Abstract
SummaryMost antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.
Highlights
Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Zhou et al, 2020b) rapidly escalated to an ongoing global pandemic of coronavirus disease 2019 (COVID19) (Kissler et al, 2020)
COVA1-16 Binds to a Conserved Epitope on the SARSCoV-2 receptor-binding domain (RBD) that Overlaps with the CR3022 Epitope The antibody COVA1-16 was recently isolated from an individual recovering from COVID-19 and cross-neutralizes SARS-CoV-2 and SARS-CoV (IC50, 2.5 mg/mL) pseudovirus (Brouwer et al, 2020)
Consistent with structural identification of its epitope, COVA1-16 can compete with CR3022 for RBD binding (Figure S2)
Summary
Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Zhou et al, 2020b) rapidly escalated to an ongoing global pandemic of coronavirus disease 2019 (COVID19) (Kissler et al, 2020). Given the current lack of protective vaccines and antiviral agents, virus clearance and recovery from SARS-CoV-2 have to rely mainly on generation of a neutralizing antibody response. SARS-CoV-2 and SARS-CoV only share 73% amino acid sequence identity in their RBD compared with 90% in their S2 fusion domain. A highly conserved epitope on the SARS-CoV-2 RBD has been identified previously from studies of a SARS-CoV-neutralizing antibody, CR3022
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