Association of influenza vaccination with SARS-CoV-2 infection and associated hospitalization and mortality among patients aged 66 years or older

Importance — Vaccine effectiveness studies have rarely implemented strategies to reduce the healthy vaccinee bias arising from differences in healthcare–seeking behavior between vaccinated and unvaccinated individuals. Although previous observational studies suggest that influenza vaccination is associated with a reduced risk of SARS-CoV-2–associated outcomes, the healthy vaccinee bias may have led to overestimating the vaccination effect.

Objective — To estimate the association between influenza vaccination and SARS-CoV-2–associated outcomes.

Design, Setting, and Participants — This cohort study was conducted over 2 consecutive influenza vaccination campaigns (2019-2020 and 2020-2021), owing to the substantial COVID-19 burden and the greater validity of influenza vaccination data in the studied age group. The study population included community-dwelling adults aged 66 years or older in Ontario, Canada.

Exposure — Influenza vaccination for a given season.

Main Outcomes and Measures — The outcomes of interest included SARS-CoV-2 infection, SARS-CoV-2–associated hospitalization, SARS-CoV-2–associated death, and a composite of SARS-CoV-2–associated hospitalization or death. Cox proportional hazards models were used to measure the association between influenza vaccination and SARS-CoV-2–associated outcomes, censoring individuals who moved into long-term care, received COVID-19 vaccines, or died before the observation period end date. Primary care periodic health examinations (PHEs) were explored as a negative tracer exposure (ie, no association expected with SARS-CoV-2 outcomes) and as an effect modifier of the association between influenza vaccination and SARS-CoV-2 outcomes.

Results — Of 2 922 449 individuals aged 66 years or older (54.2% female) living in Ontario, 2 279 805 were included in the study. Among these, 1 234 647 (54.2%) were female and 1 045 158 (45.8%) were male; their mean (SD) age was 75.08 (7.21) years. Those who had received influenza vaccination exhibited a lower incidence of SARS-CoV-2 infection than unvaccinated individuals for the 2019-2020 cohort (adjusted hazards ratio [aHR], 0.78; 95% CI, 0.73-0.84) and the 2020-2021 cohort (aHR, 0.76; 95% CI, 0.74-0.78). This association was also observed for SARS-CoV-2–associated hospitalization or death (2019-2020: aHR, 0.83; 95% CI, 0.74-0.92; 2020-2021: aHR, 0.66; 95% CI, 0.63-0.70). Similarly, undergoing a PHE was also associated with a lower incidence of SARS-CoV-2 infection (aHR, 0.85; 95% CI, 0.78-0.91) and SARS-CoV-2–associated hospitalization or death (aHR, 0.80; 95% CI, 0.70-0.90), and modified the association between influenza vaccination and SARS-CoV-2 infection for vaccinated individuals who underwent PHE (aHR, 0.62; 95% CI, 0.52-0.74) and for vaccinated individuals who did not undergo PHE (aHR, 0.81; 95% CI, 0.76-0.87), and also SARS-CoV-2–associated hospitalization or death in vaccinated individuals who underwent PHE (aHR, 0.66; 95% CI, 0.49-0.88) and vaccinated individuals who did not undergo PHE (aHR, 0.85, 95% CI, 0.76-0.95).

Conclusions and Relevance — The findings of this cohort study suggest that undergoing a PHE may at least partially modify the association between influenza vaccination and SARS-CoV-2–associated outcomes in individuals aged 66 years or older, providing evidence of the healthy vaccinee bias that may affect vaccine effectiveness studies.