Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets

Abstract

Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients. IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.

Rapidin vitroassays for screening neutralizing antibodies and antivirals against SARS-CoV-2

“…Due to the high impact of COVID-19 and the lack of commercially available vaccines and/or NAbs, many United States (US) Food and Drug Administration (FDA)-approved or repurposed drugs are currently being suggested for the treatment of clinicallyinfected COVID-19 patients (Elfiky, 2020;Park et al, 2020b;Xu et al, 2020). As scientist and clinicians race to identify drugs for the treatment of SARS-CoV-2 infection and associated COVID-19 disease, some have been used in clinical settings with no supporting evidence of antiviral activity against SARS-CoV-2 (Reihani et al, 2020).…”

A Novel Neutralizing Antibody Targeting Receptor Binding Domain of SARS-CoV-2

“…Because no animal models are available that accurately re ect clinical symptoms (e.g. lung damage) of patients with severe COVID-19 [25][26][27][28][29] , ferrets, Syrian hamsters and rhesus monkeys have been used together for evaluation of SARS-COV-2 pathogenesis/transmission and to assess the e cacy of therapeutics and vaccines against COVID-19 [30][31][32][33] . In vivo challenge studies using these models has demonstrated that CT-P59 is capable of quickly decreasing virus titres, particularly improving clinical symptoms and pathological changes in ferrets.…”

Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak

“…Initially, CQ and HCQ were considered for their therapeutic potential due to previous reports on their strong anti-SARS-CoV activity in vitro after the 2003 coronavirus outbreak [94]. Other derivatives of CQ, such as HCQ sulphate have been reported to reduce inflammation in autoimmune diseases [95]. Such information ignited interest in the potential of CQ and HCQ to treat COVID-19 ill patients.…”