Rosenke Kyle, Lewis Matt C, Feldmann Friederike, Bohrnsen Eric, Schwarz Benjamin, Okumura Atsushi, Bohler W Forrest, Callison Julie, Shaia Carl, Bosio Catharine M, Lovaglio Jamie, Saturday Greg, Jarvis Michael A, Feldmann Heinz
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
bioRxiv. 2022 Sep 5:2022.09.03.506479. doi: 10.1101/2022.09.03.506479.
The periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, have each recently been approved as monotherapy for use in high risk COVID-19 patients. As preclinical data are only available for rodent and ferret models, we originally assessed the efficacy of MK-4482 and PF-07321332 alone and then in combination Against infection with the SARS-CoV-2 Delta VOC in the rhesus macaque COVID-19 model. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs. Combined treatment resulted in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections as demonstrated here in the closest COVID-19 surrogate model.
The combination of molnupiravir and nirmatrelvir inhibits SARS-CoV-2 replication and shedding more effectively than individual treatments in the rhesus macaque model.
值得关注的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变异株（VOCs）定期出现，其临床严重程度不可预测且能够逃避既往免疫力，这凸显了对抗病毒干预措施的持续需求。两种小分子抑制剂，核苷类似物莫努匹拉韦（MK-4482）和3C样蛋白酶抑制剂奈玛特韦（PF-07321332），最近均已被批准作为单一疗法用于高危COVID-19患者。由于临床前数据仅适用于啮齿动物和雪貂模型，我们最初评估了MK-4482和PF-07321332单独使用以及联合使用时对恒河猴COVID-19模型中SARS-CoV-2 Delta变异株感染的疗效。值得注意的是，联合使用MK-4482和PF-07321332可提高两种药物的个体抑制效果。联合治疗导致疾病进展更轻，上呼吸道黏膜组织病毒载量的降低更强，下呼吸道病毒复制的降低更强，并且肺部病理变化减轻。我们的数据有力地表明，如在此最接近COVID-19的替代模型中所证明的，MK-4482和PF-07321332联合治疗SARS-CoV-2感染具有优越性。
在恒河猴模型中，莫努匹拉韦和奈玛特韦联合使用比单独治疗更有效地抑制SARS-CoV-2复制和病毒载量。
