7D4G

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

Summary for 7D4G

• Entry DOI: 10.2210/pdb7d4g/pdb
• EMDB information: 30573
• Descriptor: Spike glycoprotein S1, Light chain of FC05 Fab, Heavy chain of FC05 Fab (3 entities in total)
• Functional Keywords: sars-cov-2, spike, antibody, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 3
• Total formula weight: 56473.02

Authors

Cao, L.,Wang, X. (deposition date: 2020-09-23, release date: 2021-04-07, Last modification date: 2024-10-16)

Primary citation

Zhang, L.,Cao, L.,Gao, X.S.,Zheng, B.Y.,Deng, Y.Q.,Li, J.X.,Feng, R.,Bian, Q.,Guo, X.L.,Wang, N.,Qiu, H.Y.,Wang, L.,Cui, Z.,Ye, Q.,Chen, G.,Lu, K.K.,Chen, Y.,Chen, Y.T.,Pan, H.X.,Yu, J.,Yao, W.,Zhu, B.L.,Chen, J.,Liu, Y.,Qin, C.F.,Wang, X.,Zhu, F.C.
A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2.
Natl Sci Rev, 8:nwab053-nwab053, 2021

PubMed 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 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.

PubMed: 34676098
DOI: 10.1093/nsr/nwab053

Experimental method

ELECTRON MICROSCOPY (3.9 Å)