Liu Zhuoming, VanBlargan Laura A, Bloyet Louis-Marie, Rothlauf Paul W, Chen Rita E, Stumpf Spencer, Zhao Haiyan, Errico John M, Theel Elitza S, Liebeskind Mariel J, Alford Brynn, Buchser William J, Ellebedy Ali H, Fremont Daved H, Diamond Michael S, Whelan Sean P J
bioRxiv. 2021 Jan 11:2020.11.06.372037. doi: 10.1101/2020.11.06.372037.
Although 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, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants ( ., S477N) were resistant to neutralization by multiple mAbs, whereas others ( ., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.
尽管针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突（S）蛋白的中和抗体是新冠病毒疫苗的目标，并且已作为治疗药物获得紧急使用授权，但病毒逃逸突变体可能会损害其疗效。为了确定S蛋白中免疫选择的突变情况，我们使用了一种水疱性口炎病毒-eGFP-SARS-CoV-2-S嵌合病毒和19种针对受体结合域（RBD）的中和单克隆抗体（mAb）来产生50种不同的逃逸突变体。将这些变体映射到RBD结构上，并评估其对mAb和康复期人血清的交叉抗性。尽管许多mAb在一个表位内共享残基，但每种mAb都有独特的抗性谱。一些变体（例如，S477N）对多种mAb的中和作用具有抗性，而其他变体（例如，E484K）则能逃避康复期血清的中和作用，这表明一些人诱导产生的中和抗体种类有限。将S蛋白中抗体介导的突变情况与循环中的SARS-CoV-2的序列变异进行比较，我们确定了可能会减弱某些人中和免疫反应的替代突变。
