Structural basis of spike RBM-specific human antibodies counteracting broad SARS-CoV-2 variants

Broadly neutralizing antibodies to SARS-CoV-2 variants including Omicron were isolated from long-term hospitalized convalescent patients with early SARS-CoV-2 strain B.1.1, and the mechanisms are identified from crystal structures. The decrease of antibody efficacy to mutated SARS-CoV-2 spike RBD explains the breakthrough infections and reinfections by Omicron variants. Here, we analyzed broadly neutralizing antibodies isolated from long-term hospitalized convalescent patients of early SARS-CoV-2 strains. One of the antibodies named NCV2SG48 is highly potent to broad SARS-CoV-2 variants including Omicron BA.1, BA.2, and BA.4/5. To reveal the mode of action, we determined the sequence and crystal structure of the Fab fragment of NCV2SG48 in a complex with spike RBD from the original, Delta, and Omicron BA.1. NCV2SG48 is from a minor V-H but the multiple somatic hypermutations contribute to a markedly extended binding interface and hydrogen bonds to interact with conserved residues at the core receptor-binding motif of RBD, which efficiently neutralizes a broad spectrum of variants. Thus, eliciting the RBD-specific B cells to the longitudinal germinal center reaction confers potent immunity to broad SARS-CoV-2 variants emerging one after another.

Automated summary

Broadly neutralizing antibodies against SARS-CoV-2 variants, including Omicron, were found in long-term hospitalized convalescent patients infected with early SARS-CoV-2 strain B.1.1, and their mechanisms were identified through crystal structures. The decrease in antibody efficacy against mutated SARS-CoV-2 spike RBD explains breakthrough infections and reinfections by Omicron variants. Therefore, eliciting RBD-specific B cells in the longitudinal germinal center reaction provides potent immunity against emerging wide range of SARS-CoV-2 variants.