An overview of preclinical animal models for SARS-CoV-2 pathogenicity

Itti Munshi; Aditya Khandvilkar; Shrinivas M. Chavan; Geetanjali Sachdeva; Smita D. Mahale; Uddhav K. Chaudhari

doi:10.4103/ijmr.IJMR_3215_20

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Review Article

153 (

1-2

); 17-25

doi:

10.4103/ijmr.IJMR_3215_20

An overview of preclinical animal models for SARS-CoV-2 pathogenicity

Itti Munshi¹, Aditya Khandvilkar¹, Shrinivas M. Chavan¹, Geetanjali Sachdeva¹, Smita D. Mahale², Uddhav K. Chaudhari^1,

1Department of Primate Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India

2Department of Structural Biology, ICMR-National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India

For correspondence: Dr Uddhav K. Chaudhari, Division of Primate Biology, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai 400 012, Maharashtra, India e-mail: chaudhariu@nirrh.res.in

Received: 2020-07-27,

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This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of fatalities globally since its origin in November 2019. The SARS-CoV-2 shares 79 and 50 per cent genome similarity with its predecessors, severe SARS-CoV and Middle East respiratory syndrome (MERS) coronavirus, all belonging to the same genus, Betacoronavirus. This relatively new virus has stymied the effective control of COVID-19 pandemic and caused huge social and economic impact worldwide. The FDA-approved drugs were re-purposed to reduce the number of fatalities caused by SARS-CoV-2. However, controversy surrounds about the efficacy of these re-purposed antiviral drugs against SARS-CoV-2. This necessitates the identification of new drug targets for SARS-CoV-2. Hence, the development of pre-clinical animal model is warranted. Such animal models may help us gain better understanding of the pathophysiology of SARS-CoV-2 infection and will be effective tools for the evaluation and licensure of therapeutic strategies against SARS-CoV-2. This review provides a summary of the attempts made till to develop a suitable animal model to understand pathophysiology and effectiveness of therapeutic agents against SARS-CoV-2.

Keywords

Animal models

COVID-19

pathogenesis

preclinical

SARS-CoV-2

therapy

vaccine

Show Related Articles from PubMed

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is an enveloped positive-sense single-stranded RNA virus, belonging to the genus Betacoronavirus1. Though not as big scale as SARS-CoV-2, the members of the same genus, i.e. SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), have caused epidemic in 2002 and 2012, respectively2 3. SARS-CoV-2 shares 79 and 50 per cent genome similarity with SARS-CoV and MERS-CoV, respectively1. Further, SARS-CoV-2 genome shares 96.2 and 87 per cent similarity with genomes of bat coronavirus, bat CoV RatG13 and bat SL CoVZXC21, respectively4 5. Thus, SARS-CoV-2 is believed to have a zoonotic origin1 4 5.

The transmission of COVID-19 occurs through respiratory droplets. Incubation period of COVID-19 lasts for 14 days. However, the median duration for the onset of symptoms after exposure is around 4-5 days6 7. The severity of clinical signs and symptoms of COVID-19 illness varies among patients. Individuals afflicted with COVID-19 may experience fever, chills, dry cough, shortness of breath, fatigue, body pain, headache, loss of smell and taste, sore throat, runny nose, vomiting and diarrhoea over the course of disease8 9 10 11. A few individuals infected with SARS-CoV-2 may remain asymptomatic12 13 14.

Major reason underlying alarming COVID-19 pandemic in a short span is the lack of an effective therapeutic/prophylactic drug against SARS-CoV-2. About 450 COVID-19 therapeutics are in pre-clinical trials15. These include viral, RNA, DNA, protein and nanoparticle-based vaccines as well as re-purposed therapeutics including vasodilator, immune modulator, steroids, anti-inflammatory agents, anti-coagulatory molecules, anti-parasitic and antiviral drugs. Antiviral drugs target viral replication, cellular entry and viral trafficking16. Availability of ideal animal models would help in assessment of the efficacy of vaccines before their entry into the clinical trials. Animal models are also essential to assess the efficacy of drugs in vivo, since in vitro evaluation of drugs may not suffice for clinical use. For instance, hydroxychloroquine showed promising results against COVID-19 in vitro but failed to show any remedial effect in Cynomolgus macaques exposed to SARS-CoV-217.

