Agenda Break & Stretching Session

The discovery of durable memory B cell (MBC) subsets targeting protective viral epitopes is critical for determining immune correlates of protection from SARS-CoV-2 infection. Here, we identified functionally distinct SARS-CoV-2-specific B cell subsets by profiling the repertoire of convalescent COVID-19 patients using a high-throughput B cell sorting and sequencing platform. Utilizing distinct barcoded SARS-CoV-2 antigen baits, we isolated thousands of B cells reactive to the spike protein, spike receptor binding domain, nucleoprotein (NP), and open reading frame proteins (ORF) 7 and 8. Spike-reactive B cells were enriched in canonical MBC clusters even in subjects with low serum titers, and monoclonal antibodies (mAbs) from these cells were potently neutralizing. B cells reactive to ORF8 and NP were enriched in naïve-like clusters and mAbs against these targets were exclusively non-neutralizing. Moreover, our approach offers a high-throughput method for the identification of mAbs reactive to distinct SARS-CoV-2 antigens.