Rosenke Kyle, Okumura Atsushi, Lewis Matthew C, Feldmann Friederike, Meade-White Kimberly, Bohler W Forrest, Griffin Amanda, Rosenke Rebecca, Shaia Carl, Jarvis Michael A, Feldmann Heinz
Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Hamilton, MT, USA.
Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Hamilton, MT, USA.
bioRxiv. 2022 Feb 23:2022.02.22.481491. doi: 10.1101/2022.02.22.481491.
The recent emergence of the SARS-CoV-2 Omicron variant of concern (VOC) containing a heavily mutated spike protein capable of escaping preexisting immunity, identifies a continued need for interventional measures. Molnupiravir (MK-4482), an orally administered nucleoside analog, has demonstrated efficacy against earlier SARS-CoV-2 lineages and was recently approved for SARS-CoV-2 infections in high-risk adults. Here we assessed the efficacy of MK-4482 against the earlier Alpha, Beta and Delta VOCs and Omicron in the Syrian hamster COVID-19 model. Omicron replication and associated lung disease in vehicle treated hamsters was reduced compared to the earlier VOCs. MK-4482 treatment inhibited virus replication in the lungs of Alpha, Beta and Delta VOC infected hamsters. Importantly, MK-4482 profoundly inhibited virus replication in the upper and lower respiratory tract of hamsters infected with the Omicron VOC. Consistent with its mutagenic mechanism, MK-4482 treatment had a more pronounced inhibitory effect on infectious virus titers compared to viral RNA genome load. Histopathologic analysis showed that MK-4482 treatment caused a concomitant reduction in the level of lung disease and viral antigen load in infected hamsters across all VOCs examined. Together, our data indicate the potential of MK-4482 as an effective antiviral against known SARS-CoV-2 VOCs, especially Omicron, and likely future SARS-CoV-2 variants.
最近出现的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）奥密克戎变异株（VOC）含有高度突变的刺突蛋白，能够逃避先前存在的免疫力，这表明持续需要采取干预措施。莫努匹韦（MK-4482）是一种口服核苷类似物，已证明对早期的SARS-CoV-2谱系有效，最近被批准用于治疗高危成年人的SARS-CoV-2感染。在此，我们在叙利亚仓鼠新冠病毒疾病（COVID-19）模型中评估了MK-4482对早期的阿尔法、贝塔和德尔塔变异株以及奥密克戎变异株的疗效。与早期的变异株相比，在接受赋形剂治疗的仓鼠中，奥密克戎变异株的复制及相关肺部疾病有所减少。MK-4482治疗可抑制感染阿尔法、贝塔和德尔塔变异株的仓鼠肺部的病毒复制。重要的是，MK-4482能显著抑制感染奥密克戎变异株的仓鼠上、下呼吸道中的病毒复制。与其诱变机制一致，与病毒RNA基因组载量相比，MK-4482治疗对感染性病毒滴度的抑制作用更为明显。组织病理学分析表明，在所有检测的变异株感染的仓鼠中，MK-4482治疗可同时降低肺部疾病水平和病毒抗原载量。总之，我们的数据表明MK-4482作为一种有效的抗病毒药物，对已知的SARS-CoV-2变异株，尤其是奥密克戎变异株以及未来可能出现的SARS-CoV-2变异株具有潜在疗效。
