Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; UNSW Sydney, Faculty of Medicine, Sydney, NSW 2010, Australia.
Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Immunity. 2021 Dec 14;54(12):2908-2921.e6. doi: 10.1016/j.immuni.2021.10.019. Epub 2021 Oct 29.
Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.
病毒突变是降低 SARS-CoV-2 疫苗效力的一个新出现的问题。第二代疫苗将需要诱导针对在 sarbecovirus 亚属中进化上保守的位点的中和抗体。在这里，我们用多种 sarbecovirus 受体结合域（RBD）免疫含有人抗体库的小鼠，以鉴定针对保守脆弱性位点的抗体。针对保守的第 4 类表位的广泛反应性的、针对不同分支 B RBD 的抗体，带有反复出现的 IGHV/IGKV 对，很容易被诱导出来，但没有中和作用。然而，少数结合这种保守 RBD 超位点的第 4 类抗体能够有效地中和 SARS-CoV-2 及其所有关注的变体。结构分析表明，交叉反应性抗体的中和能力仅保留在那些具有长 CDRH3 的抗体中，CDRH3 延伸了反平行的β-折叠 RBD 核心，并使抗体轻链定向以阻碍 ACE2-RBD 相互作用。这些结果确定了一种结构上定义的疫苗策略，可诱导对 SARS-CoV-2 具有抗性的中和抗体。
