Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection

Abstract

Following emergence in late 2019, SARS-CoV-2 rapidly became pandemic and is presently responsible for millions of infections and hundreds of thousands of deaths worldwide. There is currently no approved vaccine to halt the spread of SARS-CoV-2 and only very few treatment options are available to manage COVID-19 patients. For development of preclinical countermeasures, reliable and well-characterized small animal disease models will be of paramount importance. Here we show that intranasal inoculation of SARS-CoV-2 into Syrian hamsters consistently caused moderate broncho-interstitial pneumonia, with high viral lung loads and extensive virus shedding, but animals only displayed transient mild disease. We determined the infectious dose 50 to be only five infectious particles, making the Syrian hamster a highly susceptible model for SARS-CoV-2 infection. Neither hamster age nor sex had any impact on the severity of disease or course of infection. Finally, prolonged viral persistence in interleukin 2 receptor gamma chain knockout hamsters revealed susceptibility of SARS-CoV-2 to adaptive immune control. In conclusion, the Syrian hamster is highly susceptible to SARS-CoV-2 making it a very suitable infection model for COVID-19 countermeasure development.

Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model

“…Disease manifestation in Syrian hamsters following SARS-CoV-2 infection is transient with only mild clinical signs 16,17 , and no discernible difference in disease manifestation based on clinical symptoms was observed between any group over the course of the study. Virus shedding was measured with oral swabs collected on day 2 and 4 post-infection.…”

“…Having verified in vitro efficacy and determined the IC50 value of EIDD-1931, we next assessed efficacy of the MK-4432 prodrug in the Syrian hamster model, which is regarded as a preclinical model of mild disease, with animals having self-limiting pneumonia 16,17 . Given the possibility for oral dosing, we were interested in the utility of MK-4432 as a treatment following high-risk exposure.…”

“…Hamsters were infected intranasally with SARS-CoV-2 using a dose of 5x10 2 TCID50 (100 times infectious dose 50; ID50). The ID50 value was determined in a separate study concerned with further refinement of the Syrian hamster SARS-CoV-2 model 17 . Treatment in all groups was continued for 3 consecutive days and hamsters in all groups were euthanized on day 4 post-infection.…”

“…In the present study, we used the established Syrian hamster animal model 16,17 Currently, only a single drug (GS-5734) has been given EUA for treatment of SARS-CoV-2 induced COVID-19 disease 9 . Rather than having an impact on mortality, the EUA was based on a demonstration of reduced recovery time for hospitalized patients with COVID-19 10 .…”

“…In the present study, we determined the half-maximal inhibitory concentration (IC50) value for EIDD-1931 in tissue culture and subsequently assessed the potential of MK-4482 following oral administration to control SARS-CoV-2 in the highly susceptible Syrian hamster model 16,17 . We show that MK-4482, when administered either starting at 12 hours prior to SARS-CoV-2 infection, or even 12 hours post-infection, significantly decreased viral lung loads and pathology, but did not affect shedding from the upper respiratory tract.…”