Drivers of differential antibody breadth in SARS-CoV-2 mRNA vaccination and infection 4823

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Abstract Description mRNA vaccination for SARS-CoV-2 (CoV-2) results in initial polyclonal antibodies of greater breadth compared to those stimulated by viral infection. Cellular, immunogenetic and antigenic factors leading to human antibody responses with broad viral variant recognition are poorly defined. Existing databases of CoV-2 binding antibodies have limited data about patient and B cell subset origins of the antibodies and their antigen variant binding. We used highly multiplexed panels of DNA-tagged CoV-2 antigens including Spike receptor binding domains from up to 20 viral variants to label and sort 6,262 antigen-binding B cells from peripheral blood of mRNA vaccinees, infected patients and the spleen and lymph nodes of deceased organ donors. Single-cell transcriptome and antigen DNA-tag data showed antigen-specific B cells enriched in a circulating class-switched memory subset with evidence of recent germinal center exposure, and in CD11c+ atypical B cells. Surprisingly, mRNA vaccination preferentially stimulates a subset of B cell receptor (BCR)-defined clonotypes, resulting in greater initial antigen binding breadth. Spleens show greater variant binding breadth than blood B cells from the initial months post-vaccination or infection. Together, these results systematically define the influence of CoV-2 mRNA vaccination and infection on particular B cell receptors and clonotypes, a topic of increasing importance as mRNA vaccination is evaluated for other pathogens. Funding Sources Supported by NIH/NIAID R01AI127877, NIH/NIAID R01AI130398, NIH 1U54CA260517, David Crown Foundation endowment/COVID-19 gift funds, NIH HIPC U19AI090023, U19AI057266, Sean N Parker Foundation/Sunshine Foundation, Early Postdoc.Mobility Fellowship Stipend (SNSF), Fulbright Fellowship, NHMRC Investigator grant, NSFC32270937/NSFC82341068 (Chinese NSF), Coulter COVID-19 Rapid Response Award, MSD kits. Topic Categories Viral Immunology (VIR)

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