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.