The U.S. Food and Drug Administration (FDA) approval of any therapeutic agent requires its efficacy to be proven in at least two animal models. An ideal animal model should imitate the clinical symptoms of a disease as observed in humans. Here, we present a comparative report on the replication and transmission capability of SARS-CoV-2 in various animal models.

Non-primate models

Non-primate models popularly utilized for therapeutic screening include rabbits, ferrets, golden Syrian hamsters and mice.

Rabbits

SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE-2) and transmembrane serine protease 2 receptor to enter the cell18. The spike protein receptor binding domain (RBD) of SARS-CoV-2 interacts strongly with rabbit ACE-2 compared with its human homologue hACE-219. Rabbits are susceptible to MERS-CoV infection but show no significant histopathological changes or clinical symptoms. In a recent study, New Zealand white rabbits exposed to SARS-CoV-2 virus at a dose of 106 tissue culture infectious dose 50 (TCID₅₀) showed viral shedding from nose, throat and rectum after 15, 11 and 5 days post-infection (d.p.i.), respectively. The infected rabbits remained asymptomatic throughout the study with severe bronchus-associated lymphoid tissue proliferation and macrophage infiltration in the alveoli20. More studies are needed to explain the absence of symptoms in rabbit and to conclusively determine the utility of rabbit as animal model to study SARS-CoV-2 infection.

Ferrets

Ferrets are susceptible to many human respiratory viruses such as influenza virus, syncytial virus, para influenza virus and coronavirus21 22 23. Ferrets reproduce the clinical symptoms of viral diseases due to the presence of viral receptors and the similarity of their respiratory tract anatomy with that of humans24. ACE-2 is mainly expressed in type II pneumocytes and serous epithelial cells of tracheobronchial sub-mucosal glands in ferrets25. The domain in ferret ACE-2 that binds the spike protein of SARS-CoV-2 differs by only two amino acids from its human homologue domain. Ferrets infected intra-nasally (IN) at 105 TCID₅₀ with SARS-CoV-2 virus, isolated from Korean patients, recapitulated clinical pattern observed in humans26 (Table I). Infected animals exhibited lethargy, cough at 2-6 d.p.i. and elevated body temperature at 2-8 d.p.i. Viral RNA copies were detected from 4 to 8 d.p.i. in nasal and saliva swabs26. In a study conducted by Shi et al32, ferrets were exposed at a dose of 105 plaque-forming units (pfu) with human SARS-CoV-2 isolates and environment isolates from wet market in Wuhan. The ferrets exposed to human SARS-CoV-2 isolates showed an increase in body temperature and loss of appetite at 10 d.p.i., whereas those exposed to environment isolates showed similar symptoms at 12 d.p.i. The viral replication in ferrets exposed to either of these isolates was observed in the nasal turbinate, soft palate and tonsils32. The delay in appearance of overt symptoms of SARS-CoV-2 infection in this study³² compared with the study by Kim et al26 could be due to different viral strains or sub-species of the ferrets used in the study. These investigations revealed that ferrets were susceptible to SARS-CoV-2 infection, and hence, they could be used to screen re-purposed drugs for the efficacy against SARS-CoV-2 infection. The ferrets have been used to screen lopinavir, ritonavir, hydroxychloroquine sulphate and emtricitabine-tenofovir for their efficacy against SARS-CoV-233 (Table II).

