Comparable levels of neutralizing antibody titers are present in convalescent COVID-19 subjects and vaccine recipients ( 11) further supporting the role of adaptive immune responses in helping to control and prevent disease severity.īoth infection and vaccine-elicited antibodies predominantly target the major SARS-CoV-2 envelope glycoprotein, spike, present on the virion surface. Furthermore, the two arms of humoral immune memory, long-lived bone marrow plasma cells ( 8) and circulating memory B cells ( 9, 10), are induced by natural infection in humans and may persist for at least 8 months after primary infection, providing potentially durable long-term protection. In humans, the presence of neutralizing antibodies can predict disease severity and survival after primary SARS-CoV-2 infection ( 6) or vaccination ( 7). The initial engagement of the naive repertoire begins this cascade and often coincides with the eventual generation of a protective or neutralizing antibody response ( 3).įor SARS-CoV-2, the etiological agent of COVID-19, the development of a neutralizing antibody response after primary infection or vaccination is associated with protection against reinfection in non-human primates ( 4, 5). An early step in generating humoral immunity involves activation of these naive B cells through recognition of a cognate antigen ( 1) which in turn can lead to affinity maturation through somatic hypermutation (SHM) and subsequent differentiation ( 2). The naive repertoire contains potential B cell receptor (BCR) rearrangements capable of recognizing these antigens, which are often surface-exposed glycoproteins. Initial exposure to viral antigens by natural infection or vaccination primes an immune response and often establishes immune memory which can prevent or control future infections. Understanding the SARS-CoV-2 RBD-specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses. Additionally, the minimally mutated, affinity-matured antibodies potently neutralized SARS-CoV-2. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution we could select for a higher affinity RBD interaction, conferred by a single amino acid change. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as pre-emergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. Single cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. Here, we isolated naive B cells from 8 seronegative human donors targeting the SARS-CoV-2 receptor-binding domain (RBD). Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat.
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