The decrease of antibody efficacy to mutated SARS-CoV-2 spike RBD explains the breakthrough infections and reinfections by Omicron variants. Here, we analyzed broadly neutralizing antibodies isolated from long-term hospitalized convalescent patients of early SARS-CoV-2 strains. One of the antibodies named NCV2SG48 is highly potent to broad SARS-CoV-2 variants including Omicron BA.1, BA.2, and BA.4/5. To reveal the mode of action, we determined the sequence and crystal structure of the Fab fragment of NCV2SG48 in a complex with spike RBD from the original, Delta, and Omicron BA.1. NCV2SG48 is from a minor V_H but the multiple somatic hypermutations contribute to a markedly extended binding interface and hydrogen bonds to interact with conserved residues at the core receptor-binding motif of RBD, which efficiently neutralizes a broad spectrum of variants. Thus, eliciting the RBD-specific B cells to the longitudinal germinal center reaction confers potent immunity to broad SARS-CoV-2 variants emerging one after another.

抗体对突变的 SARS-CoV-2 刺突 RBD 的效力降低解释了 Omicron 变体的突破性感染和再感染。在这里，我们分析了从早期 SARS-CoV-2 毒株的长期住院康复患者中分离出的广泛中和抗体。其中一种名为 NCV2SG48 的抗体对包括 Omicron BA.1、BA.2 和 BA.4/5 在内的广泛 SARS-CoV-2 变体非常有效。为了揭示作用模式，我们确定了复合物中 NCV2SG48 Fab 片段的序列和晶体结构，该复合物具有来自原始、Delta 和 Omicron BA.1 的尖峰 RBD。NCV2SG48 来自未成年人 V _H但多个体细胞超突变有助于显着扩展结合界面和氢键，从而与 RBD 核心受体结合基序上的保守残基相互作用，从而有效地中和广谱变异。因此，引发 RBD 特异性 B 细胞对纵向生发中心的反应赋予了对相继出现的广泛 SARS-CoV-2 变体的强大免疫力。