Rapidly Adaptable Multiplexed Yeast Surface Display Serological Assay for Immune Escape Screening of SARS-CoV-2 Variants

With numerous variations in the Spike protein, including concentrated mutations in the receptor-binding domain (RBD), the SARS-CoV-2 Omicron variant significantly shifted in the trajectory of the COVID-19 pandemic. To understand individual patient risk profiles in the face of rapidly emerging variants, there is an interest in sensitive serological tests capable of analyzing patient IgG response to multiple variants in parallel. Here, we present a serological test based on yeast surface display and serum biopanning that characterizes immune profiles against SARS-CoV-2 RBD variants. We used this yeast-based multi-variant serology method to examine IgG titers from 30 serum samples derived from COVID-19-convalescent and vaccinated individuals in Switzerland and assessed the relative affinity of polyclonal serum IgG for Wuhan (B lineage), Delta (B.1.617.2 lineage), and Omicron (B.1.1.529 lineage) RBD domains. We validated and benchmarked our system against a commercial lateral flow assay and showed strong concordance. Our assay demonstrates that serum IgGs from patients recovered from severe COVID-19 between March-June 2021 bound tightly to both original Wuhan and Delta RBD variants, but became indistinguishable from background when assayed against Omicron, representing an affinity loss of >10-20 fold. Our yeast immunoassay is easily tailored and parallelized with newly emerging RBD variants. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the University of Basel, ETH Zurich, the Basel University Hospital, the Swiss Nanoscience Institute, the Mexican CONACYT program, the Swiss National Science Foundation (NCCR Molecular Systems Engineering), and the Botnar Research Centre for Child Health (FTC Covid-19 to MAN and YG). ### 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 Ethical Committee of Northwest-Central Switzerland (EKNZ) overseeing the University Hospital Basel gave ethical approval for this work (Project-ID 2021-00214). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.