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Infectious Diseases

AuthorEARA team
From furthering our basic understanding of infectious organisms, such as bacteria, viruses, fungi and parasites (collectively known as pathogens), all the way to creating new treatments and even cures, animal research has been, and continues to be, a major contributor in our fight against infectious diseases, both to protect the health of humans and animals too. For now, information from animal studies is crucial for the discovery of entirely new treatments and the development of improved ones that have a widespread effect and benefit. 
Treatments for infectious organisms (collectively known as pathogens) are needed more than ever, as they are responsible for some of the most deadly and devastating diseases, and are capable of affecting virtually every part of the body, whether that is the blood or vital organs like the brain. Sometimes, it is the infection itself that does the most damage, or else it can trigger side effects or reactions from the body that range from mild to life-threatening.  
For many types of infectious diseases, we are unfortunately still lacking cures. The most recent reminder of that is, of course, the Covid-19 pandemic and the role of research using animals was at the core of both the fundamental research needed to understand the virus and then the development of effective vaccines that could meet this challenge. Thanks to such studies, these Covid vaccines were developed in record time. 
Infectious diseases remain one of the most significant threats to global health. From long-established killers such as tuberculosis and malaria to emerging viruses such as SARS-CoV-2, pathogens continue to challenge healthcare systems worldwide. According to the World Health Organization (WHO), infectious diseases and antimicrobial resistance remain among the top global health risks of the 21st century. 
Biomedical research into infectious diseases focuses not only on the microbes themselves — viruses, bacteria, fungi and parasites — but also on how the immune system responds, how inflammation develops, and how treatments or vaccines can safely interrupt disease progression. 
Although cell cultures, organoids and computer models are increasingly important, many aspects of infection — such as immune memory, systemic inflammation and transmission — can only currently be understood in whole living systems. 
Animal research has played a decisive role in the development of vaccines, antiviral drugs, antibiotics and immunotherapies that have saved millions of lives. 
Man receives injection. CREDIT: Unsplash


Why are animals used in infectious disease research? 

Basic research is a key pillar of the study of infectious diseases and using a complex organism, such as a lab animal, can reveal an understanding of how a pathogen enters and infects the body, how it evades the body’s defences, and then infects other people. 
One reason that non-animal methods have not completely replaced the use of animals in research into infectious diseases is that many animal species can be naturally infected by the same pathogens as humans; for instance, hamsters and ferrets can catch Covid-19 and flu, which allows researchers to investigate how these agents progress to cause the disease. 

An animal model can be useful to, in a very short time sometimes, show proof of concept – of how the virus transmits, or how it causes disease – but also if you want to test interventions. It is difficult to test interventions that are focused on preventing infection in humans. 

Koen van Rompay, California National Primate Research Center, USA
Mice, in particular, are suited to having their genetics altered so that they can harbour a disease of interest, even if they are not normally affected by it in the wild. Genetic approaches also have the benefit of being able to make mice and rats ‘immunodeficient’ so that their immune systems do not act against the infection, which would hamper the study of disease pathogens.  
Specific components of an animal’s immune system can also be ‘switched off’ to target the desired parts of the immune response to infections. Genetic approaches have been used in this way to model infections including HIV, Epstein-Barr virus, dengue and hepatitis.  
Developing vaccines also involves the use of animals, for example so that the right parts of the body, or bodily processes, are targeted, to successfully eliminate the infection. In turn, these new potential drugs and treatments are then tested on animals in preclinical studies, before they reach human trials.   
Using animals in Covid-19 research 
Animal research has played a critical role in helping researchers understand the SARS-CoV-2 virus itself, not only the mechanics of its transmission, but also the safety and efficiency of all the vaccines so far produced to bring the end of the pandemic a step closer.
Video on how animal research led to Covid-19 vaccines in record time, from Americans for Medical Progress.  
In an example of the value of fundamental research to lay the groundwork for potential treatments and cures, genetically altered mice were developed in 2007 at the University of Iowa, USA, as a suitable model to study coronaviruses, such as Middle Eastern Respiratory Disease (MERS). The availability of this model meant that the disease could quickly be studied in the context of how the SARS-CoV-2 virus would affect human cells. Among the research on animals that has helped shed light on effective Covid-19 vaccines was a study involving EARA members Ghent University and VIB, both in Belgium, which found that antibodies from llamas could stop the coronavirus from breaking into host cells – watch the VIB video on the role of llamas in Covid-19 research. 
Meanwhile, mRNA vaccines, which were a critical part of the treatment of Covid-19, had been under development for many years thanks to early research in mice, which led to the understanding that mRNA could be manipulated to produce an immune response in the body – the discoverers were recently awarded the 2023 Nobel Prize in Medicine for this vital work. 
A leading member of the Oxford Vaccine Group, the developers of the Oxford-AstraZeneca Covid-19 vaccine (not based on mRNA), also described the contribution of animal studies in its success. 

