Research into drugs and vaccines to combat the COVID-19 pandemic caused by the SARS-CoV-2 virus has been and remains in full swing. With that as backdrop, how do you choose the right animal model for your nonclinical research? To begin with, defining precise and clear goals before starting a nonclinical study will help support the species selection choice. This will also ensure that the study leads to meaningful results that contribute to program success.
COVID-19 is primarily a respiratory disease, and much research has been focused on lung histopathology and on upper and lower respiratory tract viral loads. Since a virus is behind this disease, inhibiting viral replication has been another primary goal of research efforts. Given that end goals for research can vary widely and that financial and operational considerations can come into play, it is imperative that sponsors look at the full picture before choosing an animal model.
Key considerations for species selection
The same factors that typically apply when looking at animal models apply here as well, along with several pandemic-specific, COVID-19-specific, and, of course, SARS-CoV-2-specific factors:
- Availability of the animals globally: Where in the world animals are being shipped from can have a large impact on timelines, particularly for non-human primates
- Availability of the models within CROs: SARS-CoV-2 can be handled only in a BSL3 lab
- Size of the animals: This becomes important in managing test item availability and for repeat sampling
- Similarity to human anatomy and respiratory physiology
- ACE2 receptor amino acid sequence: Receptor homology is particularly relevant for mice
- Viral replication characteristics
- Immune response properties
- Manifestation of clinical disease: Sponsors should consider this as it relates to both the symptoms themselves and their severity
- Cost and timelines
Key characteristics of animal species in use for COVID-19 research
A variety of animal models have been in use for the nonclinical study of the SARS-CoV-2 virus, each with its own advantages and disadvantages. Listed below are the most common species currently involved in these studies, and some key considerations for the best use of each.
NHPs are often considered the best models to study biologics due to their similarity to humans. In this case, commonalities between the human and macaque ACE2 receptor amino acid sequence make macaques susceptible to the SARS-CoV-2 infection, which targets the ACE2 receptor.
In addition, the disease has been demonstrated to be more severe in older animals and in certain species of macaques. Rhesus macaques have been used to look at immunity following disease recovery, an important avenue of research in vaccine research. On the other hand, common marmosets have a more divergent amino acid sequence from humans and are more resistant to the virus.
A regular mouse is not a good model for COVID-19, since the ACE2 receptor is not well conserved between mice and humans. The differences in the amino acid residue sequence that make mice resistant to the virus have led researchers to use transgenic mice with the human ACE2 receptor instead.
These hACE2 (humanized ACE2 receptor) mice were originally bred for SARS research, and the sperm remained frozen at the Jackson Laboratory until they again became needed. Although species-specific reagents are widely available since mice are a commonly used animal model globally, high demand has limited the availability of this transgenic strain.
While mice have a productive viral replication and visible histopathology, they exhibit minimal if any symptoms. Animals exhibiting such mild infections could be useful for testing drugs and vaccines, but scientists will need to look to other models to gain an understanding of more severe cases of the virus.
Hamsters have strong upper and lower respiratory tract viral loads, and infected models exhibit pulmonary histopathology characteristic of human COVID-19 cases. In addition, studies have shown transmission by direct contact in hamsters, but access to species-specific reagents is more limited than with mice since hamsters are not as widely used. However, there are hamster transgenic strains that could help with the study of the molecular pathways that help to restrict systemic viral dissemination.
Ferrets have a particularly robust upper respiratory tract viral burden, and infected models exhibit fever and sneezing characteristic of human COVID-19 cases. Previous research into their applicability in the study of disease transmission, by both direct and indirect contact, resulted in their use in SARS-CoV-2 transmission research. Although access to species-specific reagents is also limited with ferrets, they have the advantage of size, which facilitates repeated sampling to monitor viral load, immune response, and other markers as required.
Surrogate animal models
Sponsors researching the impact of COVID-19 but not attempting to inhibit viral replication should consider an additional class of animal models for which the competition for resources is lower: surrogate animal models.
Two examples are the lymphocytic choriomeningitis virus (LCV) and the respiratory syncytial virus (RSV) mice and rat inflammation models. The LCV model can be used to look at the T cell-oriented immune response, while the RSV model can be used to look at lung pathology.
In short, macaques are the gold standard for testing, transgenic mice are widely used and easy to adapt, hamsters are useful to study viral replication, ferrets are good for clinical disease research, and surrogate animal models should not be forgotten.
With such an abundance of options and factors involved, the choice is not an easy or clear one. Premier Consulting’s experts can help you to select the right species for your nonclinical program. Contact us to learn how we can help advance your product toward the clinic.
Rudi Erlemann, PhD
Vice President of Business Development and External Scientific Affairs
Camille Delouche, MSc
Commercial Operations Associate