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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement There was no specific funding provided for the study ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The use of the NHS database, REGVACU and SERLB for the purpose of monitoring vaccine effectiveness has been approved by the research ethics committee at the Instituto de Salud Carlos III (CEI PI 98\_2020 and CEI PI 08\_2022). Informed consent was not required because this study is based on national population registries. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The databases used in the observational data analysis are owned by the Ministry of Health and the Autonomous Communities in Spain, which establish the requirements for their access and use.