The Architecture of Inactivated SARS-CoV-2 with Postfusion Spikes Revealed by Cryo-EM and Cryo-ET

• Published in: Structure (London) Vol. 28; no. 11; pp. 1218 - 1224.e4
• Main Authors: Liu, Chuang, Mendonça, Luiza, Yang, Yang, Gao, Yuanzhu, Shen, Chenguang, Liu, Jiwei, Ni, Tao, Ju, Bin, Liu, Congcong, Tang, Xian, Wei, Jinli, Ma, Xiaomin, Zhu, Yanan, Liu, Weilong, Xu, Shuman, Liu, Yingxia, Yuan, Jing, Wu, Jing, Liu, Zheng, Zhang, Zheng, Liu, Lei, Wang, Peiyi, Zhang, Peijun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 03.11.2020; Cell Press
• Subjects: Animals; Betacoronavirus - drug effects; Betacoronavirus - immunology; Betacoronavirus - ultrastructure; Chlorocebus aethiops; Coronavirus Infections - immunology; Coronavirus Infections - prevention & control; COVID-19; COVID-19 Vaccines; cryo-EM; cryo-ET; Cryoelectron Microscopy; Disinfectants - pharmacology; Electron Microscope Tomography; glycosylation; Humans; postfusion; Propiolactone - pharmacology; SARS-CoV-2; Short; spike; Spike Glycoprotein, Coronavirus - ultrastructure; subtomogram averaging; vaccine; Vaccines, Inactivated - immunology; Vero Cells; Viral Vaccines - immunology; Virion - drug effects; Virion - ultrastructure; β-propiolactone-inactivated viruses; COVID-19; SARS-CoV-2; vaccine; postfusion; β-propiolactone-inactivated viruses; subtomogram averaging; glycosylation; cryo-ET; cryo-EM; spike
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2020.10.001

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) resulted from the outbreak of SARS-CoV-2 in December 2019. Currently, multiple efforts are being made to rapidly develop vaccines and treatments to fight COVID-19. Current vaccine candidates use inactivated SARS-CoV-2 viruses; therefore, it is important to understand the architecture of inactivated SARS-CoV-2. We have genetically and structurally characterized β-propiolactone-inactivated viruses from a propagated and purified clinical strain of SARS-CoV-2. We observed that the virus particles are roughly spherical or moderately pleiomorphic. Although a small fraction of prefusion spikes are found, most spikes appear nail shaped, thus resembling a postfusion state, where the S1 protein of the spike has disassociated from S2. Cryoelectron tomography and subtomogram averaging of these spikes yielded a density map that closely matches the overall structure of the SARS-CoV postfusion spike and its corresponding glycosylation site. Our findings have major implications for SARS-CoV-2 vaccine design, especially those using inactivated viruses. [Display omitted] •β-propiolactone-inactivated SARS-CoV-2 viruses display postfusion spikes•Cryo-ET structure of SARS-CoV-2 postfusion spikes was determined at 11 Å resolution•This study calls for crucial structural characterization of vaccine candidates Several vaccine candidates using inactivated SARS-CoV-2 viruses are under development. Liu et al. used state-of-the-art cryoelectron microscopy technologies to characterize the architecture of inactivated SARS-CoV-2 viruses. They found that the viral spikes are mostly in a postfusion state, which is not desirable for vaccine development.