Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK.
Cell. 2021 May 27;184(11):2939-2954.e9. doi: 10.1016/j.cell.2021.03.055. Epub 2021 Mar 30.
Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.
终止 SARS-CoV-2 大流行依赖于全人类范围的疫苗接种。目前的疫苗可诱导针对病毒刺突蛋白的中和抗体反应，该刺突蛋白源自早期分离株。然而，新的毒株已经出现了多种突变，包括来自巴西的 P.1、来自南非的 B.1.351 和来自英国的 B.1.1.7（刺突蛋白分别有 9、10 和 12 处突变）。所有这些突变都发生在 ACE2 结合部位，其中 P.1 和 B.1.351 的突变相同（E484K、K417N/T 和 N501Y），我们发现这使它们对 ACE2 的亲和力增加相似。令人惊讶的是，我们发现 P.1 对自然获得或疫苗诱导的抗体反应的抗性明显低于 B.1.351，这表明受体结合域（RBD）以外的变化会影响中和。单克隆抗体 222 可中和所有三种变体，尽管它与两个 ACE2 结合部位的突变都相互作用。我们通过结构分析解释了这一点，并使用 222 轻链在很大程度上恢复了主要公共抗体类别的中和效力。
