Tatham Lee, Kipar Anja, Sharp Jo, Kijak Edyta, Herriott Joanne, Neary Megan, Box Helen, Gallardo Toledo Eduardo, Valentijn Anthony, Cox Helen, Pertinez Henry, Curley Paul, Arshad Usman, Rajoli Rajith Kumar Reddy, Rannard Steve, Stewart James P, Owen Andrew
Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, Liverpool, United Kingdom.
Microbiol Spectr. 2024 Aug 6;12(8):e0391623. doi: 10.1128/spectrum.03916-23. Epub 2024 Jul 16.
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 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.
除了一些例外情况，由于对新变体的中和作用丧失，全球政策制定者已建议不要在新冠病毒疾病（COVID-19）中使用现有的单克隆抗体。本研究的目的是使用针对易感和不易感变体的范例，研究罗那普瑞韦（Ronapreve）对区室化病毒复制的影响。在用Delta或BA.1奥密克戎变体接种的K18-hACE2小鼠中评估了病毒学疗效及其对致病性的影响。罗那普瑞韦在感染Delta变体后的第4天和第6天降低了肺和鼻甲中的亚基因组病毒RNA水平，但对奥密克戎变体无效。它还阻止了脑部感染，Delta变体感染后的K18-hACE2小鼠中脑部感染很常见。在第6天，对Delta变体肺部感染的炎症反应转变为多灶性肉芽肿性炎症，病毒似乎局限在其中。本研究提供了证据，表明用保留中和活性的单克隆抗体组合治疗后，组织对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的反应发生了改变。这些数据表明，在单克隆抗体的动物模型中可以实现反映治疗用例的实验设计。在解释可能不代表治疗的预防性实验设计时应格外谨慎。
重要性
在SARS-CoV-2奥密克戎变体出现后，世界卫生组织（WHO）在其新冠病毒疾病治疗指南中建议不要使用罗那普瑞韦，因为根据目前的药代动力学-药效学理解其缺乏疗效。然而，基于中和数据，一些人主张继续使用罗那普瑞韦，特别是在易感患者中。在此，以Delta作为易感变体的范例，在肺和脑区室中均证明了罗那普瑞韦的病毒学疗效。相反，证明罗那普瑞韦对奥密克戎变体缺乏病毒学疗效。在感染Delta和奥密克戎的小鼠血浆中观察到两种单克隆抗体的浓度相当。本研究使用了可靠的SARS-CoV-2感染小鼠模型，一种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。
