Background: Influenza vaccine effectiveness (VE) against a spectrum of severe disease, including critical illness and death, remains poorly characterized.

Methods: We conducted a test-negative study in an intensive care unit (ICU) network at 10 United States hospitals to evaluate VE for preventing influenza-associated severe acute respiratory infection (SARI) during the 2019-2020 season, which was characterized by circulation of drifted A/H1N1 and B-lineage viruses. Cases were adults hospitalized in the ICU and a targeted number outside the ICU (to capture a spectrum of severity) with laboratory-confirmed influenza-associated SARI. Test-negative controls were frequency-matched based on hospital, timing of admission, and care location (ICU vs non-ICU). Estimates were adjusted for age, comorbidities, and other confounders.

Results: Among 638 patients, the median (interquartile) age was 57 (44-68) years; 286 (44.8%) patients were treated in the ICU and 42 (6.6%) died during hospitalization. Forty-five percent of cases and 61% of controls were vaccinated, which resulted in an overall VE of 32% (95% CI: 2 to 53%), including 28% (-9% to 52%) against influenza A, and 52% (13% to 74%) against influenza B. VE was higher in adults 18-49 years old (62%; 95% CI: 27% to 81%) than those 50-64 years old (20%, -48% to 57%) and ≥65 years old (-3%; 95% CI: -97% to 46%) (p=0.0789 for interaction). VE was significantly higher against influenza-associated death (80%, 95% CI: 4% to 96%) than non-fatal influenza illness.

Conclusions: During a season with drifted viruses, vaccination reduced severe influenza-associated illness among adults by 32%. VE was high among young adults.