Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: The test-negative design case-control study with different control groups

Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE estimates. We have conducted a TND study using the Dutch Sentinel Practices of NIVEL Primary Care Database which includes data from patients who consulted the General Practitioner (GP) for an episode of acute influenza-like illness (ILI) or acute respiratory infection (ARI) with known influenza vaccination status. Cases were patients tested positive for influenza virus. Controls were grouped into those who tested (1) negative for influenza virus (all influenza negative), (2) negative for influenza virus, but positive for respiratory syncytial virus, rhinovirus or enterovirus (non-influenza virus positive), and (3) negative for these four viruses (pan-negative). We estimated the IVE over all epidemic seasons from 2003/2004 through 2013/2014, pooled IVE for influenza vaccine partial/full matched and mismatched seasons and the individual seasons using generalized linear mixed-effect and multiple logistic regression models. The overall IVE adjusted for age, GP ILI/ARI diagnosis, chronic disease and respiratory allergy was 35% (95% CI: 15-48), 64% (95% CI: 49-75) and 21% (95% CI: −1 to 39) for all influenza negative, non-influenza virus positive and pan-negative controls, respectively. In both the main and subgroup analyses IVE estimates were the highest using non-influenza virus positive controls, likely due to limiting inclusion of controls without laboratory-confirmation of a virus causing the respiratory disease.