Table I Symptoms observed after SARS-CoV-2 infection in humans and various animal models

Animal/Human	Days post infection (d.p.i)	Symptoms	RNA load detected	Reference
Humans	1-5	Cough, chills, fever and shortness of breath	Natural infection	8 9 10 11
	5-10	Diarrhoea, vomiting, sore throat
	10-15	Fatigue, muscle weakness
Ferret	1-5	Elevated body temperatures/loss of activity, cough	3.83 log₁₀ copies/ml on 4-8 d.p.i.	26
	5-10	Seroconversion
	10-15	Mild peri-bronchitis
Hamster	1-10	Weight loss, seropositive/rapid breathing and lethargy/triggered immune response, interstitial inflammation	7 log₁₀ TCID₅₀/g on 2-7 d.p.i.	27
HB-01-hACE2 transgenic mice	1-5	Weight loss/lung lesions/interstitial pneumonia/triggered immune response	10^6.77 copies/ml	28
African Green Monkey	1-5	Triggered immune response/increase in body temperature/loss of appetite	2-4 log pfu/ml on 2 d.p.i.	29
	5-10	Pulmonary lesions/seroconversion/pneumonia/acute systemic inflammation
Cynomolgus macaques	1-5	Lungs infiltrated with neutrophils/pulmonary lesions,	10e² TCID₅₀/ml on 2-4 d.p.i. depending on age	30
	10-15	Seroconversion
Rhesus macaques	1-5	Loss of appetite/neutropenia and lymphopenia/pneumonia/lungs infiltrated with lymphocytes and oedema	7 log₁₀ RNA copies/swab in 2 d.p.i.	31

pfu, plaque-forming units; TCID₅₀, Tissue culture infectious dose 50

Table II Animal model used to exhibit the effectiveness of repurposed drugs against SARS-CoV-2infection

Repurposed drugs	Mechanism of action	Animal model	Reference
Lopinavir/ritonavir	Protease inhibitors	Ferrets	33
Favipiravir	Nucleotide analogue. Inhibits the viral RdRp	Syrian hamsters	34
Remdesivir (GS-5734)	Nucleotide analogue. Inhibits the viral RdRp	Rhesus macaques	35
Hydroxychloroquine	Increasing endosomal pH, immunomodulater, autophagy inhibitors	Cynomolgus macaques, ferrets and Syrian hamsters	33 34 36 37

RdRp, RNA-dependent RNA polymerase

Liu et al38 reported gene signatures of SARS-CoV-2 infection in ferrets for both short-term (three days) and long-term (21 days) infection. The genes involved in the immune response showed higher expression during long-term SARS-CoV-2 infection in ferrets. Further network analysis revealed that metabolic, glucocorticoid and reactive oxygen species-associated genes were enriched in both short- and long-term infection models38. These studies suggest that ferrets are good model to study SARS-CoV-2 disease pathogenesis and potential targets for therapy.

Hamsters

Golden Syrian hamsters are susceptible to SARS-CoV and SARS-CoV-2 infection39,40 but not to MERS-CoV41. Both SARS-CoV and SARS-CoV-2 use ACE-2 to enter the cell. Comparison of hamster ACE-2 to its human homologue shows that 29 amino acid residues are conserved between the human and hamster. The spike protein of SARS-CoV-2 interacts strongly with ACE-2 receptor of hamsters due to the presence of asparagine at 82nd position in the ACE-2 receptor27,42. High-affinity interaction between hamster ACE-2 with SARS-CoV-2 RBD makes lung epithelial cells permissive to the virus.

