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 Omicron in people who received a third booster dose. This finding has been interpreted as evidence of immune imprinting of COVID-19 vaccines. We propose an alternative explanation: the increased risk of reinfection in individuals vaccinated with a vaccine booster compared with no booster is the result of selection bias and is expected to arise even if there is no immune imprinting. To clarify this alternative explanation, we describe 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. We use causal diagrams(directed acyclic graphs), data simulations and analysis of real data to illustrate the mechanism and magnitude of this bias, which is the result of conditioning on a collider.