Novel neutralization mechanism of a human antibody with pan-coronavirus reactivity (preprint)

The recurrent outbreak of coronaviruses and variants underscores the need for broadly reactive antivirals and vaccines. Here, a novel broad-spectrum human antibody named 76E1 was isolated from a COVID-19 convalescent patient and showed broad neutralization activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants and also exhibited the binding breath to peptides containing the epitope from γ- and δ- coronaviruses. 76E1 cross-protects mice from SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and treatment models. The epitope including the fusion peptide and S2’ cleavage site recognized by 76E1 was significantly conserved among α-, β-, γ- and δ- coronaviruses. We uncovered a novel mechanism of antibody neutralization that the epitope of 76E1 was proportionally less exposed in the prefusion trimeric structure of spike protein but could be unmasked by binding to the receptor ACE2. Once the epitope exposed, 76E1 inhibited S2’ cleavage, thus blocked the membrane fusion process. Our data demonstrate a key epitope targeted by broadly-neutralizing antibodies and will guide next-generation epitope-based pan-coronavirus vaccine design.

Comprehensive Mapping of Binding Hot Spots of SARS-CoV-2 RBD-specific Neutralizing Antibodies for Tracking Immune Escape Variants (preprint)

The receptor-binding domain (RBD) variants of SARS-CoV-2 could impair antibody-mediated neutralization of the virus by host immunity; thus, prospective surveillance for such antibody escape mutants is urgently needed. Here, we comprehensively profiled four antigenic sites of the RBD and mapped the binding hot spots for a panel of RBD-specific monoclonal antibodies isolated from COVID-19 convalescents, especially dominant VH3-53/3–66 antibodies, which are valuable indicators of antigenic changes in the RBD. We further demonstrated that several natural mutations, namely, K417N, F486L, N450K, L452R, E484K, F490S and R346S, significantly decreased the neutralizing activity of multiple human monoclonal antibodies and of human convalescent plasma obtained in the early stage of the COVID-19 pandemic. Of note, among the natural escape mutations, L452R enhanced ACE2 binding affinity, indicating that it potentially increased virulence. Overall, the in-depth maps may have far-reaching value for surveillance of SARS-CoV-2 immune escape variants and guidance of vaccine design.