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; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
Cell. 2022 Jun 9;185(12):2116-2131.e18. doi: 10.1016/j.cell.2022.05.014. Epub 2022 May 20.
Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.
高度传染性的 SARS-CoV-2 奥密克戎变体目前在全球占主导地位。在这里，我们比较了奥密克戎 BA.1、BA.1.1 和 BA.2 的中和作用。BA.2 的 RBD 与 ACE2 的亲和力略高于 BA.1，而疫苗血清的中和作用略有降低，这可能与其更高的传染性有关。单克隆抗体（包括治疗性抗体）亚谱系之间的中和作用差异主要源于与 ACE2 结合位点相邻的残基的变异；然而，更远的突变 S371F（BA.2）和 R346K（BA.1.1）显著降低了治疗性抗体 Vir-S309 的中和作用。对 27 种从接种疫苗的志愿者中分离出的、针对突破性奥密克戎 BA.1 感染的有效 RBD 结合单克隆抗体进行的深入结构和功能分析表明，它们集中在 RBD 的两个主要簇内，具有强大右肩抗体的出现频率更高。选择和体细胞成熟优化了在突变较少的表位中的抗体效力，并在高度突变的表位中恢复了效力。所有 27 种单克隆抗体都能有效地中和早期大流行株，并且许多抗体对关注变体具有广泛的反应性。
