Lessons learned from animal models of COVID-19

Ravi Mahalingam PhD Department of Neurology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado 80045, USA

Abstract

COVID-19 is a scary household term due to the continuing devastation. Management efforts include active testing, contact tracing and social distancing. There are at least 10 times more people infected than confirmed by testing. Asymptomatic virus shedding continues to be an unnerving experience around the world. Development and establishment of an animal model for studying SARS-CoV-2, the causative agent for COVID-19, is essential. The criteria for a good animal model includes the ability to reproduce the clinical features such as route of infection, severity of disease, levels of mortality, distribution of virus receptors, correlation of virus titers to severity of disease, availability of immunological reagents, demographics of infection and ability to study large numbers. Several laboratories have used mice, hamsters, ferrets and non-human primates towards this goal. Multiple clinical features of COVID -19 seen in humans that need to be addressed include asymptomatic infection, contact and air transmission, respiratory tract infection, inflammation in lung, multi organ disease, loss in sense of smell, age-related outcome, reinfection, generation of neutralizing antibodies, passive transfer of convalescent plasma, virus in stools and vaccine studies. Establishment of a single animal model that can address all these disease outcomes has been a challenge. Because of Ace-receptor incompatibility, transgenics have replaced direct mouse models. Hamsters, ferrets, cats and primates are the only susceptible models likely driven by similarity to human Ace receptors. Pigs, chickens and ducks have been shown to be not permissive for COVID-19. Contact and air transmission with minimal clinical symptoms have been demonstrated in ferrets and cats. While asymptomatic infection was found in cats, kittens were affected more than older cats. Outcomes of COVID-19 infection in non-human primates varied in different species. Experimentally infected Cynomologous macaques did not show clinical symptoms but shed virus in respiratory track and did not display age-related severity. Rhesus macaques, infected with COVID-19, showed respiratory track (pneumonia) and gastric infection and rectal shedding of virus. Presymptomatic and asymptomatic shedding has also been demonstrated using these model and neutralizing antibodies were seen more than one month after infection. Rechallenge of infected rhesus macaques resulted in immunologic control but protection was not sterilizing. RNA-based vaccine has also been shown to induce neutralizing antibodies and vaccination provided protection from pathological damage to the lungs after COVID-19 infection in rhesus macaques. Adenovirus-based vaccine has also been shown, in rhesus macaques, to offer protection as well as age-related effect on the disease. Recently, SARS-CoV2 subunit vaccine has been shown to elicit humoral and cell-mediated immune response in baboons. Taken together, since the first identification of COVID in Dec 2019, several animal models have been developed and a few of them have been extended to be able to test vaccine candidates.