Neutralizing antibodies that recognize the SARS-CoV-2 spike glycoprotein are the principal host defense against viral invasion. Variants of SARS-CoV-2 bear mutations that allow escape from neutralization by many antibodies, especially those belonging to classes widely distributed in the human population. Identifying antibodies that neutralize these variants of concern and determining their prevalence are important goals for understanding immune protection. To determine the Delta- and Omicron BA.1-variant specificity of B cell repertoires established by an initial Wuhan strain infection, we measured neutralization potencies of 73 antibodies from an unbiased survey of the early memory B cell response. Antibodies recognizing each of three, previously defined, epitopic regions on the spike receptor-binding domain (RBD) varied in neutralization potency and variant-escape resistance. The ACE2 binding surface (“RBD-2”) harbored the binding sites of the neutralizing antibodies with highest potency but with the greatest sensitivity to viral escape; two other epitopic regions on the RBD (“RBD-1 and “RBD-3”) bound antibodies of more modest potency but greater breadth. The structures of several Fab:spike complexes that neutralized all five variants of concern tested, including one Fab each from the RBD-1, -2 and -3 clusters, illustrated the determinants of broad neutralization and showed that B cell repertoires can have specificities that avoid immune escape driven by widely distributed (“public”) antibodies. The structure of the RBD-2-binding, broad neutralizer shows why it retains neutralizing activity for Omicron BA.1, unlike most others in the same public class. Our results correlate with real-world data on vaccine efficacy, which indicate mitigation of disease caused by Omicron BA.1.

中文翻译：

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由祖先 SARS-CoV-2 菌株诱导的抗体，可交叉中和从 Alpha 到 Omicron BA.1 的变体


识别 SARS-CoV-2 刺突糖蛋白的中和抗体是宿主抵御病毒入侵的主要防御机制。 SARS-CoV-2 的变体带有突变，可以逃避许多抗体的中和作用，特别是那些属于广泛分布于人群中的抗体。识别中和这些相关变异的抗体并确定其患病率是了解免疫保护的重要目标。为了确定由最初的武汉病毒株感染建立的 B 细胞库的 Delta 和 Omicron BA.1 变体特异性，我们通过对早期记忆 B 细胞反应的公正调查测量了 73 种抗体的中和效力。识别刺突受体结合域 (RBD) 上三个先前定义的表位区域的抗体在中和效力和变体逃逸抗性方面各不相同。 ACE2结合表面（“RBD-2”）具有中和抗体的结合位点，具有最高的效力，但对病毒逃逸的敏感性最高； RBD 上的另外两个表位区域（“RBD-1 和“RBD-3”）结合的抗体效力较弱，但范围更大。几个 Fab:spike 复合物的结构中和了所测试的所有五种相关变体，包括来自 RBD-1、-2 和 -3 簇的各一个 Fab，说明了广泛中和的决定因素，并表明 B 细胞库可以具有以下特异性：避免由广泛分布的（“公共”）抗体驱动的免疫逃逸。与 RBD-2 结合的广泛中和剂的结构表明了为什么它保留了 Omicron BA.1 的中和活性，与同一公共类别中的大多数其他中和剂不同。 我们的结果与疫苗功效的真实数据相关，这表明 Omicron BA.1 引起的疾病得到了缓解。