Molnupiravir (MK-4482) is efficacious against Omicron and other SARS-CoV-2 variants in the Syrian hamster COVID-19 model
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Abstract
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.
One Sentence Summary
MK-4482 inhibits replication of multiple SARS-CoV-2 variants of concern, including Omicron, in the Syrian hamster COVID-19 model
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SciScore for 10.1101/2022.02.22.481491: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Biosafety and ethics: SARS-CoV-2 work was approved by the Institutional Biosafety Committee (IBC) and performed in high biocontainment at Rocky Mountain Laboratories (RML), NIAID, NIH. IBC-approved Standard Operating Protocols were followed for sample removal from biocontainment. Sex as a biological variable Syrian hamster study design: Male and female 8–10-week-old hamsters were divided into vehicle (N=15 for Omicron infected, N=11 Alpha, Beta, Delta infected) or treatment (N=10 for Alpha, Beta, Delta, Omicron infected; N=9 for the Omicron high dose infected) groups prior to infection and treatments with MK-4482 (MedChemExpress). Randomization not detected. Blinding not detected. Power … SciScore for 10.1101/2022.02.22.481491: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Biosafety and ethics: SARS-CoV-2 work was approved by the Institutional Biosafety Committee (IBC) and performed in high biocontainment at Rocky Mountain Laboratories (RML), NIAID, NIH. IBC-approved Standard Operating Protocols were followed for sample removal from biocontainment. Sex as a biological variable Syrian hamster study design: Male and female 8–10-week-old hamsters were divided into vehicle (N=15 for Omicron infected, N=11 Alpha, Beta, Delta infected) or treatment (N=10 for Alpha, Beta, Delta, Omicron infected; N=9 for the Omicron high dose infected) groups prior to infection and treatments with MK-4482 (MedChemExpress). Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources The secondary antibody was an anti-rabbit IgG polymer (cat# MP-6401) from Vector Laboratories ImPress VR. anti-rabbit IgGsuggested: (Biorbyt Cat# orb14385, RRID:AB_10735740)Experimental Models: Cell Lines Sentences Resources Virus titration assay: Virus end-point titrations were performed in Vero E6 cells. Vero E6suggested: RRID:CVCL_XD71)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has limitations. The hamster model does not accurately represent COVID-19 disease for all human age- and comorbidity-associated subpopulations as the animals only develop mild-to-moderate disease (11, 20, 21), but this is a drawback of most current animal models (22). The more recently identified dwarf hamster model is associated with higher disease severity, but the extremely acute disease progression with animals reaching clinical endpoints within as quickly as 3 dpi (23) does not parallel the more prolonged course of severe disease in humans (24). In all cases, the current intranasal delivery of the challenge virus, whilst mimicking the most biologically relevant route of infection in humans, may interfere with readout parameters for the upper respiratory tract negatively impacting analysis of virus replication and shedding. Future transmission studies need to confirm the impact of MK-4482 on virus shedding and ultimately transmission to naïve animals. A study awaiting peer-review has shown an inhibitory effect of MK-4482 on shedding and transmission in the upper respiratory disease ferret model (25), which is encouraging; transmission studies are more difficult to perform in the hamster (26) and should be targeted for future experiments. The greatest limitation in the current situation is the incomplete experience with molnupiravir in clinical studies against the Omicron VOC. Those studies are underway, and results are expected in the near future. Nevertheless, ...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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