Syrian hamsters exposed to 1×10^5.5 TCID₅₀ SARS-CoV-2 showed progressive weight loss till six d.p.i, after which animals started gaining weight43. Viral RNA was detected in respiratory tract, kidney and intestine with serum neutralizing antibodies from 3 to 5 d.p.i.43. Chan et al²⁷ challenged golden Syrian hamsters IN with SARS-CoV-2, isolated from a patient in Hong Kong, at a dose of 105 pfu. The hamster tested positive for SARS-CoV-2 on four d.p.i. and lung histopathology showed inflammation with alveolar haemorrhage and necrosis. The signs of lethargy, increased respiratory rate and weight loss were observed 2-4 d.p.i. In addition, infected hamsters exhibited extra-pulmonary manifestations such as myocardial degenerative changes, intestinal mucosal inflammation and lymphoid necrosis, similar to the clinical manifestations such as heart failure, diarrhoea and lymphopaenia seen in humans (Table I). In female hamsters exposed to 2×106 TCID₅₀, viral replication was observed in lungs on one d.p.i. whereas in ileum and stools on 2-3 d.p.i. Clinical symptoms included slight weight loss, bronchopneumonia and peri-bronchial inflammation34. Transmission of SARS-CoV-2 through direct contact was established and faecal-oral route was debunked34. Young and mature hamster model exposed to a dose of 10^5.6 pfu through IN and ocular routes developed pneumonia, pulmonary oedema, alveolar haemorrhage and a dose-dependent change in body weight44. Unlike observations made by Chan et al27, viral titre was similar in lung and nasal turbinate. Administration of convalescent plasma in infected hamsters reduced the viral replication in the respiratory tract44. Further, an aged hamster model has been developed by Osterrieder et al45. Aged hamsters exposed IN to SARS-CoV-2 at a dose of 1×105 pfu presented more weight loss compared to younger hamsters. However, no difference in body temperature was noted between the two groups. Although the viral titres at initial time points were higher in young hamsters, rapid clearance of virus was seen in younger hamsters. Faster recovery was associated with a higher level of neutralizing antibody titres and a higher influx of immune cells in the lungs in aged hamsters45.

The passive immunization of hamsters on one d.p.i. with convalescent serum, from SARS-CoV-2 infected hamsters, resulted in reduced viral load27. This suggests that hamsters recapitulate clinical symptoms of human COVID-19 and can be useful for research on convalescent plasma therapy27. Syrian hamsters have also been employed as an infection model to test favipiravir and hydroxychloroquine against SARS-CoV-234 (Table II).

Transgenic mice

Wild mice are not susceptible to SARS-CoV-2. The Asn31 and Ser82 amino acids in mice ACE-2 prevent the interaction of ACE-2 with spike protein RBD due to electrostatic or hydrophilic repulsion. Due to the presence of ACE-2, His353 in mice cannot form salt bridge with RBD. This poor interaction between mice ACE-2 and SARS-CoV-2 makes wild-type mice an unsuitable model46.

However, genetic manipulation in standard inbred mouse strains (C57BL6, BALB/c or 129S) to express human receptor ACE-2 and DPP4 has been used as an alternate strategy to develop SARS-CoV-2 permissive mouse model47. Transgenic mice strain HB-01–expressing hACE2 receptor developed by Bao et al28 showed high susceptibility to IN inoculation of SARS-CoV-2 at a dosage of 105 TCID₅₀. These mice showed marked weight loss, virus replication, infiltration of lymphocytes and monocytes in alveolar interstitium and accumulation of macrophages in alveolar cavities at 3-5 d.p.i.28. Similarly, another transgenic mouse (HFH4-hACE2 mice) expressing the human ACE-2 protein created by Jiang et al48 developed interstitial pneumonia upon IN inoculation of 3×104 TCID₅₀ virus. The lung lesions were similar to the lesions observed in COVID-19–infected humans. The tissue tropism of SARS-CoV-2 infection and viral quantification revealed lungs as the major site of infection. SARS-CoV-2 viral RNA was also detected in the eye, heart and brain in some infected mice48. Another transgenic mice developed using adenovirus vector also successfully imitated the manifestations of SARS-CoV-2 infection49. Sun et al50 utilized CRISPR/Cas9 knock in technology to express hACE2 receptor in C57BL6 mice. Aged hACE2-expressing mice lost 10 per cent body weight, while no symptoms were observed in young mice after inoculation with 4×105 pfu SARS-CoV-2 infection. Viral replication was observed in lung, trachea and brain tissue (~7-8 log₁₀ RNA copies/g). Infection via intragastric route was also established in these mice50. Thus, transgenic mice can be useful tool to study the pathophysiology of the SARS-CoV-2 infection.

