Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera , including the nine human coronaviruses, through recognition of a conserved motif that includes the S2´ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice expressing human ACE2 against infection when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae , including SARS-CoV-2 variants.

中文翻译：

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针对 SARS-CoV-2 刺突糖蛋白冷线性表位和子结构域 1 的人类中和抗体


SARS-CoV-2 变种的出现降低了疫苗和抗病毒单克隆抗体的功效。因此，有必要继续开发能够抵抗病毒进化的免疫疗法和疫苗免疫原。使用冷点引导抗体发现（一种专注于功能相关且不愿改变的病毒刺突糖蛋白部分的筛选方法），我们鉴定了针对高度保守的病毒表位的人类中和抗体。抗体fp.006结合融合肽并与四种冠状病毒发生交叉反应属，包括九种人类冠状病毒，通过识别包括蛋白水解裂解的 S2´ 位点的保守基序。抗体 hr2.016 靶向茎螺旋并中和 SARS-CoV-2 变体。抗体 sd1.040 与子结构域 1 结合，与抗体 rbd.042 协同进行中和，并且与 fp.006 和 hr2.016 一样，当作为双特异性抗体存在时，可以保护表达人 ACE2 的小鼠免受感染。因此，冷点引导的抗体发现揭示了供体来源的中和抗体，这些抗体与正冠状病毒亚科，包括 SARS-CoV-2 变种。