Structure and function of an unusual R452-dependent monoclonal antibody against SARS-CoV-2

ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is still a major public health concern worldwide. Currently, SARS-CoV-2 variants have been widely used to develop the updated vaccine. However, whether these mutated residues still have good immunogenicity remains elusive. In particular, we know little about what kind of antibodies can be induced by the infection or vaccination of SARS-CoV-2 variants and their biological characteristics. Here, we identified an R452-dependent monoclonal neutralizing antibody, ConD-852, from a primarily Delta variant-infected individual, indicating that the mutated R452 residue has good immunogenicity. We determined the high-resolution cryo-electron microscopy (cryo-EM) structure of ConD-852 complexed with the Delta receptor-binding domain (RBD), revealing how it binds to the R452-related epitopes and their detailed interactions. Interestingly, ConD-852 could only bind to the amino acid residue “R” at the 452 position on RBD, displaying a strict restriction to recognize SARS-CoV-2. Overall, our findings regarding ConD-852 confirmed the good immunogenicity of SARS-CoV-2 variants carrying the L452R mutation and enriched our knowledge of the binding model involving the neutralizing antibody and the mutated virus. IMPORTANCE Although SARS-CoV-2 variants have been widely used to update the COVID-19 vaccine candidate, whether these mutations still have good immunogenicity is unknown. This study demonstrates that the mutated R452 residue can induce potent neutralizing antibodies and reports a high-resolution cryo-EM structure of an R452-dependent monoclonal antibody binding to the epitopes around the R452 residue on SARS-CoV-2 RBD. Although SARS-CoV-2 variants have been widely used to update the COVID-19 vaccine candidate, whether these mutations still have good immunogenicity is unknown. This study demonstrates that the mutated R452 residue can induce potent neutralizing antibodies and reports a high-resolution cryo-EM structure of an R452-dependent monoclonal antibody binding to the epitopes around the R452 residue on SARS-CoV-2 RBD.