National Science Review, 27 March, 2021, DOI：https://doi.org/10.1093/nsr/nwab053
A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2
Li Zhang, Lei Cao, Xing-Su Gao, Bin-Yang Zheng, Yong-Qiang Deng, Jing-Xin Li, Rui Feng, Qian Bian, Xi-Ling Guo, Nan Wang, Hong-Ying Qiu, Lei Wang, Zhen Cui, Qing Ye, Geng Chen, Kui-Kui Lu, Yin Chen, Yu-Tao Chen, Hong-Xing Pan, Jiaping Yu, Wenrong Yao, Bao-Li Zhu, Jianping Chen, Yong Liu, Cheng-Feng Qin, Xiangxi Wang, Feng-Cai Zhu
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.