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. 2019 Aug 2;10:1781. doi: 10.3389/fmicb.2019.01781

TABLE 1.

Animal models used for vaccine development against Middle East respiratory syndrome-coronavirus.

Animal models Results Advantages/Limitations References
Rhesus macaques The animals manifested clinical signs within 24 h following infection, including increase in respiratory rate and body temperature, hunched posture, piloerection, cough, reduced food intake and varying degree of pneumonia. No mortality was observed in the infected animals throughout the study. The increase in white blood cell counts was early and transient, and viral-load was reported to be higher in lower respiratory tract and decreased overtime. Munster et al., 2013
Rhesus macaques The animals experienced early increase in neutrophil at day-1 post-infection (P.I.), and restored at day-3 P.I. Development of pneumonia in the animals was rapid after the infection but short-lived. No mortality or virus dissemination to other non-respiratory tissue was observed in the infected animals. Infection is restricted primarily at lower respiratory tract. –Genetically closer to human
–Do not recapitulate severe diseases in human
–Expensive model due to high husbandry requirement
de Wit et al., 2013
Rhesus macaques The rectal temperature of the animals increased at 1 to 2 days P.I. and restored thereafter. Extensive lung lesions and varying degree of inflammation were observed in the lungs of the animals collected at day-3 P.I. Other pathological changes of the infected lungs include interstitial pneumonia, pulmonary edema, hemorrhaging, degeneration and necrosis of pneumocytes and bronchial epithelial cells. No sign of damage in other non-respiratory organs was observed. Yu et al., 2017
Immunosuppressed rhesus macaques The immunosuppressed animals developed rapid pneumonia but less severe than the non-immunosuppressed monkey. Higher viral load, viral shedding, and virus dissemination to other non-respiratory organs were observed in the immunosuppressed animals following infection. –Potential model for mimicking MERS-CoV infection in immunocompromised patients
–Expensive model due to high husbandry requirement
–Additional treatment is required to produce immunosuppressed animals
Prescott et al., 2018
Common marmosets Most of the infected animals developed progressive severe pneumonia characterized by interstitial infiltration. Some animals were euthanized because of diseases severity. Extensive lung lesions were observed in all the infected animals at different necropsies time points. Viral RNA could be detected in blood, respiratory organs and other non-respiratory organs including kidney, suggesting virus dissemination. –Severe, partially lethal animal model
–Able to manifest renal damage
–Expensive model due to high husbandry requirement
Falzarano et al., 2014
Common marmosets Infected animals developed severe pneumonia at day-3 P.I. characterized by exudative pathological changes with widespread pulmonary edema, hemorrhaging, and huge number of inflammatory cells. Yu et al., 2017
Common marmosets In vitro analysis using lung and kidney cells showed that hyperexpression of Smad7 or FGF2 induced by MERS-CoV led to an immense apoptotic response. Common marmosets infected with MERS-CoV demonstrated acute respiratory distress and disseminated infection in kidneys and other organs. Yeung et al., 2016
Dromedary camels The animals infected experimentally with MERS-CoV developed mild symptoms such as increase in body temperature and rhinorrhea. Symptoms of the infected animals lasted less than 2 weeks. Shedding of infectious virus was detected in less than 7 days P.I. but viral RNA remained detectable up to 35 days P.I. in the nasal swabs. Viral RNA, but not infectious virus, was detected in the exhaled breath of the infected animals at day-3 and -5 P.I. The Infection was restricted to upper-respiratory tract. –Potential model for pathogenesis studies of MERS-CoV and transmission to human
–Do not recapitulate severe diseases in human
–Expensive model due to high husbandry requirement
Adney et al., 2014
hDPP4-transduced mice Mice transduced with adenoviral vector to express hDPP4 in lungs were susceptible to MERS-CoV infection. Following the infection, mice developed interstitial pneumonia in addition to reduced weight gain in young mice and weight loss in aged mice. No mortality was observed in all infected animals, and virus clearance was detected at day-6 to -8 P.I. Expression of hDPP4 in the animals’ lungs lasted for 17 to 22 days after transduction. –Ease of manipulation
–Low husbandry requirement
–Readily available methods in testing vaccine efficacy
–Do not recapitulate severe diseases in human
Zhao et al., 2014
Transgenic mice expressing hDPP4 globally Following the infection, the transgenic animals developed severe pneumonia, and 100% mortality was detected at day-6 P.I. Virus dissemination to other non-respiratory organs was detected with significantly high viral RNA in the brains and lungs. No viral RNA could be detected in the kidney or the liver of the infected mice. –Lethal animal model
–Ease of manipulation
–Low husbandry requirement
–Readily available methods in testing vaccine efficacy
–Lack physiological expression pattern because all mouse cells express hDPP4
Agrawal et al., 2015
hDPP4-humanized transgenic mice Humanized mice can be infected with MERS-CoV but do not demonstrate clinical sign of diseases. Pathological changes including peri-bronchiolar inflammation, interstitial infiltration, and minimal peri-vascular inflammation were observed at 2 to 4 days P.I. Viral RNA was detected in the lungs, and no virus dissemination to other organs was observed –Ease of manipulation
–Low husbandry requirement
–Readily available methods in testing vaccine efficacy
–Correct physiological expression pattern
–Little to no clinical sign
Pascal et al., 2015
CRISPR/Cas9-engineered mice Mice genome was modified to incorporate human codons at amino acid positions 288 and 330 in the mouse DPP4 gene causing them to become susceptible to MERS-CoV infection. The infected mice did not demonstrate any sign of diseases but supported viral replication in the lungs. Inflammation of the infected lungs was moderate. Severe disease could be induced in these mice by infecting them with mouse-adapted MERS-CoV. –Severe, partially lethal animal model (challenged with mouse-adapted MERS-CoV only)
–Ease of manipulation
–Low husbandry requirement
–Readily available methods in testing vaccine efficacy
Cockrell et al., 2016
hDPP4-knockin mice using CRISPR/Cas9 hDPP4-knockin mice were susceptible to MERS-CoV infection. The mice experienced drastic weight loss above the typical euthanization endpoint (20%) by day-5 P.I. Lesions and virus load were detected in the brains and the lungs of the mice but not in the kidneys or livers. –Lethal animal model
–Ease of manipulation
–Low husbandry requirement
–Readily available methods in testing vaccine efficacy
–Lack physiological expression pattern because all mouse cells express hDPP4
Fan et al., 2018

MERS-CoV, Middle East respiratory syndrome-coronavirus; DPP4, dipeptidyl peptidase 4; hDPP4, human dipeptidyl peptidase 4; P.I., post-infection.

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