A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2

Zhang, Li; Cao, Lei; Gao, Xing-Su; Zheng, Bin-Yang; Deng, Yong-Qiang; Li, Jing-Xin; Feng, Rui; Bian, Qian; Guo, Xi-Ling; Wang, Nan; Qiu, Hong-Ying; Wang, Lei; Cui, Zhen; Ye, Qing; Chen, Geng; Lu, Kui-Kui; Chen, Yin; Chen, Yu-Tao; Pan, Hong-Xing; Yu, Jiaping; Yao, Wenrong; Zhu, Bao-Li; Chen, Jianping; Liu, Yong; Qin, Cheng-Feng; Wang, Xiangxi; Zhu, Feng-Cai

Mutations and transient conformational movements of receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable, present immune escape routes to SARS-CoV-2. To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, combination of RBD-targeting NAbs and NTD-binding NAb, FC05, enhanced the neutralization potency in cell-based assays and animal model. Results of competitive SPR assays and cryo-EM structures of Fabs bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in NTD and RBD of S, when immunized in rabbits and macaques elicited potent protective immune responses against SARS-CoV-2. More importantly, two immunizations of this combination of NTD and RBD immunogens provided complete protection in macaques against SARS-CoV-2 challenge, without observable antibody-dependent enhancement of infection. These results provide a proof-of-concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD.