Evaluation of Nafamostat as Chemoprophylaxis for SARS-CoV-2 Infection in Hamsters

Abstract

The successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention that is implementable alongside vaccination programmes. Nafamostat is a serine protease inhibitor that inhibits SARS-CoV-2 entry in vitro, but it has not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and has an extremely short plasma half-life. This study sought to determine whether intranasal dosing of nafamostat at 5 mg/kg twice daily was able to prevent the airborne transmission of SARS-CoV-2 from infected to uninfected Syrian Golden hamsters. SARS-CoV-2 RNA was detectable in the throat swabs of the water-treated control group 4 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, throat swabs from the intranasal nafamostat-treated hamsters remained SARS-CoV-2 RNA negative for the full 4 days of cohabitation. Significantly lower SARS-CoV-2 RNA concentrations were seen in the nasal turbinates of the nafamostat-treated group compared to the control (p = 0.001). A plaque assay quantified a significantly lower concentration of infectious SARS-CoV-2 in the lungs of the nafamostat-treated group compared to the control (p = 0.035). When taken collectively with the pathological changes observed in the lungs and nasal mucosa, these data are strongly supportive of the utility of intranasally delivered nafamostat for the prevention of SARS-CoV-2 infection.

Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters

“…Two longitudinal sections were prepared from each lung and routinely paraffin wax embedded. Consecutive sections (3-5 µm) were prepared and stained with haematoxylin eosin (HE) for histological examination or subjected to immunohistological staining to detect SARS-CoV-2 antigen (performed in an autostainer; Agilent), using the horseradish peroxidase (HRP) method and rabbit anti-SARS-CoV nucleocapsid protein (Rockland) as previously described [24,30].…”

“…These data present a solid basis for further evaluation of the potential utility of combined polymerase and exonuclease inhibition in vivo. Syrian golden hamsters are a well-established model of SARS-CoV-2 respiratory infection [19], which has been proven useful for the investigation of chemoprophylactic agents in SARS-CoV-2 transmission studies [20][21][22][23][24]. Intranasal administration deployed in a transmission model offers the opportunity to maximise drug concentrations at the site and time of infection, thereby minimising the bar for demonstrating in vivo antiviral potential.…”