The Causal Interpretation of "Overall Vaccine Effectiveness" in Test-Negative Studies

Test-negative studies are commonly used to estimate influenza vaccine effectiveness (VE). In a typical study, an "overall VE" estimate based on data from the entire sample may be reported. However, there may be heterogeneity in VE, particularly by age. Therefore, in this article we discuss the potential for a weighted average of age-specific VE estimates to provide a more meaningful measure of overall VE. We illustrate this perspective first using simulations to evaluate how overall VE would be biased when certain age groups are overrepresented. We found that unweighted overall VE estimates tended to be higher than weighted VE estimates when children were overrepresented and lower when elderly persons were overrepresented. Then we extracted published estimates from the US Flu VE network, in which children are overrepresented, and some discrepancy between unweighted and weighted overall VE was observed. Differences in weighted versus unweighted overall VE estimates could translate to substantial differences in the interpretation of individual risk reduction among vaccinated persons and in the total averted disease burden at the population level. Weighting of overall estimates should be considered in VE studies in the future.