PDF(Pubmed)
Abstract：
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using \"public\" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs\' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
摘要：
严重急性呼吸道综合症冠状病毒2（SARS-CoV-2）Omicron变体的后代现在几乎占所有SARS-CoV-2感染的原因。Omicron变体及其亚谱系具有与大流行创始人和第一代疫苗株高度不同的尖峰糖蛋白，导致大量逃避单克隆抗体疗法和疫苗。了解通常引发的抗体如何扩大到交叉中和逃逸变体是至关重要的。我们分离IGHV3-53，使用“公共”单克隆抗体（mAb）从感染祖先病毒后7个月的个体，并鉴定出具有有效和广泛交叉中和的抗体，扩展到Omicron的BA.1，BA.2和BA4/BA.5子谱系。深度突变扫描揭示了这些单克隆抗体对病毒逃逸的高抗性。通过低温电子显微镜对代表性的广泛中和抗体进行结构分析，与OmicronBA.1尖峰复合的CAB-A17突出了该宽中和的结构基础。通过将体细胞超突变重新引入种系还原的CAB-A17，我们描述了亲和力成熟在公共抗体交叉中和发展中的作用。