Primate models

Non-human primates (NHPs) models are phylogenetically closest to humans, with 93.54 per cent genome similarity51. Akin to humans, NHPs models also tested positive after exposure to the SARS-CoV-2 and showed clinical symptoms such as mild-to-severe pneumonia, elevated body temperature, viral shedding, chest radiographic abnormality, inflammation and immune cell infiltration within lungs51 52 53.

Despite significant homology in ACE-2 receptors between human and NHPs, differences were observed in the viral latency and clinical features of COVID-19. These differences could be attributed to subtle immunological variations and expression levels of ACE-2 between the two species. NHP models are believed to be more approximate to human in terms of recapitulating human SARS-CoV-2 infection.

Some of the COVID-19–associated conditions such as effects of SARS-CoV-2 in aged individuals can be studied using NHPs. Yu et al54 developed an aged NHPs infected with SARS-CoV-2. Old NHPs developed more severe interstitial pneumonia compared with young monkeys. Such models can provide insight into the various causes of high mortality in aged individuals54.

African Green monkey (Chlorocebuss abaeus) challenged with viral isolates, obtained from Italy, through intratracheal (IT) and IN routes showed elevated body temperature and acute systemic inflammation on two d.p.i. and multifocal pulmonary lesions on five d.p.i. Viral RNA was detected in the mucosal swabs and bronchoalveolar lavage (BAL) fluid²⁹ (Table I). In another study, cynomolgus macaques (Macaca fascicularis) were inoculated with SARS-CoV-2 isolates, through IT and IN routes30. The Cynomolgus macaques were susceptible to infection without any overt clinical symptoms. However, viral shedding and replication were observed in respiratory tract, ileum, colon and tonsil. All these macaques inoculated with SARS-CoV-2 showed seropositivity and lung lesions on 14 d.p.i. Viral RNA was detected in nasal swabs with the highest titre in older macaques on four d.p.i³⁰ (Table I). Chandrashekar et al31, inoculated rhesus macaques (Macacamulatta) with SARS-CoV-2 through IN and IT routes at a dose of 104 pfu. The viral RNA was detected on two d.p.i. and symptoms such as loss of appetite and interstitial pneumonia were observed. These macaques were also protected from re-infection with SARS-CoV-2 after 35 d.p.i. indicating neutralizing antibodies generated in the primary infection, could protect macaques against secondary infection31 (Table I). These findings were replicated by Shan et al53 where rhesus macaques infected with SARS-CoV-2 developed pneumonia, and the virus could be detected in the respiratory tract tissues including trachea, bronchus and lungs. The symptoms exhibited by rhesus macaque were similar to those of mild cases of COVID-19 in humans. In addition, the infected rhesus macaques were protected from re-infection53. Rhesus macaques that are protected from re-infection of SARS-CoV-2 is further substantiated by a study, conducted by Deng et al55.

Among the new world monkeys, marmosets have been used to study the viral infection. However, compared with marmosets, old world monkeys seem to be a better animal model as reported in the comparative study conducted by Lu et al51. Rhesus macaques, Cynomolgus macaques and marmosets were exposed to SARS-CoV-2 with 106 pfu dose. Among the three, the old-world monkeys were reported to support viral replication with clinical symptoms similar to humans. Clinical manifestations of viral infection included a rise in body temperature, abnormal computed tomography scans, lymphopaenia, esoinopenia, inflammation in liver and heart, viral shedding. Moreover, viral RNA copies were detected in nasal and oral swabs in old world monkeys51.

In addition to investigating viral pathogenesis, some drugs have been tested for their efficacy against coronaviruses in NHPs. Remdesivir and lopinavir/ritonavir have been tested against SARS-CoV and MERS-CoV in the marmoset model, respectively56.

