Effects of Confounding Bias in COVID-19 and Influenza Vaccine Effectiveness Test-Negative Designs Due to Correlated Influenza and COVID-19 Vaccination Behaviors

Background The test-negative design is commonly used to estimate influenza and COVID-19 vaccine effectiveness (VE). In these studies, correlated COVID-19 and influenza vaccine behaviors may introduce a confounding bias where controls are included with the other vaccine-preventable acute respiratory illness (ARI). We quantified the impact of this bias on VE estimates in studies where this bias is not addressed. Methods We simulated study populations under varying vaccination probabilities, COVID-19 VE, influenza VE, and proportions of controls included with the other vaccine-preventable ARI. Mean bias was calculated as the difference between true and estimated VE. Absolute mean bias in VE estimates was classified as low (<10%), moderate (10% to <20%), and high (≥20%). Results Where vaccination probabilities are positively correlated, COVID-19 and influenza VE test-negative studies with influenza and SARS-CoV-2 ARI controls, respectively, underestimate VE. For COVID-19 VE studies, mean bias was low for all scenarios where influenza represented ≤50% of controls. For influenza VE studies, mean bias was low for all scenarios where SARS-CoV-2 represented ≤10% of controls. Although bias was driven by the conditional probability of vaccination, low VE of the vaccine of interest and high VE of the confounding vaccine increase its magnitude. Conclusions Where a low percentage of controls are included with the other vaccine-preventable ARI, bias in COVID-19 and influenza VE estimates is low. However, influenza VE estimates are likely more susceptible to bias. Researchers should consider potential bias and its implications in their respective study settings to make informed methodological decisions in test-negative VE studies.