A human monoclonal antibody neutralizes SARS-CoV-2 Omicron variants by targeting the upstream region of spike protein HR2 motif
Hang Su, Jun Zhang, Zhenfei Yi, Sajid Khan, Mian Peng, Liang Ye, Alan Bao, Han Zhang, Guangli Suo, Qian Li, Housheng Zheng, Dandan Wu, Thomas J. Kipps, Lanfeng Wang, Zhenghong Lin, Suping Zhang
Abstract
The continuous emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants means there is a need to explore additional strategies to develop broad-spectrum vaccines or therapeutics for individuals remaining at risk of coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibody (mAb) that binds the conserved S2 subunit of the SARS-CoV-2 spike (S) protein alone, or in combination with mAb that binds the receptor-binding domain (RBD) of S protein, might be effective in eliciting protection from infection by a variety of SARS-CoV-2 variants. Using high-throughput single-cell immunoglobulin sequencing of B cells from COVID-19-convalescent donors, we identified a high-affinity S2-specific mAb-39, that could inhibit original SARS-CoV-2 strain, Omicron BA.1, BA.2.86, BA.4, BA.5, and EG.5.1 S protein-mediated membrane fusion, leading to the neutralization of these pseudoviral infections. Moreover, mAb-39 could also improve the neutralizing activity of anti-RBD antibody against the highly neutralization-resistant Omicron variants. Molecular docking and point mutation analyses revealed that mAb-39 recognized epitopes within the conserved upstream region of the heptad repeat 2 (HR2) motif of the S2 subunit. Collectively, these findings demonstrate that targeting the conserved upstream region of the HR2 motif (e.g., using mAbs) provides a novel strategy for preventing the infection of SARS-CoV-2 and its variants.