North-Western Tuscany Blood Bank, Pisa University Hospital, Italy.
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Drug Resist Updat. 2023 Nov;71:100991. doi: 10.1016/j.drup.2023.100991. Epub 2023 Jul 31.
The mutation rate of the Omicron sublineage has led to baseline resistance against all previously authorized anti-Spike monoclonal antibodies (mAbs). Nevertheless, in case more antiviral mAbs will be authorized in the future, it is relevant to understand how frequently treatment-emergent resistance has emerged so far, under different combinations and in different patient subgroups. We report the results of a systematic review of the medical literature for case reports and case series for treatment-emergent immune escape, which is defined as emergence of a resistance-driving mutation in at least 20% of sequences in a given host at a given timepoint. We identified 32 publications detailing 216 cases that included different variants of concern (VOC) and found that the incidence of treatment emergent-resistance ranged from 10% to 50%. Most of the treatment-emergent resistance events occurred in immunocompromised patients. Interestingly, resistance also emerged against cocktails of two mAbs, albeit at lower frequencies. The heterogenous therapeutic management of those cases doesn't allow inferences about the clinical outcome in patients with treatment-emergent resistance. Furthermore, we noted a temporal correlation between the introduction of mAb therapies and a subsequent increase in SARS-CoV-2 sequences across the globe carrying mutations conferring resistance to that mAb, raising concern as to whether these had originated in mAb-treated individuals. Our findings confirm that treatment-emergent immune escape to anti-Spike mAbs represents a frequent and concerning phenomenon and suggests that these are associated with mAb use in immunosuppressed hosts.
奥密克戎亚谱系的突变率导致其对所有先前授权的抗刺突单克隆抗体（mAbs）产生基线耐药性。然而，如果将来会有更多的抗病毒 mAbs 获得批准，那么了解迄今为止在不同组合和不同患者亚组中出现治疗后耐药性的频率就很重要。我们报告了对医学文献中关于治疗后免疫逃逸的病例报告和病例系列的系统评价结果，治疗后免疫逃逸定义为在给定时间点，至少 20%的给定宿主中出现耐药驱动突变。我们确定了 32 篇详细描述了 216 例不同关注变体（VOC）的出版物，并发现治疗后出现耐药性的发生率从 10%到 50%不等。大多数治疗后耐药性事件发生在免疫功能低下的患者中。有趣的是，尽管频率较低，但对两种 mAb 的鸡尾酒疗法也出现了耐药性。这些情况下的异质性治疗管理不允许对治疗后出现耐药性的患者的临床结果进行推断。此外，我们注意到 mAb 治疗的引入与全球范围内携带对该 mAb 耐药性的突变的 SARS-CoV-2 序列的后续增加之间存在时间相关性，这引发了人们对这些突变是否起源于 mAb 治疗个体的担忧。我们的研究结果证实，抗刺突 mAb 的治疗后免疫逃逸是一种常见且令人担忧的现象，并表明这些现象与免疫抑制宿主中 mAb 的使用有关。
