Background: The COVID-19 pandemic was associated with historically low influenza circulation during the 2020-2021 season, followed by increase in influenza circulation during the 2021-2022 US season. The 2a.2 subgroup of the influenza A(H3N2) 3C.2a1b subclade that predominated was antigenically different from the vaccine strain.

Methods: To understand the effectiveness of the 2021-2022 vaccine against hospitalized influenza illness, a multi-state sentinel surveillance network enrolled adults aged ≥18 years hospitalized with acute respiratory illness (ARI) and tested for influenza by a molecular assay. Using the test-negative design, vaccine effectiveness (VE) was measured by comparing the odds of current season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative controls, adjusting for confounders. A separate analysis was performed to illustrate bias introduced by including SARS-CoV-2 positive controls.

Results: A total of 2334 patients, including 295 influenza cases (47% vaccinated), 1175 influenza- and SARS-CoV-2 negative controls (53% vaccinated), and 864 influenza-negative and SARS-CoV-2 positive controls (49% vaccinated), were analyzed. Influenza VE was 26% (95%CI: -14 to 52%) among adults aged 18-64 years, -3% (95%CI: -54 to 31%) among adults aged ≥65 years, and 50% (95%CI: 15 to 71%) among adults 18-64 years without immunocompromising conditions. Estimated VE decreased with inclusion of SARS-CoV-2-positive controls.

Conclusions: During a season where influenza A(H3N2) was antigenically different from the vaccine virus, vaccination was associated with a reduced risk of influenza hospitalization in younger immunocompetent adults. However, vaccination did not provide protection in adults ≥65 years of age. Improvements in vaccines, antivirals, and prevention strategies are warranted.

Keywords: Influenza; SARS-CoV-2; antigenic drift; vaccine effectiveness.