Identification, structures and ontogenies of SARS-CoV-2 antibodies

National Institute Of Allergy And Infectious Diseases

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Abstract

The recent emergence of SARS-CoV-2 Omicron and its sub-variant evaded neutralization by antibodies elicited against the viral spike protein of early variants. Rapid development of molecular probes based on new variants of concern and identification of neutralizing monoclonal antibodies against the new variants or with broad neutralizing potency against SARS-CoV-2 variants and diverse beta-coronaviruses could be one approach to treat or prevent infection by new variants. To discover novel monoclonal antibodies from the convalescent samples, we utilized our established probes platform and successfully designed and rapidly purified SARS-CoV-2 spike-ectodomain probes based on new variant sequences. To respond to the challenge of SARS-CoV-2 Omicron, we have identified antibodies that maintained the ability to neutralize the Omicron variant, despite most of the previously discovered antibodies failed to neutralize. We solved cryo-EM structures of representative antibodies in complex with the Omicron B.1.1.529 spike to reveal the structural basis of neutralization. We also identified antibody combinations with synergy in neutralization. We also identified antibody from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. Our study revealed that this new antibody bound to diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. High-resolution x-ray crystal structure indicated that this antibody recognize a conserved S2 helix, which was occluded in both pre- and post-fusion spike conformations. Structural and neutralization analyses indicated that this new antibody neutralizes by inhibiting fusion and post-viral attachment. Comparison with other recently identified antibodies that broadly neutralize beta-coronaviruses enabled us to define a stem-helical supersite that can be a promising target for vaccine design.