Development of Medical Countermeasures to Middle East Respiratory Syndrome Coronavirus

Timothy M. Uyeki; Karl J. Erlandson; George Korch; Michael O'Hara; Michael Wathen; Jean Hu-Primmer; Sally Hojvat; Erik J. Stemmy; Armen Donabedian

Disclosures

Emerging Infectious Diseases. 2016;22(7):e1-e11. 

In This Article

Animal Models and Virus Strains

Preclinical development of MERS-CoV medical countermeasures has been hindered by several factors, including limited data on the natural history of MERS-CoV infection in humans; the lack of a small animal model that is naturally susceptible to MERS-CoV; and the inability to consistently replicate severe human disease in MERS-CoV–infected nonhuman primates (NHPs). Another factor is limited access to clinical samples and recent virus isolates; for example, a MERS-CoV strain isolated from a patient in 2012, rather than a more recently isolated strain, is currently used by most investigators worldwide.

Small animal and NHP models are useful for testing potential medical countermeasures for efficacy (Table 1). Studies in mice, both dipeptidyl peptidase-4 (DDP-4 or cluster differentiation 26) transduced and transgenic, and in rabbits, hamsters, and ferrets have been reviewed elsewhere.[16,20,21] These small animal models have been used for screening potential MERS-CoV medical countermeasures.[13,14,22]

The major NHP models under development include rhesus macaques and common marmosets.[17,18,23] Overall, common marmosets appear to be better suited than rhesus macaques for therapeutic studies designed to target severe disease because marmosets show slightly slower onset of illness and longer duration and severity of disease and their small size requires lower doses of therapeutic drugs. However, the marmoset model has not been standardized and is not consistent between laboratories.[18,24,25] Furthermore, the size of marmosets substantially limits sequential blood sampling for virologic or pharmacokinetic testing. Challenges to the development of NHP models include determination and standardization of the optimal MERS-CoV challenge dose and of the volume and route of exposure, as well as the limited availability of NHPs, especially marmosets.

Large animal models in development include camels and camelids such as alpacas.[19,26,27] These models may be vital in understanding the virology and immunology of MERS-CoV infection in dromedaries, a natural host. In addition, serologic evidence of MERS-CoV infection in alpacas has been reported in Qatar.[28] Major gaps for all animal models include a lack of consensus and availability of the optimal animal model to replicate severe human illness from MERS-CoV infection; limited availability of currently or recently circulating MERS-CoV strains; the lack of understanding of clinically relevant symptoms that can be incorporated into clinical scores or used as a signal to begin treatment in animal models; and competition for funding, laboratory space, availability of animals, and expertise with other emerging or reemerging infectious diseases, such as Ebola virus disease and Zika virus disease.

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