A DNA vaccine candidate expressing various spike protein immunogens has been tested on rhesus macaques57. The vaccine protected against SARS-CoV-2 as evident by substantial reductions in viral loads in BAL and nasal swabs, in immunized animals⁵⁷ (Table III). An intramuscular dose of ChAdOx1 nCoV-19 (adenovirus vector) vaccine candidate in rhesus macaques protected against the challenge from SARS-CoV-2 in both upper and lower respiratory tract. Vaccination resulted in the absence of any lesion from pneumonia and the absence of viral RNA in the lung tissue58. The utility of NHPs in testing of vaccine is further corroborated by a study conducted by Yadav et al59, which tested three different whole virion-inactivated vaccines including BBV152 vaccine, in rhesus macaques. In the study59, 20 macaques were divided into four groups consisting of five each. One group received placebo while other three groups were vaccinated with three different vaccine using two-dose vaccine regimen. All the macaques were challenged with SARS-CoV-2 14 days after the administration of second dose of the vaccine. Three weeks after immunization, significantly increased levels of neutralizing antibody (IgG) titre were detected from the vaccinated group. Histopathological examination revealed the absence of pneumonia in vaccinated group compared with placebo group which exhibited interstitial pneumonia, presence of antigen in alveolar epithelium and macrophages59.Similarly, other vaccine candidates such as RNA vaccine and inactivated vaccine (Table III) have been tested on rhesus macaques to understand the vaccine-mediated immune response and to evaluate the efficacy of vaccine60 62.

Table III Animal model used to exhibit the effectiveness of vaccines against SARS-CoV-2 infection

Vaccine type	Design strategy	Animal model	Reference
DNA vaccine	Full length and truncated forms of SARS-CoV-2 Spike gene	Rhesus macaques	58
Vector (ChAdOx1 nCoV-19)	Adenovirus vector expressing SARS-CoV-2 Spike protein	Rhesus macaques and mice	59
Inactivated virus	Undisclosed	Rhesus macaques	60
RNA vaccine	SARS-CoV-2 S gene mRNA encapsulated in nanoparticle	Rhesus macaques and mice	61 62
Inactivated virus	Inactivation of virus using β-propiolactone	Rhesus macaques, mice and rats	63
DNA vaccine (INO-4800)	Construct with SARS-CoV-2 S gene	Mice and guinea pigs	64

Conclusion

Although the clinical presentations of COVID-19 are now being better understood, the pathophysiology and long-term sequelae of disease are yet to be completely known in humans. Animal models could play an important role in bridging gap between SARS-CoV-2 infection and disease progression of COVID-19. Significant progress has been made in the development of small and large animal models for understanding pathogenesis of SARS-CoV-2 infection. NHPs are phylogenetically closest to humans and show natural susceptibility to SARS-CoV-2 infection. The comparable susceptibility has been attributed to homologue hACE2 receptor present in NHPs. However, the severity of COVID-19 progression and the development of symptoms in the NHPs are relatively milder as compared to severe cytokine storm and fatality seen in humans. Limited numbers of NHPs have been used to develop comorbid and aged model mimicking the human conditions; however, NHPs pose substantial limitations on their use in high-throughput studies involving large number of animals.

Genetically engineered transgenic mice expressing hACE-2 receptor are permissive to SARS-CoV-2 infection and can recapitulate the clinical features of COVID-19 including lung histology, pulmonary inflammation and pneumonia. The limitations with transgenic mice are aberrant expression of receptor on all cells types which may change tissue or cellular tropism of virus. Golden Syrian hamsters have also exhibited symptoms as seen humans such as weight loss, viral replication in the upper respiratory tract and presence of antibody in the plasma. However, caveat with hamster model is limited availability of research reagents compared with mice.

Animal models can be utilized to identify novel targets, host cell-virus interactions, to study immunological response at different stages of the disease and to invent antiviral drugs or vaccines against SARS-CoV-2. However, continuous refinement is needed to develop suitable animal model recapitulating COVID-19 pathogenesis and its sequelae in human.

