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COVID-19: an opportunity to review the bigger picture of animal research

Amy BealeIn the first article in a series looking at the current pandemic, FRAME Scientific Liaison Officer Amy Beale discusses the current COVID-19 crisis and how it may provide unique insights into the value of non-animal approaches in vaccine development.

The COVID-19 opportunity

The current COVID-19 pandemic has had a huge impact on our way of life during 2020. Many of us have had to change our routines and habits to help slow down the spread of a virus which is deadly to many and currently has no effective vaccine or treatment.  Google tells me today (9th September 2020) that the total recorded number of coronavirus cases globally is over 27 million with an estimated 898,000 deaths.

Understandably, stories about the virus, its transmission, the effect it has on the body, and potential vaccines have been hitting the headlines as scientists around the world work on potential treatments. The global crisis caused by the pandemic has created an unprecedented level of openness and information sharing in the research community as universities, research organisations and industry search for treatments. This has provided the public with the unique opportunity to access information about different COVID-19 related animal research projects and alternative, non-animal technologies currently being used to learn about the virus and potential vaccines.

It is possible that there is currently a disproportionately high level of animal use as the search for a vaccine is so urgent, however there are also many examples of non-animal projects hitting the headlines. On the 9th of June 2020, the WHO (World Health Organisation) reported that there were 10 candidate vaccines in clinical evaluation and 126 candidates in preclinical evaluation. (1) Many of these projects involve collaborations as the pandemic brings together scientists from across the world.

In this series, I will look at some of the information that has been made available through the coronavirus crisis, and track some of the animal and non-animal projects happening to see what progress is being reported. This first article provides background information on COVID-19, the requirement to use animals in vaccine development, and the initial research projects and stories reported in the press.

Animal testing and the alternatives

Human disease research and drug and vaccine development today still rely heavily on laboratory animals to prove the safety and efficacy of treatments before they progress to human trials. Yet we know there are cases, due to differences in physiology, metabolism, and biochemistry, where animal models fail to predict human responses. This can lead to adverse reactions in clinical trials that were missed in preclinical testing, a failure to identify treatments that would work in humans but fail in animals, and the progression of drugs to human trials that fail to get to market, costing time, money and animal lives.

Animal research is still necessary where there are no better or alternative methods, and historic animal research has led to many important discoveries that have improved human health. Preclinical research and regulatory guidance for drug testing tell us that animal methods are still the first choice for assessing safety or evaluating drug efficacy (whether the drug works). Whilst there is no question animal testing has benefitted mankind historically – is this still the best way?

The cosmetic industry has moved on from animal testing methods with the EU ban and European chemical regulations are tightly controlled, allowing the introduction and validation of non-animal, alternative tests, albeit at a very slow rate. In the area of disease research and drug development, alternative, human-relevant technologies are being developed that often provide more accurate insight into how the human body will respond in comparison to an animal. These methods include in vitro techniques such as cell culture and organ-on-a-chip (using channels with different types of living cells and flowing nutrients to represent a whole organ) and predictive mathematical and in silico (computer) models.

A reliance on animals is ingrained in the drug development process, changes to regulatory guidelines are slow and where valid, non-animal methods might exist, there is not enough confidence to completely drop animal tests. It is acknowledged that it would take a range of non-animal tests to assess the efficacy and safety of a new drug or vaccine. Perhaps there are not enough alternative methods to do this, or perhaps these non-animal methods are not yet robust enough to take over from traditional animal tests – but what if they are?

The coronavirus pandemic is a chance to look at the bigger picture. We can see how both animal research and non-animal research projects are adding to our understanding of the disease, and hopefully the discovery of a vaccine. It will be interesting to view the scale of animal use across the crisis and take stock of useful discoveries that have been provided by both animal and non-animal approaches. In the aftermath, governments and regulatory bodies may question the value of all the COVID-19 animal research that took place and there may be a chance to evaluate the role alternative methods have played and how they can be embedded more effectively moving forward. Perhaps there are lessons to be learned from 2020 that will impact the role of animal research in pharmacology, disease research and drug development in the future.

What is COVID-19?