If the animal trials showed the vaccine was not safe, or not effective, we would not have wasted time preparing clinical trials that could not go ahead. This time, we did all the clinical trial preparation while the animal trials were still going on. 
That way, it was within days of receiving the safety data from our animal trials that we were putting the vaccine into the arms of our first volunteers. 


Professor Dame Sarah Gilbert, Oxford Vaccine Group, UK 

Which research on infectious diseases benefits from animal research?

A universal vaccine targeting a range of strains of meningitis B, which affects the brain, has been developed by EARA member Novartis, Switzerland, which used earlier research in mice and rats. Novartis researchers were able to create the vaccine by searching the genome of the Neisseria meningitides bacterium (the main cause of meningitis) for proteins that could be targeted by antibodies, before producing these antibodies in mice and testing whether they could kill the bacteria. Rats treated with the mouse antibodies confirmed that the vaccine worked and could be rolled out to protect thousands from disability and death.   
Zebrafish have also been used to study meningitis. A study at the Paris Brain Institute, France, and UMC Amsterdam, Netherlands, identified that brain neurons that detect bitter tastes played a role in protecting against bacterial meningitis.  

Chronic myeloid leukaemia (CML) is one such rare cancer that develops slowly over a person’s lifetime, but thanks to medical advances can now be kept under control with the right treatments. Studies in mice were an instrumental part in finding the protein abnormality that causes CML. The precision medicine Gleevec was developed, by Oregon Health & Science University, USA, to just target this protein abnormality in cancer cells in mice (not targeting all cells, like most chemotherapy drugs), and was later used to reduce cancer growth in CML patients. Other species, including dogs, rabbits and monkeys, were also involved in the development of Gleevec (and its rapid approval by the US Food and Drug Administration), by shedding light on how the drug behaved in the body and potential toxicities. 
​There are several different types of rare cancer that start in childhood, including neuroblastoma that mainly affects children under five-years-old and starts in nerve cells called a neuroblast, often in the adrenal glands located on the top of each kidney. Several studies in mice have contributed to improving survival rates and developing treatments with less severe side effects, for example a team at the University of Gothenburg, Sweden, were able to find an effective drug that worked against one of the two gene mutations that cause neuroblastoma.  
Mice were also used in a study of the rare eye cancer retinoblastoma (which mainly affects young children) at the St Jude’s Research Hospital, USA, to confirm that the cancer’s cause was not a series of mutations, like most cancers, but the loss of a single gene – explaining why it develops so quickly.

An animal model can be useful to, in a very short time sometimes, show proof of concept – of how the virus transmits, or how it causes disease – but also if you want to test interventions. It is difficult to test interventions that are focused on preventing infection in humans.

