Table 1.

Opportunities and limitations of current SARS-CoV and SARS-CoV-2 model systems

Model system	Opportunities	Limitations
Rhesus macaque	NHPs share human anatomy, physiology and immune system; SARS-CoV-2 infects rhesus macaques and replicates in the respiratory tract155,156; SARS-CoV replicates in rhesus and cynomolgus macaques and AGM157; infection results in pulmonary infiltrates and a shedding pattern similar to mild-to-moderate human infections156; viral RNA widespread in the trachea, bronchus tract and lungs155,156; neutralizing antibodies similar to human COVID-19 patients156; relevant model for testing SARS-CoV-2 drugs or vaccines	Limited availability and handling, major costs, variation among individuals; limited statistical power because of small sample sizes; only mild-to-moderate clinical manifestations and not representative of severe human cases156
AGM	AGM support high levels of SARS-CoV-2 replication and develop substantial respiratory disease compared with other NHP models158, acute inflammatory reactions, increased body temperature, systemic responses, pronounced viral pneumonia and abnormalities in the small intestine without gastrointestinal distress, similar to humans	Limitations for NHP studies apply; only mild-to-moderate clinical manifestations and not representative of severe human cases158
Mouse	Critical for drug and vaccine development; human ACE2 transgenic mice display weight loss and virus replication in lungs upon SARS-CoV and SARS-CoV-2 infection; representative symptoms of mild viral pathogenicity159,160	Limited SARS-CoV-2 binding to mouse ACE2; transgenic ACE2 mice not yet readily available; human ACE2 transgenic mice show extra-pulmonary organ damage upon SARS-CoV infection (not observed in human SARS patients)161
Ferret	Commonly used to study human respiratory viruses; replication of SARS-CoV-2 in upper respiratory tract, elevated body temperature162,163; stable ferret-to-ferret transmission upon direct contact and aerosols, recapitulating human-to-human transmission163; FDA-approved drug (lopinavir-ritonavir, hydroxychloroquine sulfate and emtricitabine-tenofovir) application in ferrets reduced overall clinical scores and shortened viral shedding (emtricitabine-tenofovir treatment)164; replication of SARS-CoV in upper and lower respiratory tract165	Wide human clinical spectrum not recapitulated; no severe disease or death162
Syrian golden hamster	Efficient viral replication in the nasal mucosa and lower respiratory epithelium with higher titres in the upper respiratory tract166; effective transmission upon direct contact and via aerosols166; recovery and induction of neutralizing antibodies166; passive immunization reduces viral loads, yet no clinical improvements166; histopathological resemblance of human upper and lower respiratory tract infections167; IFNγ response and expression of inflammatory cytokines, coherent with severe human COVID-19 cases167	Only recapitulate mild human COVID-19
Organoid	Complex 3D structure composed by various cell types, designed to recapitulate the structure of the respective organ; readily available alternative when in vivo models are not available (for example, robust SARS-CoV-2 replication in Rhinolophus sinicus enteroids enables studies with respect to virus origin, and facilitates the isolation of bat severe acute respiratory syndrome-related coronaviruses168); human gastroenteric symptoms mimicked by active replication of SARS-CoV-2 in intestinal organoids; SARS-CoV-2 replication in human capillary organoids and kidney organoids169,170; (personalized) immunomodulatory or antiviral drug screening possible; SARS-CoV-2 replication in human lung organoids with similar innate immune response pattern compared to human COVID-19 infections; organoid co-culture models with various immune cells possible	Physical forces and extracellular matrix component interactions, an important parameter in regulating cellular behaviour, are neglected; less suitable to study clinical disease, systemic pathologies and vaccine development
Primary epithelial cell culture	Readily available to study SARS-CoV-2 replication and tropism or to conduct virus isolation; the 3D culture system mimics their tissue of origin, containing various characteristic cell types, competent of innate immune response171; versatile in vitro model recapitulates in vivo conditions; genetically modifiable	The establishment of airway epithelial cell cultures is time consuming compared with 2D cell culture systems; experimental studies in animal models are necessary to confirm specific findings in an in vivo background
Infectious clone	Genetic modifications of viral genomes enable functional characterizations; insertion of reporter genes into the viral genome and creation of deletion mutants possible; synthetic clones obtained by reverse genetic approaches do not rely on primary patient material availability83; provide a major opportunity to characterize SARS-CoV-2 (refs83,172,173)	The usage of other animal or culture models is necessary for infection studies
Mouse-adapted SARS-CoV-2	Mouse-adapted SARS-CoV strains, developed by serial passages of SARS-CoV in the mouse respiratory tract; pathological impact in mice similar to SARS in humans174,175; a recombinant SARS-CoV-2 mouse-adapted strain with a remodelled spike for mouse ACE2 utilization replicates in the upper and lower airways of mice159; possibility for selection towards strains causing more severe pathologies and other outcomes observed in human COVID-19 (ref.159); synthetic reverse genetic approaches provide another opportunity for the rapid construction of mouse-adapted SARS-CoV-2 strains for infection of wild-type mice	Mutations in the receptor-binding domain, which enable mouse ACE2 binding, might impair the function of selected human monoclonal antibodies or vaccines159; mutations in the receptor-binding domain might attenuate the function of selected human monoclonal antibodies or vaccines159

ACE2, angiotensin-converting enzyme 2; AGM, African green monkeys; NHP, non-human primates; SARS-CoV, severe acute respiratory syndrome coronavirus.