Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
PLoS Pathog. 2024 Apr 18;20(4):e1011680. doi: 10.1371/journal.ppat.1011680. eCollection 2024 Apr.
To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.
为了减轻 COVID-19 大流行期间的生命损失，几种抗 SARS-CoV-2 单克隆抗体（mAb）疗法被紧急授权用于治疗有进展为重症疾病高风险的轻度至中度 COVID-19 患者。用于治疗 SARS-CoV-2 的单克隆抗体针对病毒的刺突蛋白，并阻断其进入和感染靶细胞的能力。因此，单克隆抗体疗法可以加速病毒载量的下降，并降低易受 mAb 治疗影响的高危患者的住院率。然而，已经观察到病毒耐药性，在某些情况下导致暂时的病毒反弹，其幅度可达 3-4 个数量级。由于 mAbs 是治疗 SARS-CoV-2 和其他病毒感染的有效选择，因此评估治疗中出现的 mAb 耐药性可以帮助揭示 SARS-CoV-2 感染的潜在病理生物学，也有助于开发下一代 mAb 疗法。尽管可以预期会出现耐药性，但观察到的大量反弹更难解释。我们假设需要补充靶细胞才能产生高瞬时病毒反弹。因此，我们提出了两种具有不同靶细胞补充机制（稳态增殖和从先天免疫反应抗病毒状态返回）的模型，并将它们拟合到接受 mAb 治疗的 SARS-CoV-2 患者的数据中。我们表明，这两种模型都可以解释与高瞬时病毒反弹相关的耐药病毒的出现。我们发现，靶细胞供应率和适应性免疫参数的变化对与耐药病毒出现相关的病毒反弹的幅度或可观测性有很大影响。靶细胞供应率和适应性免疫参数的变化都可能解释为什么只有一些人会出现可观测的瞬时耐药病毒反弹。我们的研究强调了在急性感染期间 mAb 治疗中可能导致耐药性和随后病毒反弹的条件。
