Zhou Panpan, Yuan Meng, Song Ge, Beutler Nathan, Shaabani Namir, Huang Deli, He Wan-Ting, Zhu Xueyong, Callaghan Sean, Yong Peter, Anzanello Fabio, Peng Linghang, Ricketts James, Parren Mara, Garcia Elijah, Rawlings Stephen A, Smith Davey M, Nemazee David, Teijaro John R, Rogers Thomas F, Wilson Ian A, Burton Dennis R, Andrabi Raiees
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
bioRxiv. 2022 Jan 21:2021.03.30.437769. doi: 10.1101/2021.03.30.437769.
Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and, importantly, as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a coronavirus disease 2019 (COVID-19)-convalescent donor that exhibits broad reactivity with human beta-coronaviruses (β-CoVs). Here, we showed that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem-peptide at 1.6 Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 infection and therefore their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan-β-CoV vaccines.
A human mAb isolated from a COVID-19 donor defines a protective cross-neutralizing epitope for pan-β-CoV vaccine design strategies.
针对冠状病毒（CoV）的广泛中和抗体（bnAb）本身作为预防和治疗试剂，可用于治疗多种CoV，重要的是，还可作为合理设计泛CoV疫苗的模板，具有重要价值。我们最近描述了一种来自2019年冠状病毒病（COVID-19）康复供体的bnAb，CC40.8，它对人类β冠状病毒（β-CoV）具有广泛的反应性。在这里，我们表明CC40.8靶向冠状病毒刺突融合机制中保守的S2茎螺旋区域。我们确定了CC40.8 Fab与SARS-CoV-2 S2茎肽在1.6 Å分辨率下的晶体结构，发现该肽主要呈螺旋结构。β-CoV中的保守残基与CC40.8抗体相互作用，从而为其广泛的反应性提供了分子基础。CC40.8在两种动物模型中对SARS-CoV-2攻击均表现出体内保护功效。在这两种模型中，与对照组相比，接受CC40.8治疗的动物体重减轻更少，肺部病毒滴度降低。此外，我们注意到在人类COVID-19感染中，类似CC40.8的bnAb相对罕见，因此其诱导可能需要基于合理结构的疫苗设计策略。总体而言，我们的研究描述了β-CoV刺突蛋白上一个针对保护性抗体的靶点，这可能有助于泛β-CoV疫苗的开发。
从COVID-19供体中分离出的一种人单克隆抗体为泛β-CoV疫苗设计策略定义了一个保护性交叉中和表位。
