Abstract
BackgroundFavipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.MethodsWe here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.FindingsWhen animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. Interpretation: Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19. Funding: stated in the acknowledgment.
Highlights
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) was first identified in Wuhan, China in December 2019 [1]
This study reports on the potent antiviral effect of the combination of Molnupiravir and Favipiravir in the SARS-CoV-2 hamster infection model
To study the combined efficacy of Molnupiravir and Favipiravir in the hamster infection model, we selected a suboptimal dose for each compound that results in 2 log10 reduction in the lung infectious virus titers (TCID50/mg lung tissue)
Summary
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) was first identified in Wuhan, China in December 2019 [1]. We reported earlier that the influenza drug Favipiravir results in a marked protective activity against SARS-CoV-2 infection in the hamster model. Recent data from a phase 2 trial with Molnupiravir showed a reduction in the time required to reach negative isolation of infectious virus from nasopharyngeal swabs from participants with symptomatic SARS-CoV-2 infection. Methods: We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. Findings: When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals.
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