Coronaviruses are a group of related RNA viruses that cause respiratory tract illnesses. Most infections are harmless or mild such as the common cold. However, some coronavirus strains infect the lower respiratory tract leading to more serious illnesses such as bronchitis or pneumonia. (2) In the past 20 years, coronavirus strains have emerged that cause more serious symptoms in some of the population, resulting in acute respiratory disease which is often life-threatening. Previous examples of this include the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) outbreak in China in 2002 and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemic in Saudi Arabia in 2012. (2)

COVID-19COVID-19 is caused by the virus SARS-CoV-2. It has been well publicised that COVID-19 emerged in late 2019 in Wuhan, China, and as with SARS and MERS is thought to have originated from bats. Specifically, the first cases of COVID-19 were linked to a food market in Wuhan. Cases of COVID-19 spread across the globe to 18 other countries and the WHO announced it a Public Health Emergency of International Concern (PHEIC) on the 30th January 2020. COVID-19 has now been recorded in over 200 countries.

Here in the UK, it is widely known that the main initial symptoms to be concerned about include a persistent cough, high temperature and a loss of taste and/or smell, but others include fatigue, sore throat, headaches and shortness of breath. It has also been well reported that the majority of people will experience only mild to moderate symptoms, whilst some will suffer from more severe symptoms which may lead to oxygen therapy in hospital or mechanical ventilator support to help with breathing. Sadly, in many severe cases the disease is fatal, particularly in older members of society or those with underlying conditions where severe COVID-19 has led to organ failure. Underlying conditions that make someone more susceptible to COVID-19 include cardiovascular disease, diabetes, chronic respiratory disease, and cancer. (3)

There is also widespread awareness that the disease is contagious and transmitted via saliva and droplets from the mouth or nose, for example when a person coughs or sneezes, hence the call to use face masks and PPE (Personal Protective Equipment) in various contexts.

Coronavirus strains affect other mammals and birds and can for example cause respiratory conditions such as ‘kennel cough’ in dogs. These strains do not normally affect humans. (4)  COVID-19 however, is an example of a zoonotic disease, meaning it can pass between humans and other animal species. These diseases are particularly deadly because there is no immunity to them. (6) The first confirmed case of COVID-19 in an animal was a tiger with a respiratory illness at a New York Zoo, thought to have been passed on from a zoo employee infected with the virus. (5) So far only around 20 animal cases have been reported in cats, dogs, ferrets, mink, lions, and tigers. It is important to note most of these animals had no, or only very mild respiratory symptoms. (4)

Fighting COVID-19: the initial research

At the start of the coronavirus pandemic, scientists and academics across the world began work to create a vaccine and investigate the effects of various existing drugs on COVID-19. In March, the WHO (World Health Organisation) said they had begun trialling some potential drugs already used to treat Ebola, HIV and Malaria, and later other countries joined the trials, including the UK (2).

These drugs included: (2)

  • Chloroquine (antimalarial drug)
  • Hydroxychloroquine (antimalarial drug)
  • Remdesiver (a new antiviral drug)
  • Lopinavir and Ritonavir (HIV drugs) in combination with Interferon Beta (antiviral drug)

To date, only Remdesiver is being recommended for COVID-19 patent use by the NIH (National Institutes of Health) in the US. (16)

Johns Hopkins Hospital, alongside Johns Hopkins School of Public Health, were the first to hit headlines for trialling potential antibody treatments for coronavirus. Unlike vaccines, antibody treatments do not prevent the illness: they are used to treat it. These treatments involve removing blood plasma (serum) from COVID-19 survivors. This plasma contains antibodies to COVID-19 which can be separated and transfused into those suffering from the disease. (7) It was reported in April that the US FDA (Food and Drug Administration) had fast tracked clinical trial approval to allow the therapy to be trialled on patients.

Studies into potential antibody therapies had already started in China prior to this (8) and it has been reported that one study has now completed preclinical tests in mice and is being prepared for human trials (9). More recently, in the US, the first human trials on a potential antibody treatment have now started (17). With a vaccine possibly years off discovery, antibody therapies which have previously been used to help shorten recovery time from other diseases and treat symptoms may offer an interim solution in fighting coronavirus.

Elsewhere in the US, there is another example of an antibody therapy being progressed quickly through in vitro cell culture tests and ‘animal infection models’ within 7 weeks, with the potential to have progressed through initial clinical trials by January 2021. (10)

Fast tracking vaccines

In one of the many daily UK government briefings during the pandemic, the Chief Scientific Advisor Sir Patrick Vallance said: “Just to put some realism on vaccine development, each single project does not have a high probability of success. So, although everyone goes out with great enthusiasm and we hope they work, it’s never the case that you know you’ve got a vaccine that’s going to work.” (11)

Vaccines can take many years to develop: the Ebola vaccine was finally approved in 2019 after 5 years of development. (12) The stages of vaccine development include preclinical development, which involves research and discovery in the laboratory followed by animal trials, then clinical development which involves clinical trials including Phase I, II and III studies on human volunteers. After this, the vaccine must gain regulatory approval before being marketed and manufactured. (12) Pharmaceutical giant and vaccine developer GSK states: “Animal trials follow strict guidelines laid down by the regulatory authorities, and will only be carried out when questions cannot be answered with another method.”

