SARS-CoV-2 is a new virus, causing a new disease, COVID-19. It is possible that existing anti-viral and immunomodulatory drugs may be able to be repurposed for treating COVID-19. However, there is no guarantee that a safe and effective treatment will be found immediately: the symptoms and progression of COVID-19 are different from diseases caused by even closely related viruses.
A key part of translating safe and effective treatments is testing potential treatments in the right model in animals. Using animals to model disease has advanced medical science, improving understanding of disorders and playing a critical role in assessing the safety and effectiveness of medicines for human and animal use. A good model recapitulates the symptoms of the disease in question (‘face validity’) and the biological mechanisms that cause it (‘construct validity’). Importantly, a good model also has ‘predictive validity’ – that is, it helps develop understanding of the disease and which treatments might be effective.
There are currently no models of disease in animals that capture all the features of COVID-19. Developing an appropriate model brings several challenges. Firstly, common species used to model disease (such as mice and dogs) do not appear to be suitable, although genetic approaches may be able to address this. Secondly, the development of COVID-19 depends on multiple known risk factors (e.g. male sex, age, coexistence of other diseases such as diabetes) but models are generally carried out in young, healthy animals. Studies in aged macaques indicate that incorporating this risk factor helps mirror the infectivity and lung pathology associated with human COVID-19. Finally, COVID-19 has three disease phases: mild (no symptoms, mild pneumonia), severe (moderate to severe pneumonia) and critical (onset of the cytokine storm that leads to acute respiratory distress syndrome – ARDS – septic shock and multi-organ failure). It is imperative that models of disease can be mapped to the right patient population – and that the right treatments are tested at the right time. For example, there is likely to be little point in testing an antiviral drug in severe disease models because at this point it is the host immune reaction that causes damage and death.
There is a pressing need for coordinated approaches to drug discovery that will speed up assessment of known drugs and identify new potential treatments. Importantly, this includes using pharmacological principles to identify a suitable dose and route of administration.
Animal models used in the global effort to find a treatment for COVID-19 must be valid – and they must be used and reported consistently. The Society supports the conclusions of a recent paper* published in the British Journal of Pharmacology and call for the research and drug discovery community to work together to agree guidelines for the use of animals to model COVID-19. These guidelines should include:
- Incorporation of known risk factors. It is challenging to incorporate multiple risk factors, but important to capture this so far as is possible to give the best possible chance of translation.
- The right model at the right time. COVID-19 has distinct disease phases (from mild to critical) that appear to be caused by distinct biological mechanisms. Knowledge of the disease mechanism, and likely mechanism of the drug can help stratify models in a way that can be mapped to patient population. It is critical to test the drug in a model that recapitulates the right phase of disease.
- Inoculation protocols. Effective delivery of virus to the lung is critical to ensure consistent viral load and disease progression.
- Monitoring disease time course. Use of non-invasive monitoring to study disease development will evolve understanding of the disease and importantly, appropriate treatment windows for different disease stages
- Disease-relevant endpoints. Using appropriate endpoints (symptoms/signs of disease, such as lung pathology) and reporting them consistently through descriptive and quantitative measures will enable statistically meaningful interpretation of whether a treatment has worked.
- Safety of laboratory researchers and technicians. It is imperative that those working in COVID-19 laboratories have access to appropriate personal protective equipment (PPE)
The Society welcomes ongoing work, both nationally and internationally, to ensure the robustness of animal models. For example, as part of their COVID-19 rapid response funding, UKRI have awarded £0.4 million towards the development of an animal model in non-human primates with the intention that it can be used to test if new vaccines and therapies are safe and effective. Further, the WHO has established a COVID-19 animal models working group. In addition to ensuring the quality of the scientific approach, it will be important to work with regulators to ensure alignment with requirements and with decision makers (e.g. through the UK therapeutics taskforce) to ensure that candidates selected to go through to clinical research have been tested in animal models that uphold these principles.
*The Society’s President-Elect, Professor Clive Page, is the corresponding author on this paper