Abstract
BACKGROUND: Vaccination history may confound estimates of influenza vaccine effectiveness (VE) when two conditions are present: (1) Influenza vaccination is associated with vaccination history and (2) vaccination modifies the risk of natural infection in the following seasons, either due to persisting vaccination immunity or due to lower previous risk of natural infection. METHODS: Analytic arguments are used to define conditions for confounding of VE estimates by vaccination history. Simulation studies, both with accurate and inaccurate assessment of current and previous vaccination status, are used to explore the potential magnitude of these biases when using different statistical models to address confounding by vaccination history. RESULTS: We found a potential for substantial bias of VE estimates by vaccination history if infection- and/or vaccination-derived immunity persisted from one season to the next and if vaccination uptake in individuals was seasonally correlated. Full adjustment by vaccination history, which is usually not feasible, resulted in unbiased VE estimates. Partial adjustment, i.e. only by prior season's vaccination status, significantly reduced confounding bias. Misclassification of vaccination status, which can also lead to substantial bias, interferes with the adjustment of VE estimates for vaccination history. CONCLUSIONS: Confounding by vaccination history may bias VE estimates, but even partial adjustment by only the prior season's vaccination status substantially reduces confounding bias. Misclassification of vaccination status may compromise VE estimates and efforts to adjust for vaccination history.