Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

中文翻译：

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单克隆抗体治疗出现 SARS-CoV-2 耐药性

已经报道了对单克隆抗体 (mAb) 治疗的耐药性突变，但在非免疫抑制人群中，尚不清楚是否在体内SARS-CoV-2 耐药性突变的出现改变了病毒复制动力学或治疗效果。在 ACTIV-2/A5401 中，有症状的 SARS-CoV-2 感染的非住院参与者被随机分配到 bamlanimab（700mg 或 7000mg）或安慰剂组。与安慰剂相比，在 bamlanimab 700mg 治疗后检测到治疗出现的耐药突变的可能性显着高于安慰剂（111 名参与者的 7% 与 112 名参与者的 0%，P=0.003）。在接受 bamlanimab 7000mg 的 48 名参与者中，没有出现治疗出现的耐药性突变。具有新出现的 mAb 抗性病毒的参与者在治疗前鼻咽和前鼻部病毒载量显着升高。密集的呼吸道病毒采样揭示了 SARS-CoV-2 进化的动态性质，有证据表明出现耐药性突变后病毒快速和持续反弹，并且症状严重程度恶化。具有新出现的 bamlanivimab 耐药性的参与者经常积累在当前关注/感兴趣的变体中发现的额外多态性，并与免疫逃逸相关。这些结果强调了单克隆抗体单药治疗期间快速出现耐药性的可能性，导致呼吸道病毒载量延长和临床恶化。在 COVID-19 抗病毒治疗的开发和临床实施过程中，应优先考虑仔细的病毒学评估。这些结果强调了单克隆抗体单药治疗期间快速出现耐药性的可能性，导致呼吸道病毒载量延长和临床恶化。在 COVID-19 抗病毒治疗的开发和临床实施过程中，应优先考虑仔细的病毒学评估。这些结果强调了单克隆抗体单药治疗期间快速出现耐药性的可能性，导致呼吸道病毒载量延长和临床恶化。在 COVID-19 抗病毒治疗的开发和临床实施过程中，应优先考虑仔细的病毒学评估。