Acknowledgment:

The first author (IM) acknowledges the Lady Tata Memorial Trust for fellowship. The second author (AK) acknowledges the Council of Scientific and Industrial Research, New Delhi, for fellowship. The third author (SMC) thanks Science and Engineering Research Board for providing fellowship.

Financial support & sponsorship: Authors acknowledge the Indian Council of Medical Research, Department of Health Research, Government of India, for financial support.

Conflicts of Interest: None.

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[Google Scholar]
Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, . Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020;585:273-6.
[Google Scholar]
Maisonnasse P, Guedj J, Contreras V, Behillil S, Solas C, Marlin R, . Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non-Human primates. Nature. 2020;585:584-7.
[Google Scholar]
Rosenke K, Jarvis M, Feldmann F, Schwarz B, Okumura A, Lovaglio J, . Hydroxychloroquine proves ineffective in hamsters and macaques infected with SARS-CoV-2. JCI Insight. 2020;5:e143174.
[Google Scholar]
Liu HL, Yeh IJ, Phan NN, Wu YH, Yen MC, Hung JH, . Gene signatures of SARS-CoV/SARS-CoV-2-infected ferret lungs in short- and long-term models. Infect Genet Evol. 2020;85:104438.
[Google Scholar]
Roberts A, Lamirande EW, Vogel L, Jackson JP, Paddock CD, Guarner J, . Animal models and vaccines for SARS-CoV infection. Virus Res. 2008;133:20-32.
[Google Scholar]
Lamirande EW, DeDiego ML, Roberts A, Jackson JP, Alvarez E, Sheahan T, . A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden syrian hamsters. J Virol. 2008;82:7721-4.
[Google Scholar]
de Wit E, Prescott J, Baseler L, Bushmaker T, Thomas T, Lackemeyer MG, . The Middle East respiratory syndrome coronavirus (MERS-CoV) does not replicate in syrian hamsters. PLoS One. 2013;8:3-8.
[Google Scholar]
Luan J, Lu Y, Jin X, Zhang L, . Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. Biochem Biophys Res Commun. 2020;526:165-9.
[Google Scholar]
Mohandas S, Jain R, Yadav P, Shete-Aich A, Sarkale P, Kadam M, . Evaluation of the susceptibility of mice & hamsters to SARS-CoV-2 infection. Indian J Med Res. 2020;151:479-82.
[Google Scholar]
Imai M, Iwatsuki-Horimoto K, Hatta M, Loeber S, Halfmann PJ, Nakajima N, . Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc Natl Acad Sci U S A. 2020;117:16587-95.
[Google Scholar]
Osterrieder N, Bertzbach LD, Dietert K, Abdelgawad A, Vladimirova D, Kunec D, . Age-dependent progression of SARS-CoV-2 infection in syrian hamsters. Viruses. 2020;12:779.
[Google Scholar]
Wan Y, Shang J, Graham R, Baric RS, Li F, . Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94:1-9.
[Google Scholar]
Sun J, Zhuang Z, Zheng J, Li K, Wong RLY, Liu D, . Generation of a broadly useful model for COVID-19 pathogenesis, vaccination, and treatment. Cell. 2020;182:734-43.e5.
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Jiang RD, Liu MQ, Chen Y, Shan C, Zhou YW, Shen XR, . Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensin-converting enzyme 2. Cell. 2020;182:50-8.e8.
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Hassan AO, Case JB, Winkler ES, Thackray LB, Kafai NM, Bailey AL, . A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies. Cell. 2020;182:744-53.e4.
[Google Scholar]
Sun SH, Chen Q, Gu HJ, Yang G, Wang YX, Huang XY, . A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe. 2020;28:124-33.e4.
[Google Scholar]
Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER, . Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007;316:222-34.
[Google Scholar]
Lu S, Zhao Y, Yu W, Yang Y, Gao J, Wang J, . Comparison of SARS-CoV-2 infections among 3 species of non-human primates. Signal Transduct Target Ther. 2020;5:157.
[Google Scholar]
Munster VJ, Feldmann F, Williamson BN, van Doremalen N, Pérez-Pérez L, Schulz J, . Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature. 2020;585:268-72.
[Google Scholar]
Shan C, Yao YF, Yang X Lou, Zhou YW, Gao G, Peng Y, . Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques. Cell Res. 2020;30:670-7.
[Google Scholar]
Yu P, Qi F, Xu Y, Li F, Liu P, Liu J, . Age-related rhesus macaque models of COVID-19. Anim Model Exp Med. 2020;3:93-7.
[Google Scholar]
Deng W, Bao L, Liu J, Xiao C, Liu J, Xue J, . Primary exposure to SARS-CoV-2 protects against reinfection in Rhesus macaques. Science. 2020;369:818-23.
[Google Scholar]
Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, . Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9:eaal3653.
[Google Scholar]
Yu J, Tostanosk LH, Peter L, Mercad NB, McMahan K, Mahrokhia SH, . DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science (80-). 2020;369:806-11.
[Google Scholar]
van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham J, Port J, . ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020;586:578-82.
[Google Scholar]
Yadav P, Kumar S, Patil D, Mohandas S, Shete A, Bhati G, . Remarkable immunogenicity and protective efficacy of BBV152, an inactivated SARS-CoV-2 vaccine in rhesus macaques. Nat Commun. 2021;12:1386.
[Google Scholar]
Callaway E, . Coronavirus vaccine trials have delivered their first results - But their promise is still unclear. Nature. 2020;581:363-4.
[Google Scholar]
McKay PF, Hu K, Blakney AK, Samnuan K, Brown JC, Penn R, . Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat Commun. 2020;11:3523.
[Google Scholar]
Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, . Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020;369:77-81.
[Google Scholar]
Smith TR, Patel A, Ramos S, Elwood D, Zhu X, Yan J, . Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun. 2020;11:2601.
[Google Scholar]

