Oral 3CL protease inhibitor ensitrelvir suppressed SARS-CoV-2 shedding and infection in a hamster aerosol transmission model

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) remain a major global health challenge, with aerosol transmission being the primary route of spread. The use of antivirals as medical countermeasures to control SARS-CoV-2 transmission and spread is promising but remains to be clarified. The current study established and used an in vivo hamster aerosol transmission model system to evaluate the efficacy of the protease inhibitor ensitrelvir to prevent the spread of SARS-CoV-2. Male Index Syrian hamsters were intranasally infected with SARS-CoV-2, paired with naïve Contact hamsters, and co-housed for 12 h under conditions to allow for only aerosol transmission. The Index hamsters were treated three times with ensitrelvir starting 8 h post infection, or the Contact hamsters were treated once with ensitrelvir 12 h prior to co-housing. Viral infection and transmission were monitored by evaluating nasal lavage fluid, lung tissues, and body and lung weights. Post-infection administration of ensitrelvir to Index hamsters suppressed virus shedding in a dose-dependent manner. Pre-exposure administration of 750 mg/kg ensitrelvir to naïve Contact hamsters also protected against aerosol SARS-CoV-2 infection in a dose-dependent manner. Furthermore, pre-exposure treatment of 750 mg/kg ensitrelvir supressed body weight loss and lung weight increase of aerosol infected hamsters compared to vehicle-treated hamsters. These findings suggest that ensitrelvir may prevent SARS-CoV-2 spread when administered to infected patients and may prevent or limit SARS-CoV-2 infection when prophylactically administered to non-infected individuals. Both approaches may help protect at-risk individuals, such as family members living with SARS-CoV-2-infected patients.