Bivalent intra-spike binding provides durability against emergent Omicron lineages Results from a global consortium

The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%-50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organiza-tion identical to trimeric spike.

Automated summary

The SARS-CoV-2 Omicron variant and its sublineages are resistant to most therapeutic antibodies due to multiple mutations in the spike protein. However, 66 out of nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel were found to neutralize Omicron and its sublineages in a neutralization assay. Most Omicron-neutralizing antibodies in natural immunoglobulin Gs (IgGs) recognize spike bivalently, while non-neutralizing IgGs either bind monovalently or have partial monovalent occupancy. Cleaving bivalent-binding IgGs to antigen-binding fragments (Fabs) abolishes neutralization and binding affinity, particularly against Omicron. These findings suggest that antibodies resistant to variant of concerns overcome mutations through avidity. Therefore, future SARS-CoV-2 vaccine strategies should consider trimeric spike epitope display with identical spacing and organization.