Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation

Antibody responses develop following SARS-CoV-2 infection, but little is known about their epitope specificities, clonality, binding affinities, epitopes, and neutralizing activity. We isolated B cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject 21 days after the onset of clinical disease. 45 S-specific monoclonal antibodies were generated. They had undergone minimal somatic mutation with limited clonal expansion, and three bound the receptor-binding domain (RBD). Two antibodies neutralized SARS-CoV-2. The most potent antibody bound the RBD and prevented binding to the ACE2 receptor, while the other bound outside the RBD. Thus, most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 S-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive and/or therapeutic potential and can serve as templates for vaccine design. [Display omitted] •Early B cell responses to SARS-CoV-2 spike protein are analyzed from a COVID-19 patient•Most antibodies target non-neutralizing epitopes outside the RBD•A potent neutralizing mAb blocks the interaction of the S protein with ACE2•Neutralizing antibodies are minimally mutated Seydoux et al. analyze B cell responses in a COVID-19 patient and find that SARS-CoV-2 infection expands diverse B cell clones against the viral spike glycoprotein (S). Two neutralizing antibodies were identified that bind S with high affinity despite being minimally mutated. Thus, vaccine-induced neutralizing antibody responses may require activation of specific naive B cells without requiring extensive somatic mutation.