Evaluation of intranasal nafamostat or camostat for SARS-CoV-2 chemoprophylaxis in Syrian golden hamsters

Abstract

Successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention implementable alongside vaccination programmes. Camostat and nafamostat are serine protease inhibitors that inhibit SARS-CoV-2 viral entry in vitro but have not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and while camostat is orally available, both drugs have extremely short plasma half-lives. This study sought to determine whether intranasal dosing at 5 mg/kg twice daily was able to prevent airborne transmission of SARS-CoV-2 from infected to uninfected Syrian golden hamsters. SARS-CoV-2 viral RNA was above the limits of quantification in both saline- and camostat-treated hamsters 5 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, intranasal nafamostat-treated hamsters remained RNA negative for the full 7 days of cohabitation. Changes in body weight over the course of the experiment were supportive of a lack of clinical symptomology in nafamostat-treated but not saline- or camostat-treated animals. These data are strongly supportive of the utility of intranasally delivered nafamostat for prevention of SARS-CoV-2 infection and further studies are underway to confirm absence of pulmonary infection and pathological changes.

Lack of antiviral activity of probenecid in Vero E6 cells and Syrian golden hamsters: a need for better understanding of inter-lab differences in preclinical assays

“…During the pandemic, preclinical models of SARS-CoV-2 infection for the assessment of drug candidates have been developed at unprecedented speed and data to either support or refute candidacy of repurposing opportunities has been forthcoming (16)(17)(18)(19)(20). However, cross-validation of preclinical supporting evidence is needed to support a recommendation to progress a drug from preclinical testing to clinical trials.…”

Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case

“…RNA isolation from lung and nasal turbinate samples, RNA quantification, and DNAse treatment has been detailed previously. 25…”

“…Thermal cycling conditions have been detailed previously. 25 The sgE data were normalised to 18S data for subsequent quantitation.…”

“…22 Several studies have also investigated the activity of casirivumab and imdevimab (alone or in combination) against pseudovirus engineered to express the BA.1 Omicron spike protein or authentic virus. [23][24][25] All studies have demonstrated compromised activity of the Ronapreve combination in these assays. However, other studies reported residual activity of the individual antibodies when studied in isolation, albeit with substantially lower activity.…”

SARS‐CoV‐2 in animals: susceptibility of animal species, risk for animal and public health, monitoring, prevention and control

“…A large number of publications are available describing the susceptibility of ferrets and hamsters. In another literature review, performed within the project COVRIN of the One Health European Joint program (Grant agreement 773830), efficient direct contact as well as indirect contact transmission between ferrets and between hamsters was widely reported (de Vries et al, 2021 ; Dowall et al, 2021 ; Kutter et al, 2021 ; Mok et al, 2021 ; Neary et al, 2021 ; Page et al, 2021 ; Patel et al, 2021 ; Peacock et al, 2021 ; Cox et al, 2021a , b ; Kim et al, 2022 ).…”