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

Am J Epidemiol. 2018 Feb 1;187(2):389-397. doi: 10.1093/aje/kwx251.


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), VEFLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VEORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VEPAN-. 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 VEFLU- estimates, 62 VEORV+ estimates, and 33 VEPAN- estimates were extracted. Pooled estimates of the difference in VE (ΔVE) 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.

Keywords: epidemiologic methods; influenza; test-negative design; vaccine effectiveness; virus interference.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • Control Groups
  • Female
  • Humans
  • Infant
  • Influenza Vaccines / therapeutic use*
  • Influenza, Human / diagnosis
  • Influenza, Human / prevention & control*
  • Male
  • Middle Aged
  • Negative Results
  • Outcome Assessment, Health Care / methods*
  • Research Design*
  • Treatment Outcome
  • Vaccination / statistics & numerical data*
  • Young Adult


  • Influenza Vaccines