Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

Abstract

Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction 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 CDR H3, and competes with ACE2 binding due to 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 structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

“…Interestingly, the CR3022 Fab neutralized SARS-CoV-2 P384A mutant with an IC50 of 4.4 μg/ml, which is similar to that of CR3022 IgG (3.2 μg/ml) ( Figure 2). This result indicates that CR3022, unlike many other SARS-CoV-2 antibodies [21,23], does not act bivalently with the S proteins on the virus surface and, hence, neutralization is more sensitive to Fab binding affinity.…”

“…Previous studies have indicated IgG bivalent binding can play an important role in mediating neutralization of SARS-CoV-2, since the neutralization potency for many antibodies is much greater when expressed as IgG rather than Fab [21,23]. Subsequently, we also tested the neutralizing activity of CR3022 Fab.…”

“…The CR3022 epitope is exposed only when the RBD is in the "up" but not the "down" conformation on the S protein [20]. A few SARS-CoV-2 antibodies from patients have also recently been shown to target the CR3022 epitope [12,17,21], suggesting that it is an important site of vulnerability for the antibody response in SARS-CoV-2 infection. Out of 28 residues in the CR3022 epitope, 24 are conserved between SARS-CoV-2 and SARS-CoV, explaining the cross-reactive binding of CR3022.…”

COVID-19 and Cholinergic Anti-inflammatory Pathway:In silicoIdentification of an Interaction between α7 Nicotinic Acetylcholine Receptor and the Cryptic Epitopes of SARS-CoV and SARS-CoV-2 Spike Glycoproteins

“…In both open and closed conformation, the orientation of the RBD of SARS CoV-2 when interacting with the α 7 subunit is more similar with the interaction of the closed, rather than the open, conformation of the RBD of SARS CoV. which binds to SARS-CoV-2 Spike glycoprotein to a similar region [23]. Most RNA viruses through antigenic mutation can avoid adaptive immunity of the host [35].…”

“…and COVA1-16 [20,21,23]. Having previously presented the 3D structural location of this "toxin-like" sequence on the Spike glycoprotein and the superposition of the modelled structure of the Neurotoxin homolog NL1 and the SARS-CoV-2 Spike glycoprotein [18], we are extending our previously published molecular modeling and docking experiments by presenting the complexes of both SARS-CoV and SARS-CoV-2 S glycoproteins with the 7 ECD of the model of human α 7 nAChR pentamer, in their "open" and "closed" conformations, ideally adopted by Spike glycoproteins.…”