1. A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2.
- Author
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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, and Yu, Jiaping
- Subjects
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MONONUCLEAR leukocytes , *SARS-CoV-2 , *COVID-19 , *IMMUNOGLOBULINS , *PROOF of concept , *SURFACE plasmon resonance , *MONOCLONAL antibodies - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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