Non-primate models

Primate models

Conclusion

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[40] Lamirande EW, DeDiego ML, Roberts A, Jackson JP, Alvarez E, Sheahan T, . A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden syrian hamsters. J Virol. 2008;82:7721-4.
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[56] Deng W, Bao L, Liu J, Xiao C, Liu J, Xue J, . Primary exposure to SARS-CoV-2 protects against reinfection in Rhesus macaques. Science. 2020;369:818-23.
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[57] Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, . Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9:eaal3653.
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[58] Yu J, Tostanosk LH, Peter L, Mercad NB, McMahan K, Mahrokhia SH, . DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science (80-). 2020;369:806-11.
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[59] van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham J, Port J, . ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020;586:578-82.
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[60] Yadav P, Kumar S, Patil D, Mohandas S, Shete A, Bhati G, . Remarkable immunogenicity and protective efficacy of BBV152, an inactivated SARS-CoV-2 vaccine in rhesus macaques. Nat Commun. 2021;12:1386.
[Google Scholar]

[61] Callaway E, . Coronavirus vaccine trials have delivered their first results - But their promise is still unclear. Nature. 2020;581:363-4.
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[62] McKay PF, Hu K, Blakney AK, Samnuan K, Brown JC, Penn R, . Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat Commun. 2020;11:3523.
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[63] Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, . Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020;369:77-81.
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[64] Smith TR, Patel A, Ramos S, Elwood D, Zhu X, Yan J, . Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun. 2020;11:2601.
[Google Scholar]

An overview of preclinical animal models for SARS-CoV-2 pathogenicity

Abstract

Keywords

Animal models

COVID-19

pathogenesis

preclinical

SARS-CoV-2

therapy

vaccine

Non-primate models

Rabbits

Ferrets

Hamsters

Transgenic mice

Primate models

Conclusion

Acknowledgment:

References

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