National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
MRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
J Virol. 2022 Aug 10;96(15):e0055822. doi: 10.1128/jvi.00558-22. Epub 2022 Jul 13.
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, several variants of concern (VOCs) have arisen which are defined by multiple mutations in their spike proteins. These VOCs have shown variable escape from antibody responses and have been shown to trigger qualitatively different antibody responses during infection. By studying plasma from individuals infected with either the original D614G, Beta, or Delta variants, we showed that the Beta and Delta variants elicit antibody responses that are overall more cross-reactive than those triggered by D614G. Patterns of cross-reactivity varied, and the Beta and Delta variants did not elicit cross-reactive responses to each other. However, Beta-elicited plasma was highly cross-reactive against Delta Plus (Delta+), which differs from Delta by a single K417N mutation in the receptor binding domain, suggesting that the plasma response targets the N417 residue. To probe this further, we isolated monoclonal antibodies from a Beta-infected individual with plasma responses against Beta, Delta+, and Omicron, which all possess the N417 residue. We isolated an N417-dependent antibody, 084-7D, which showed similar neutralization breadth to the plasma. The 084-7D MAb utilized the IGHV3-23*01 germ line gene and had somatic hypermutations similar to those of previously described public antibodies which target the 417 residue. Thus, we have identified a novel antibody which targets a shared epitope found on three distinct VOCs, enabling their cross-neutralization. Understanding antibodies targeting escape mutations, such as K417N, which repeatedly emerge through convergent evolution in SARS-CoV-2 variants, may aid in the development of next-generation antibody therapeutics and vaccines. The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring various immune escape profiles. These variable mutations also influence the cross-reactivity of the antibody response mounted by individuals infected with each of these variants. This study sought to understand the antibody responses elicited by different SARS-CoV-2 variants and to define shared epitopes. We show that Beta and Delta infections resulted in antibody responses that were more cross-reactive than the original D614G variant, but they had differing patterns of cross-reactivity. We further isolated an antibody from Beta infection which targeted the N417 site, enabling cross-neutralization of Beta, Delta+, and Omicron, all of which possess this residue. The discovery of antibodies which target escape mutations common to multiple variants highlights conserved epitopes to target in future vaccines and therapeutics.
随着严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的不断进化，已经出现了几种令人关注的变体（VOC），这些变体的刺突蛋白中存在多种突变。这些 VOC 已经显示出对抗体反应的不同程度的逃逸能力，并且在感染过程中已经显示出引发定性不同的抗体反应。通过研究感染原始 D614G、Beta 或 Delta 变体的个体的血浆，我们表明 Beta 和 Delta 变体引发的抗体反应总体上比 D614G 引发的反应更具交叉反应性。交叉反应性模式各不相同，并且 Beta 和 Delta 变体彼此之间没有引发交叉反应性反应。然而，Beta 引发的血浆对 Delta Plus（Delta+）具有高度的交叉反应性，Delta+ 在受体结合域中仅发生单个 K417N 突变，表明血浆反应针对的是 N417 残基。为了进一步探究这一点，我们从 Beta 感染的个体中分离出针对 Beta、Delta+和奥密克戎的单克隆抗体，这些变体都具有 N417 残基。我们分离出一种依赖于 N417 的抗体 084-7D，它对 Beta 的中和广度与血浆相似。084-7D MAb 利用 IGHV3-23*01 胚系基因，并具有与先前描述的靶向 417 位残基的公共抗体相似的体细胞超突变。因此，我们已经鉴定出一种针对三个不同 VOC 上发现的共享表位的新型抗体，能够实现它们的交叉中和。了解逃避突变（如 K417N）的抗体，这些突变通过 SARS-CoV-2 变体的趋同进化反复出现，可能有助于开发下一代抗体治疗药物和疫苗。SARS-CoV-2 的进化导致了具有不同刺突突变的关注变体（VOC），这些突变赋予了不同的免疫逃逸特征。这些可变突变也影响了感染这些变体的个体所产生的抗体反应的交叉反应性。本研究旨在了解不同 SARS-CoV-2 变体引发的抗体反应，并定义共享表位。我们表明，Beta 和 Delta 感染导致的抗体反应比原始 D614G 变体更具交叉反应性，但它们的交叉反应性模式不同。我们进一步从 Beta 感染中分离出一种针对 N417 位点的抗体，能够中和 Beta、Delta+和奥密克戎，所有这些变体都具有该位点。发现针对多个变体共有的逃逸突变的抗体突出了针对未来疫苗和治疗药物的保守表位。
