Spotlight influenza: Estimation of influenza vaccine effectiveness in elderly people with assessment of residual confounding by negative control outcomes, Finland, 2012/13 to 2019/20

Background: Cohort studies on vaccine effectiveness are prone to confounding bias if the distribution of risk factors is unbalanced between vaccinated and unvaccinated study subjects. Aim: We aimed to estimate influenza vaccine effectiveness in the elderly population in Finland by controlling for a sufficient set of confounders based on routinely available register data. Methods: For each of the eight consecutive influenza seasons from 2012/13 through 2019/20, we conducted a cohort study comparing the hazards of laboratory-confirmed influenza in vaccinated and unvaccinated people aged 65-100 years using individual-level medical and demographic data. Vaccine effectiveness was estimated as 1 minus the hazard ratio adjusted for the confounders age, sex, vaccination history, nights hospitalised in the past and presence of underlying chronic conditions. To assess the adequacy of the selected set of confounders, we estimated hazard ratios of off-season hospitalisation for acute respiratory infection as a negative control outcome. Results: Each analysed cohort comprised around 1 million subjects, of whom 37% to 49% were vaccinated. Vaccine effectiveness against laboratory-confirmed influenza ranged from 16% (95% confidence interval (CI): 12-19) to 48% (95% CI: 41-54). More than 80% of the laboratory-confirmed cases were hospitalised. The adjusted off-season hazard ratio estimates varied between 1.00 (95% CI: 0.94-1.05) and 1.08 (95% CI: 1.01-1.15), indicating that residual confounding was absent or negligible. Conclusion: Seasonal influenza vaccination reduces the hazard of severe influenza disease in vaccinated elderly people. Data about age, sex, vaccination history and utilisation of hospital care proved sufficient to control confounding.