Variations in Seasonal Influenza Vaccine Effectiveness due to Study Characteristics: A Systematic Review and Meta-analysis of Test-Negative Design Studies

Background. Study characteristics influence vaccine effectiveness (VE) estimation. We examined the influence of some of these on seasonal influenza VE estimates from test-negative design (TND) studies. Methods. We systematically searched bibliographic databases and websites for full-text publications of TND studies on VE against laboratory-confirmed seasonal influenza in outpatients after the 2009 pandemic influenza. We followed the Cochrane Handbook for Systematic Reviews of Interventions guidelines. We examined influence of source of vaccination information, respiratory specimen swab time, and covariate adjustment on VE. We calculated pooled adjusted VE against H1N1 and H3N2 influenza subtypes, influenza B, and all influenza using an inverse-variance random-effects model. Results. We included 70 full-text articles. Pooled VE against H1N1 and H3N2 influenza subtypes, influenza B, and all influenza was higher for studies that used self-reported vaccination than for those that used medical records. Pooled VE was higher with respiratory specimen collection within <= 7 days vs <= 4 days of symptom onset, but the opposite was observed for H1N1. Pooled VE was higher for studies that adjusted for age but not for medical conditions compared with those that adjusted for both. There was, however, a lack of statistical significance in almost all differences in pooled VE between compared groups. Conclusions. The available evidence is not strong enough to conclude that influenza VE from TND studies varies by source of vaccination information, respiratory specimen swab time, or adjustment for age/medical conditions. The evidence is, however, indicative that these factors ought to be considered while designing or evaluating TND studies of influenza VE.