Estimating Influenza Vaccine Effectiveness with the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis

One important assumption in case-control studies is that control selection should be independent of exposure. Nevertheless, it has been hypothesized that virus interference might lead to a correlation between receipt of influenza vaccination and increased risk of infection with other respiratory viruses. We investigated whether such a phenomenon might affect a study design commonly used to estimate influenza vaccine effectiveness (VE). We searched publications in MEDLINE, PubMed, and Web of Science. We identified 12 studies using the test-negative design (2011-2017) that reported VE estimates separately derived by 3 alternative control groups: 1) all patients testing negative for influenza (FLU), VE FLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VE ORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VE PAN-. These included VE estimates from 7 countries for all age groups from 2003/2004 to 2013/2014. We observed no difference in vaccination coverage between the ORV-positive and PAN-negative control groups. A total of 63 VE FLU- estimates, 62 VE ORV+ estimates, and 33 VE PAN- estimates were extracted. Pooled estimates of the difference in VE ("VE) were very similar between groups. In meta-regression, no association was found between the selection of control group and VE estimates. In conclusion, we did not find any differences in VE estimates based on the choice of control group.