Abstract: 1 Title: Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model 2 3 Authors: Kyle Rosenke1, Atsushi Okumura1, Matthew C. Lewis1, Friederike Feldmann2, 4 Kimberly Meade-White1, W. Forrest Bohler1, Amanda Griffin1, Rebecca Rosenke2, Carl Shaia2, 5 Michael A. Jarvis1,3,4*, Heinz Feldmann1* 6 7 Affiliations: 1Laboratory of Virology, 2Rocky Mountain Veterinary Branch, National Institute 8 of Allergy and Infectious Diseases, National Institutes of Health; Hamilton, MT, USA; 3School 9 of Biomedical Sciences, University of Plymouth; Plymouth, Devon, UK; 4The Vaccine Group 10 Ltd; Plymouth, Devon, UK. 11 12 *Corresponding authors: Heinz Feldmann, Rocky Mountain Laboratories, 903 S 4th Street, 13 Hamilton, MT, US-59840; Tel: (406)-375-7410; Email: feldmannh@niaid.nih.gov; 14 Michael A. Jarvis, University of Plymouth, School of Biomedical Sciences, Derriford Research 15 Facility, Plymouth, Devon, UK, PL6 8BU; Tel: +44 (0)1752-437444; Email: 16 michael.jarvis@plymouth.ac.uk 17 18 One Sentence Summary: MK-4482 inhibits replication of multiple SARS-CoV-2 variants of 19 concern, including Omicron, in the Syrian hamster COVID-19 model 20 21 Conflict of Interest Statement: The authors have declared that no conflict of interest exists. 1 22 23 ABSTRACT 24 The recent emergence of the SARS-CoV-2 Omicron variant of concern (VOC) containing a 25 heavily mutated spike protein capable of escaping preexisting immunity identifies a continued 26 need for interventional measures. Molnupiravir (MK-4482), an orally administered nucleoside 27 analog, has demonstrated efficacy against earlier SARS-CoV-2 lineages and was recently 28 approved for SARS-CoV-2 infections in high-risk adults. Here we assessed the efficacy of MK- 29 4482 against the earlier Alpha, Beta and Delta VOCs and Omicron in the hamster COVID-19 30 model. Omicron replication and associated lung disease in vehicle treated hamsters was reduced 31 compared to the earlier VOCs. MK-4482 treatment inhibited virus replication in the lungs of 32 Alpha, Beta and Delta VOC infected hamsters. Importantly, MK-4482 profoundly inhibited virus 33 replication in the upper and lower respiratory tract of hamsters infected with the Omicron VOC. 34 Consistent with its mutagenic mechanism, MK-4482 treatment had a more pronounced inhibitory 35 effect on infectious titers compared to viral RNA genome load. Histopathologic analysis showed 36 that MK-4482 treatment caused a concomitant reduction in the level of lung disease and viral 37 antigen load in infected hamsters across all VOCs examined. Together, our data indicate the 38 potential of MK-4482 as an effective antiviral against known SARS-CoV-2 VOCs, especially 39 Omicron, and likely future SARS-CoV-2 variants. 40