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

Abstract

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.

• Authors: 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
• Journal: National science review (Natl Sci Rev) Vol. 8 Issue 8 Pg. nwab053 (Aug 2021) ISSN: 2053-714X [Electronic] China
• PMID: 34676098 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.