There is a legal requirement to prove vaccines to be safe and effective, and the regulatory bodies advise animal tests to do this. Justification must be provided to deviate from these guidelines, for example to use COVID-19alternative, non-animal methods instead of the advised procedure. I have not heard of this ever being done and suspect pharmaceutical companies, wanting to protect themselves and be as safe as possible, opt for the advised animal tests. The not-for-profit organisation Understanding Animal Research (UAR) also confirms this: (13) “Regulators require that a manufacturer shows a product is safe in animals before it goes into people, and while it isn’t enshrined in law, researchers almost always check that a new formulation is effective in lab animals before putting human volunteers at potential risk. Research ethics regulatory systems have protected us against these risks for the past 50 years.”

Early in the coronavirus pandemic, regulatory bodies such as the US FDA and the EMA (European Medicines Agency) looked for ways to safely fast track the vaccine testing and approval process. This culminated in a virtual workshop on the 18th of March 2020, between 20 global medicine regulatory organisations, alongside other WHO and EU Commission experts, to discuss the development of COVID-19 vaccines. (14)

Two main points came out of this meeting regarding COVID-19 vaccines. These can be summarised as:

  • For all SARS-CoV-2 vaccine candidates, it is necessary to obtain data in animals and to characterize the immune response induced by a SARS-CoV-2 vaccine candidate.
  • It is not required to demonstrate the efficacy of the SARS-CoV-2 vaccine candidate in animal challenge models prior to proceeding to FIH clinical trials.’ (13)

In this situation, therefore, it is no longer a requirement to provide evidence of efficacy of potential vaccine candidates in animals, only safety and an immune response – for example, the production of antibodies.

The number of drugs which show severe side effects at or after clinical testing tells us that animal models do not highlight every risk.  When developing a vaccine, there is a small risk of causing ‘immune enhancement,’ where antibodies can make the symptoms of the disease they are providing protection against worse through various biological responses. (15) There is no evidence of this with COVID-19 yet, but scientists are still learning about this ‘novel’ virus and so the question remains of whether the current testing orthodoxy of using animals will be sufficient.

So, what does COVID-19 tell us about animal research?

The urgency to halt the pandemic has already brought about regulatory change and seen concurrent animal and clinical trials, as drugs are tested on humans earlier in the vaccine development process. This shows there is in fact potential flexibility to adapt strict drug development guidelines, yet it still feels like there is a reluctance to move away from traditional animal methods. Can scientists, governments and regulatory bodies use this pandemic to analyse the overlap between animal research projects and alternative methods? Can we identify which non-animal methods are providing useful information to help fight COVID-19 and should be utilised in future vaccine and drug development? This type of reflection should highlight the need for information sharing and funding of and training in useful techniques that are not regularly used due to a lack of knowledge, experience, or access to equipment. These are techniques that could benefit human health by reducing drug development costs, more robustly predicting adverse reactions or drug efficacy, and speeding up the drug development pipeline.

Animals are still playing a major role in proving vaccines are safe before they progress to human trials and evaluating any ‘immune response.’ We know that there are hundreds of COVID-19 research projects across the world and all the main vaccine development programmes have likely involved animal research, some alongside in vitro, non-animal methods. The risk of moving away from animal testing and missing an important safety issue before human trials is too risky. However, if there are alternative methods that can safely and reliably provide the same information, they should be used.

We can estimate that the number of animals being used for coronavirus research is significant although there are no reporting methods in place to assess the scale of this or evaluate outcomes. It is good to know that despite the urgency, the Home Office is maintaining standards of justification for animal use and implementation of the 3Rs as required by UK law in line with ASPA (The Animals (Scientific Procedures) Act 1986.

I am intrigued by the many stories relating to the science of COVID-19 and hope in the aftermath of the pandemic, there will be reviews that identify and highlight learning points from the process. This would allow gains from animal research to be evaluated, alongside the contribution of non-animal methods, to assess the current state of animal testing and influence a future without it.


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