Effectiveness of trivalent influenza vaccines against hospitalizations due to laboratory-confirmed influenza a in the elderly: Comparison of test-negative design with register-based designs

•We compared test-negative and register-based designs in estimating influenza VE.•Influenza VE estimates for all designs and analyses tended to be quite similar.•None of the designs gave systematically higher or lower estimates than others.•The register-based cohort study yielded most precise estimates.•Finnish routine influenza VE surveillance uses register-based cohort design. Measuring influenza vaccine effectiveness (IVE) seasonally is important and has been conducted utilizing several observational study designs. The active test-negative design has been most widely used and the validity of passive register-based studies has been debated. We aimed to explore the potential differences, advantages, and weaknesses of different study designs in estimating influenza vaccine effectiveness. We compared three study designs in estimating IVE against hospitalization in the elderly aged 65 years or more over three influenza seasons 2015/16, 2016/17 and 2017/18. Designs compared were active test-negative design (TND), register-based cohort design and register-based case-control design with different selection criteria for cases and controls. Adjusted IVE estimates for the three consecutive seasons 2015–18 in active test-negative design were 82% (95% confidence interval 26, 96), 21% (-179, 77), 15% (-113, 66). For case-control design, estimates from different analyses ranged in 2015/16 from 47% (-16, 76) to 52% (-48, 84), in 2016/17 from 10% (-42, 43) to 29% (-20, 58), and in 2017/18 from −27% (-91, 15) to 1% (-40, 30). In the cohort design, the adjusted IVE estimates were 48% (-9, 75), 29% (1, 49), 13% (-21, 37) for the three seasons. The register-based cohort design produced results more concordant with the active test-negative design than the case-control design. Furthermore, the register-based cohort design yielded most precise estimates with narrower confidence intervals. In Finland with the availability of near real-time nationwide register data, the register-based cohort design is the method of choice to continue the annual surveillance of influenza vaccine effectiveness.