The imprinting effect of covid-19 vaccines: an expected selection bias in observational studies

Abstract

Recent observational studies have found a higher risk of reinfection with the omicron variant of SARS-CoV-2 in people who received a third covid-19 booster dose. This finding has been interpreted as evidence of immune imprinting of covid-19 vaccines. This article proposes an alternative explanation: that the increased risk of reinfection in individuals vaccinated with a booster compared with no booster is the result of selection bias and is expected to arise even in the absence of immune imprinting. To clarify this alternative explanation, this article describes how previous observational analyses were an attempt to estimate the direct effect of vaccine boosters on SARS-CoV-2 reinfections—an effect that cannot be correctly estimated with observational data. Causal diagrams (directed acyclic graphs), data simulations, and analysis of real world data are used to illustrate the mechanism and magnitude of this bias, which is the result of conditioning on a collider.