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

• 作者: 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
• 来源期刊: 国家科学评论（英文版）
• 年，卷（期）: 2021,（8）
• 所属期刊栏目: RESEARCH ARTICLES
• 页码范围: 142-152
• 页数: 11页
• 语种: 英文

摘要

Mutations and transient conformational movements of the receptor binding domain(RBD)that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory syndrome coronavirus 2(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 the N-terminal domain(NTD)and RBD domain of S,effective at nM concentrations.Remarkably,a combination of RBD-targeting NAbs and NTD-binding NAbs,FC05,enhanced the neutralization potency in cell-based assays and an animal model.Results of competitive surface plasmon resonance assays and cryo-electron microscopy(cryo-EM)structures of antigen-binding fragments bound to S unveil determinants of immunogenicity.Combinations of immunogens,identified in the 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 a 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.