A Cohort Study on Influenza Vaccine and All-Cause Mortality in Older Adults: Methodological Concerns and Public Health Implications

Introduction In 2020, the restrictions adopted to control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to an unprecedented reduction in influenza-related burden. As such, the reduced chance to characterize the circulating virus strains might have increased the risk of vaccine mismatch for the forthcoming winter seasons. The role of an effective influenza vaccination campaign might therefore assume even more value, especially for frail and multimorbid older individuals. Methodological concerns on confounding by indication are always debated in vaccine effectiveness studies and it might be instrumental to give a pragmatic message on an individual's responsibility to receive the influenza vaccine. We therefore investigated the role of specific confounders to explain the association between influenza vaccine and mortality among older adults. Methods Using a primary care database, we formed a cohort of patients aged 65 years or older who were actively registered with their general practitioner (GP) at the beginning of each of nine influenza seasons through to the 2018/2019 season. The study index date was the related seasons' starting date. Exposure to the influenza vaccine was operationally defined in the 2 months preceding the index date up to 2 weeks before the exit date. Cox regression models were estimated to calculate hazard ratios (HRs) and their 95% confidence intervals (CI) of death between vaccinated and unvaccinated patients in a time-dependent fashion. The potential confounders sequentially entered the model based on their increasing effect size observed in univariate analyses. Results Over the 10 years under study, the influenza vaccine showed a significant protective effect in terms of mortality, reaching 13% reduction (HR 0.87, 95% CI 0.80-0.95) in the 2018/2019 influenza season. When we estimated the multivariate model by sequentially adding the potential confounders, there was an inversion of HR (below the unit) that was significantly explained by the covariates coding for a prior history of lower respiratory tract infections and the presence of the pneumococcal vaccine. Conclusion In the current pandemic scenario, we cannot divert attention to proper use of face masks, social distancing, and hand hygiene, which are important measures to prevent influenza and other respiratory viral infections. Nonetheless, their effectiveness might be negligible without acceptable coverage for influenza vaccine, especially in older patients with a history of lower respiratory tract infections, which appears to be the main source of confounding by indication.