Pathogen Surveillance Program. VE was estimated using a generalized linear mixed model with logit link and binomial distribution, adjusted for confounding effects. A total of 7114 adults including 2543 medically attended, laboratory-confirmed influenza-positive cases were identified. Using influenza test-negative controls, the adjusted VE in adults was 40% [95% confidence interval (CI): 33-46%] overall, including 46% (95% CI: 36-55%) for influenza A(H1N1)pdm09, 32% (95% CI: 19-42%) for influenza A(H3N2), and 54% (95% CI: 44-62%) for influenza B. The age-stratified analysis showed that VE estimates against influenza A(H1N1)pdm09 (34%; 95% CI: -29-66%) and influenza A(H3N2) (6%; 95% CI: -60-45%) were low and non-significant for elderly adults ≥65 years of age. Overall VE estimates against any influenza or by influenza (sub)types in adults were consistent when using influenza test-negative controls, non-influenza virus positive controls, and pan-negative controls. Inactivated influenza vaccination provided moderate protection against influenza virus infection, based on the analysis from a large number of adults aged ≥18 years over multiple influenza seasons.