Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), rapidly triggered a global pandemic associated with 22 million infections and nearly 800,000 deaths to date. Animal models that accurately mimic human COVID-19 are needed to develop effective medical countermeasures against SARS-CoV-2 and to perform studies to elucidate mechanisms of pathogenesis that cannot be done in humans. A recently published report in Virology Journal by my colleagues and I at University of Texas Medical Branch demonstrates that the African green monkey is an accurate model of human COVID-19 and provides new insight into several important aspects of COVID-19.
Modeling COVID-19 in animals
It is logistically impossible to rapidly investigate the safety and efficacy of the hundreds if not thousands of possible vaccines and treatments being developed against COVID-19 in humans. Therefore, there is an urgent need for animal models that can be employed to assess and triage these possible interventions prior to use in humans. Hamsters and ferrets are currently being used as immunocompetent small animal models of COVID-19 while several nonhuman primate (NHP) models have been quickly developed. Historically, for most high consequence pathogens NHPs have served as the models that most accurately reflect human disease. Among the NHP models evaluated the African green monkey appears to best recapitulate the most prominent features of human COVID-19.
Most cases of COVID-19 likely result from inhalation of infectious droplets expelled from close quarter exposure to a sneeze, cough, or even speech.
COVID-19 studies in NHPs to date have used a variety of exposure routes and doses including exposure by contact with the eyes as well as through the mouth, nose and trachea, as well as various combinations of these routes. These are all relevant routes of infection as SARS-CoV-2 can be transmitted by inhalation of droplets or aerosols or by contact with contaminated surfaces and then touching the eyes, nose, or mouth. However, recent studies suggest that airborne transmission is the dominant route for the spread of SARS-CoV-2. A number of techniques have been used to deliver viruses such as SARS-CoV-2 to the respiratory tract of animals including direct instillation of liquid inocula into the nasal cavity or trachea and by exposure to small particle aerosols (< 10 um) generated using highly sophisticated equipment.
However, most cases of COVID-19 likely result from inhalation of infectious droplets expelled from close quarter exposure to a sneeze, cough, or even speech. These droplets or aerosols reflect a variety of sizes up to 100 μm. In order to best model how SARS-CoV-2 is transmitted in most human cases Cross et al. delivered atomized particles that range in size from < 30 μm to 100 μm to the upper respiratory tract of African green monkeys. These atomized particles containing SARS-CoV-2 are consistent with the size of droplets exhaled by humans due to sneezing or coughing thus reproducing a highly realistic mode of human transmission.
COVID-19 in African green monkeys
Exposure of humans to SARS-CoV-2 results in a wide range of outcomes from asymptomatic infection to lethal disease. While SARS-CoV-2 has infected millions of people globally the case fatality rate is very low and likely less than 1%. COVID-19 studies performed in NHPs including African green monkeys suggest that like humans the case fatality rate is very low and animals can show a wide range of clinical signs of disease. In humans the variety of outcomes depends on many factors including age, underlying medical conditions, genetics, and very likely the route and dose of the exposure.
In animal models many of these variables can be experimentally controlled. We used a relatively high dose of SARS-CoV-2 and were able to demonstrate pneumonia and coagulopathy in all African green monkeys during the acute phase of disease showing that this model can be used to study humans that develop respiratory disease.
None of the animals developed lethal infection consistent with most human infections. Importantly, this work was able to assess tissues of the monkeys at the peak phase of virus replication and clinical illness which with the exception of limited biopsies is impossible to assess in human COVID-19. Thus, biomarkers such as viral load in tissues, as well as histopathology and immunohistochemistry of tissues, can be used to compare for example the efficacy of a candidate SARS-CoV-2 vaccine against a control group.
The African green monkey provides a model as well for the evaluation of medical countermeasures in this regard as it will be important to show that any vaccine or antiviral tested can shorten or eliminate the period of shedding.
Shedding and long term sequelae
An important aspect of the report is that it begins to shed some light under controlled test conditions on the pathogenesis of SARS-CoV-2. Detection of SARS-CoV-2 RNA in nasal swabs of some animals as late as day 15 and rectal swabs as late as day 28 after virus challenge is concerning and has potential public health implications in terms of the management of recovering SARS-CoV-2 patients.
The African green monkey provides a model as well for the evaluation of medical countermeasures in this regard as it will be important to show that any vaccine or antiviral tested can shorten or eliminate the period of shedding. Finally, the report raises important concerns about long term sequelae caused by SARS-CoV-2 infection. All of the African green monkeys that were followed until the early convalescence stage of COVID-19 (day 34 after virus challenge) showed substantial lung pathology at necropsy as evidenced by pneumonia and increased collagen deposition in alveolar walls despite the absence of detectable SARS-CoV-2 in any of the lungs of these animals. While most human COVID-19 patients eventually recover their lung function SARS-CoV-2 infection can cause lasting damage to the lungs that may require surgery or even organ transplants.
The African green monkey may provide a valuable model for not only assessing efficacy of vaccines and treatments but also studying such sequela. While it is often logistically challenging to keep NHPs for long periods of time in high containment laboratories future studies are needed to examine lung function and disease in convalescent animals at longer times after recovery.