PDF(Pubmed)
Abstract：
With some exceptions, global policymakers have recommended against the use of existing monoclonal antibodies in COVID-19 due to loss of neutralization of newer variants. The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication using paradigms for susceptible and insusceptible variants. Virological efficacy and impact on pathogenicity was assessed in K18-hACE2 mice inoculated with either the Delta or BA.1 Omicron variants. Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post-infection, for the Delta variant but not the Omicron variant. It also blocked brain infection, which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a multifocal granulomatous inflammation in which the virus appeared to be confined. The current study provides evidence of an altered tissue response to SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data demonstrate that experimental designs that reflect treatment use cases are achievable in animal models for monoclonal antibodies. Extreme caution should be taken when interpreting prophylactic experimental designs that may not be representative of treatment.IMPORTANCEFollowing the emergence of the SARS-CoV-2 Omicron variant, the WHO recommended against the use of Ronapreve in its COVID-19 treatment guidelines due to a lack of efficacy based on current pharmacokinetic-pharmacodynamic understanding. However, the continued use of Ronapreve, specifically in vulnerable patients, was advocated by some based on in vitro neutralization data. Here, the virological efficacy of Ronapreve was demonstrated in both the lung and brain compartments using Delta as a paradigm for a susceptible variant. Conversely, a lack of virological efficacy was demonstrated for the Omicron variant. Comparable concentrations of both monoclonal antibodies were observed in the plasma of Delta- and Omicron-infected mice. This study made use of a reliable murine model for SARS-CoV-2 infection, an experimental design reflective of treatment, and demonstrated the utility of this approach when assessing the effectiveness of monoclonal antibodies.
摘要：
除了一些例外,全球政策制定者建议不要在COVID-19中使用现有的单克隆抗体，因为新变体的中和丢失。这项研究的目的是使用易感和不易感变体的范例研究Ronapreve对隔室病毒复制的影响。在接种Delta或BA.1Omicron变体的K18-hACE2小鼠中评估病毒学功效和对致病性的影响。Ronapreve降低了肺和鼻甲的亚基因组病毒RNA水平，感染后4天和6天，对于Delta变体，而不是Omicron变体。它还阻止了脑部感染，在Delta变异体感染后，在K18-hACE2小鼠中表现出很高的频率。在第6天，对Delta变体的肺部感染的炎症反应改变为多灶性肉芽肿性炎症，其中病毒似乎受到限制。当前的研究提供了用保留中和活性的单克隆抗体组合治疗后对SARS-CoV-2的组织反应改变的证据。这些数据表明,反映治疗用例的实验设计在单克隆抗体的动物模型中是可实现的。在解释可能不代表治疗的预防性实验设计时应格外小心。重要性随着SARS-CoV-2Omicron变体的出现，世卫组织在其COVID-19治疗指南中建议不使用Ronapreve,因为根据目前对药代动力学-药效学的理解缺乏疗效.然而,继续使用Ronapreve,特别是在脆弱的病人中，一些人基于体外中和数据主张。这里,使用Delta作为易感变异的范例,在肺区和脑区均证明了Ronapreve的病毒学功效.相反，Omicron变体缺乏病毒学功效.在Delta和Omicron感染的小鼠的血浆中观察到两种单克隆抗体的浓度相当。这项研究利用了一个可靠的SARS-CoV-2感染的小鼠模型，反映治疗的实验设计，并证明了这种方法在评估单克隆抗体有效性时的实用性。
