Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model
Kyle Rosenke, Atsushi Okumura, Matthew C. Lewis, Friederike Feldmann, Kimberly Meade-White, W. Forrest Bohler, Amanda Griffin, Rebecca Rosenke, Carl Shaia, Michael A. Jarvis, Heinz Feldmann
Kyle Rosenke, Atsushi Okumura, Matthew C. Lewis, Friederike Feldmann, Kimberly Meade-White, W. Forrest Bohler, Amanda Griffin, Rebecca Rosenke, Carl Shaia, Michael A. Jarvis, Heinz Feldmann
View: Text | PDF
Research Article COVID-19 Virology

Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model

Abstract

The recent emergence of the SARS-CoV-2 Omicron variant of concern (VOC), which contains 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 hamster COVID-19 model. Omicron replication and associated lung disease in vehicle-treated hamsters was reduced compared with replication and lung disease associated with earlier VOCs. MK-4482 treatment inhibited virus replication in the lungs of hamsters infected with Alpha, Beta, or Delta VOCs. 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 titers compared with 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.

Authors

Kyle Rosenke, Atsushi Okumura, Matthew C. Lewis, Friederike Feldmann, Kimberly Meade-White, W. Forrest Bohler, Amanda Griffin, Rebecca Rosenke, Carl Shaia, Michael A. Jarvis, Heinz Feldmann

×

Figure 3

Efficacy of MK-4482 on lung pathology in hamsters infected with multiple SARS-CoV-2 VOCs.

Options: View larger image (or click on image) Download as PowerPoint
Efficacy of MK-4482 on lung pathology in hamsters infected with multiple...
The experimental design is shown in Figure 1A. Lung tissue was collected at 4 dpi and prepared for H&E staining and IHC using an antibody directed against the SARS-CoV-2 nucleocapsid protein. (A, E, I, and M) Lung H&E staining (original magnification, ×40) of tissue from vehicle-treated hamsters infected with Alpha, Beta, Delta, and Omicron VOC, respectively, showing bronchointerstitial pneumonia and vasculitis. (B, F, J, and N) Lung IHC (original magnification, ×40). SARS-CoV-2 nucleoprotein detection in lung sections from vehicle-treated hamsters infected with Alpha, Beta, Delta, and Omicron, respectively, exhibiting immunoreactivity associated with areas of pneumonia (brown color). (C, G, K, and O) Lung H&E staining (original magnification, ×40) of tissue from MK-4482–treated hamsters infected with Alpha, Beta, Delta, and Omicron VOC, respectively, showing reduced bronchointerstitial pneumonia. (D, H, L, and P) Lung IHC (original magnification, ×40). SARS-CoV-2 nucleoprotein detection in lung sections from MK-4482–treated hamsters infected with Alpha, Beta, Delta, and Omicron VOC, respectively, exhibiting reduced or no immunoreactivity. Each panel shows a lung sections from a representative hamster. Scale bar: 500 μm.