A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2
Li Zhang, Lei Cao, Xingsu Gao, Binyang Zheng, Yong‐Qiang Deng, Jingxin Li, Rui Feng, Qian Bian, Xiling Guo, Nan Wang, Hongying Qiu, Lei Wang, Zhen Cui, Qing Ye, Geng Chen, Kuikui Lu, Yin Chen, Yutao Chen, Hongxing Pan, Jiaping Yu, Wenrong Yao, Baoli Zhu, Jianping Chen, Yong Liu, Cheng‐Feng Qin, Xiangxi Wang, Fengcai Zhu
Abstract
Abstract 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.