Distinct B cell subsets give rise to antigen-specific antibody responses against SARS-CoV-2

Wilson, Patrick; Stamper, Christopher; Dugan, Haley; Li, Lei; Asby, Nicholas; Halfmann, Peter; Guthmiller, Jenna; Zheng, Nai-Ying; Huang, Min; Stovicek, Olivia; Wang, Jiaolong; Madariaga, Maria Lucia; Shanmugarajah, Kumaran; Jansen, Maud; Amanat, Fatima; Stewart, Isabelle; Changrob, Siriruk; Utset, Henry; Huang, Jun; Nelson, Christopher; Dai, Ya-Nan; Hall, Paige; Jedrzejczak, Robert; Joachimiak, Andrzej; Krammer, Florian; Fremont, Daved; Kawaoka, Yoshihiro

Discovery of durable memory B cell (MBC) subsets against neutralizing viral epitopes is critical for determining immune correlates of protection from SARS-CoV-2 infection. Here, we identified functionally distinct SARS-CoV-2-reactive B cell subsets by profiling the repertoire of convalescent COVID-19 patients using a high-throughput B cell sorting and sequencing platform. Utilizing barcoded SARS-CoV-2 antigen baits, we isolated thousands of B cells that segregated into discrete functional subsets specific for the spike, nucleocapsid protein (NP), and open reading frame (ORF) proteins 7a and 8. Spike-specific B cells were enriched in canonical MBC clusters, and monoclonal antibodies (mAbs) from these cells were potently neutralizing. By contrast, B cells specific to ORF8 and NP were enriched in naïve and innate-like clusters, and mAbs against these targets were exclusively non-neutralizing. Finally, we identified that B cell specificity, subset distribution, and affinity maturation were impacted by clinical features such as age, sex, and symptom duration. Together, our data provide a comprehensive tool for evaluating B cell immunity to SARS-CoV-2 infection or vaccination and highlight the complexity of the human B cell response to SARS-CoV-2.