Abstract

In this work, we developed PolyMap (polyclonal mapping), a high-throughput method for mapping protein-protein interactions. We demonstrated the mapping of thousands of antigen-antibody interactions between diverse antibody libraries isolated from convalescent and vaccinated COVID-19 donors and a set of clinically relevant SARS-CoV-2 spike variants. We identified over 150 antibodies with a variety of distinctive binding patterns toward the antigen variants and found a broader binding profile, including targeting of the Omicron variant, in the antibody repertoires of more recent donors. We then used these data to select mixtures of a small number of clones with complementary reactivity that together provide strong potency and broad neutralization. PolyMap is a generalizable platform that can be used for one-pot epitope mapping, immune repertoire profiling, and therapeutic design and, in the future, could be expanded to other families of interacting proteins.