Sauer Maximilian M, Tortorici M Alexandra, Park Young-Jun, Walls Alexandra C, Homad Leah, Acton Oliver, Bowen John, Wang Chunyan, Xiong Xiaoli, de van der Schueren Willem, Quispe Joel, Hoffstrom Benjamin G, Bosch Berend-Jan, McGuire Andrew T, Veesler David
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Institut Pasteur, Unité de Virologie Structurale, Paris, France; CNRS UMR 3569, Unité de Virologie Structurale, Paris, France.
bioRxiv. 2021 Jan 4:2020.12.29.424482. doi: 10.1101/2020.12.29.424482.
Three highly pathogenic β-coronaviruses crossed the animal-to-human species barrier in the past two decades: SARS-CoV, MERS-CoV and SARS-CoV-2. SARS-CoV-2 has infected more than 64 million people worldwide, claimed over 1.4 million lives and is responsible for the ongoing COVID-19 pandemic. We isolated a monoclonal antibody, termed B6, cross-reacting with eight β-coronavirus spike glycoproteins, including all five human-infecting β-coronaviruses, and broadly inhibiting entry of pseudotyped viruses from two coronavirus lineages. Cryo-electron microscopy and X-ray crystallography characterization reveal that B6 binds to a conserved cryptic epitope located in the fusion machinery and indicate that antibody binding sterically interferes with spike conformational changes leading to membrane fusion. Our data provide a structural framework explaining B6 cross-reactivity with β-coronaviruses from three lineages along with proof-of-concept for antibody-mediated broad coronavirus neutralization elicited through vaccination. This study unveils an unexpected target for next-generation structure-guided design of a pan-coronavirus vaccine.
在过去二十年中，三种高致病性β冠状病毒跨越了动物到人类的物种屏障：严重急性呼吸综合征冠状病毒（SARS-CoV）、中东呼吸综合征冠状病毒（MERS-CoV）和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。SARS-CoV-2已在全球感染了超过6400万人，夺走了140多万人的生命，并引发了持续的新冠疫情。我们分离出一种名为B6的单克隆抗体，它能与八种β冠状病毒刺突糖蛋白发生交叉反应，包括所有五种可感染人类的β冠状病毒，并广泛抑制来自两个冠状病毒谱系的假型病毒的进入。冷冻电子显微镜和X射线晶体学表征显示，B6与位于融合机制中的一个保守隐蔽表位结合，并表明抗体结合在空间上干扰了导致膜融合的刺突构象变化。我们的数据提供了一个结构框架，解释了B6与三个谱系的β冠状病毒的交叉反应性，以及通过疫苗接种引发抗体介导的广泛冠状病毒中和作用的概念验证。这项研究揭示了下一代全冠状病毒疫苗结构导向设计的一个意想不到的靶点。
