Department of Molecular Microbiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Cell Host Microbe. 2021 Mar 10;29(3):477-488.e4. doi: 10.1016/j.chom.2021.01.014. Epub 2021 Jan 27.
Neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics. However, viral escape mutants could compromise efficacy. To define immune-selected mutations in the S protein, we exposed a VSV-eGFP-SARS-CoV-2-S chimeric virus, in which the VSV glycoprotein is replaced with the S protein, to 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) and generated 50 different escape mutants. Each mAb had a unique resistance profile, although many shared residues within an epitope of the RBD. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera. Additionally, sequential selection identified mutants that escape neutralization by antibody cocktails. Comparing these antibody-mediated mutations with sequence variation in circulating SARS-CoV-2 revealed substitutions that may attenuate neutralizing immune responses in some humans and thus warrant further investigation.
针对 SARS-CoV-2 刺突（S）蛋白的中和抗体是 COVID-19 疫苗的目标，已作为治疗药物获得紧急使用授权。然而，病毒逃逸突变可能会影响疗效。为了确定 S 蛋白中的免疫选择突变，我们使一种 VSV-eGFP-SARS-CoV-2-S 嵌合病毒暴露于 19 种针对受体结合域（RBD）的中和单克隆抗体（mAb）中，这些 mAb 中和了 S 蛋白，从而产生了 50 种不同的逃逸突变体。每种 mAb 都有独特的耐药谱，尽管许多 mAb 在 RBD 的一个表位内共享残基。一些变体（例如 S477N）对多种 mAb 的中和具有抗性，而其他变体（例如 E484K）则逃避了恢复期血清的中和。此外，连续选择确定了逃避抗体鸡尾酒中和的突变体。将这些抗体介导的突变与循环 SARS-CoV-2 中的序列变异进行比较，发现了可能在某些人中减弱中和免疫反应的替代，因此值得进一步研究。
