COVID-19 Animal Models—Non-human Primates

COVID-19, caused by the SARS-CoV-2 virus, is the most severe epidemic of the twentieth century. Since the outbreak in late 2019, animal models have been crucial in assisting in the rapid development of preventive and therapeutic vaccines/drugs, as well as understanding the pathogenesis of SARS-CoV-2 infection and the host immune response. Non-human primates (NHPs), transgenic mice, wild-type mice sensitized with Ad5 or AAV vectors expressing the hACE2 gene, and Syrian hamster, ferret, poultry, and domestic animal models have all been used in the studies on COVID-19.

In terms of physiological characteristics and immune regulation, NHPs and humans are strikingly similar. Rhesus monkeys (Macaca mulatta), Cynomolgus monkeys (Macaca fascicularis), African green monkeys (Chlorocebus sabaeus), baboons (Papio hamadryas), and common velvet monkeys (Callithrix jacchus) have been used as models for SARS-CoV-2 infection, with the former two as the most common choices.

Rhesus monkeys, like humans, exhibit mild clinical signs and high levels of respiratory viral replication. Common symptoms include mild fever, weight loss, decreased appetite, and hypoxia. Weakness, thrombocytopenia, transient neutropenia, and lymphopenia have been reported on rare occasions. Rhesus monkeys have pulmonary discoloration, congestion, vitreous turbidity, exudation, hemorrhage, scarring, necrosis, and interstitial pneumonia, which are all histopathologically similar to patients. Although the rhesus monkey model best generalizes human symptoms, the lack of some typical clinical signs, such as acute respiratory distress syndrome, has limited its use in COVID-19 studies.

Clinical signs in cynomolgus monkeys are limited to mild fever and weight loss, as well as elevated levels of nasal fluid and liver-associated enzymes in cases of SARS-CoV-2 infection via transnasal or intratracheal routes. In cynomolgus monkeys' lungs, solid histopathologic lesions are common. Diffuse alveolar damage (DAD) is another pathological change seen in patients with COVID-19 and in this animal model. Damage to the liver and spleen, in addition to the respiratory system, was observed in Cynomolgus monkeys. High levels of viral RNA were detected in the respiratory tracts of the attacked Cynomolgus monkeys, as in rhesus monkeys.

Several clinical signs, including fever, decreased appetite, hypercapnia, lymphopenia and thrombocytopenia, elevated liver-related enzymes, and increased monocyte counts, have also been observed in African green monkeys, particularly acute respiratory distress syndrome ARDS, a common and often fatal symptom of severe COVID-19, which can be observed in older African green monkeys that are particularly excellent models for the manifestations of severe diseases. African green monkeys have more severe lobar solidity and edema than rhesus monkeys.

Baboons exhibited more severe histopathological damage, longer viral RNA shedding, more significant lung inflammation, and age-related effects compared to cynomolgus monkeys and rhesus monkeys. In contrast, the common velvet monkey inoculated with SARS-CoV-2 reported only very mild clinical signs (mild fever). It is considered to be less susceptible to COVID-19.

Because they are readily available commercially and exhibit clear clinical signs, rhesus monkeys are the most widely used NHP for COVID-19 studies. Although they typically have weak clinical signs, cynomolgus monkeys typically have solid lung lesions. African green monkeys, on the other hand, typically display severe symptoms, but their scarcity severely restricts their use.

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