Koen van Rompay, California National Primate Research Center, USA
What is antibiotic resistance? 
Antibiotics have been a dependable and highly effective way to combat infectious diseases. They come in many different types, but all work by disrupting some process in bacteria that is vital to their survival, or by preventing the bacteria from spreading. 
However, in recent years, with the over-frequent use of antibiotics for both humans and animals, a phenomenon in bacteria known as antibiotic resistance is becoming a major global health threat. This has already rendered many drugs ineffective and is only set to get worse. Ultimately completely new ways will be needed to treat bacterial infections.  
Animal studies will be essential for testing alternatives to antibiotics. Phage therapy, which uses viruses to infect and kill bacteria, is emerging as a promising alternative to antibiotics, but before it can be trialled in humans, animals have been essential to testing, refining and improving this approach so it can be used in the clinic.  
Species ranging from mice to rabbits to chickens have been used to investigate phage therapy in a range of organ systems (such as the gastrointestinal) and bacterial strains. As farm animals like cows and pigs are given many antibiotics (even when they may be healthy), they are of particular interest in the study of antibiotic resistance, where diseases such as bovine tuberculosis and avian or swine flu are prevalent and pose a major health and economic burden.  
Researchers at EARA members University Libre des Bruxelles and GSK, Belgium, have also looked into making existing antibiotics effective again, using mice to show that a molecule could reverse resistance against tuberculosis bacteria.  

A lot of stuff can be done in Petri dishes, but then when it comes to testing the efficacy and potency of antibiotics, one has to look at animals models. 

Professor Gad Frankel, Imperial College London, UK


Which animals are used in infectious diseases research?

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Infectious disease research benefits from studying a range of other animals, such as ferrets and guinea pigs which naturally catch strains of human flu, for example, and therefore display similar symptoms.  
Meanwhile, the embryos of chickens develop in a way that is comparable to human foetuses and are therefore useful for studying early infection in diseases like Zika.  
More unconventional species such as insects – from moths to mosquitos to honeybees – are also emerging as valuable models, since they can be easily manipulated, for example at the genetic level, to help understand the factors that contribute to infection mechanisms, disease progression and much more. Insects have additional value because certain pathogens (such as the plasmodium parasite for malaria) use insects as a host to infect other organisms, and can also be used to better understand antibiotic resistance

While pigs do not naturally get cystic fibrosis (CF) they can be bred to develop very similar symptoms to the condition, such as lung disease which can naturally develop as a result – the lungs of pigs have been shown to be affected in a very similar way to those of humans. This means that interventions can be tested at an earlier stage than in a patient, in turn allowing researchers to come up with measures that could help to ease symptoms or detect the condition earlier on.

Pigs have also been geneticalms to people with the condition compared to rodents, such as difficulties with walking and running with age. In addition, certain brain changes were similar, such as the loss of specific neurons and immune responses. 

Meanwhile, the same similarities in body make-up to humans have also meant that pigs have been used to model Huntington’s disease, a rare disorder where the brain’s nerve cells are damaged, and that can affect movement, behaviour and communication, among other effects. 

In a study from Emory University, USA, and Jinan University, China, the genome of pigs was edited using CRISPR to insert the human gene that causes Huntington’s. This approach resulted in pigs that showed very similar symptoms to people with the condition compared to rodents, such as difficulties with walking and running with age. In addition, certain brain changes were similar, such as the loss of specific neurons and immune responses. 

Limitations of animal models 

Animal models have been central to progress against infectious diseases, but they are not perfect representations of human infection. No animal species can fully replicate the complexity of how a pathogen behaves in humans, or how the human immune system responds across different ages, genetic backgrounds and underlying health conditions. The European Commission’s Scientific Committee on Health, Environmental and Emerging Risks (SCHEER), in its 2017 review of non-human primate use, concluded that, “no single model can fully recapitulate all aspects of human disease”, and that results must always be interpreted alongside other lines of evidence. 
Species differences are an important scientific consideration. Immune systems vary among mice, ferrets, hamsters, non-human primates and humans in terms of protein and target receptor expression, inflammatory signals and susceptibility to specific pathogens. The same pathogen can behave differently across species because of differences in immune signalling, receptor biology and physiology. This is why infectious disease research typically uses a wide variety of models, selected to match the scientific question. In influenza research, for example, reviews comparing major animal models (including mice, ferrets and non-human primates) describe both strengths and limitations for studying disease severity, transmission and vaccine responses, underlining that no single species is “the” influenza model.   
Because of these differences, translation from animals to humans is not guaranteed. Some interventions that look promising in animal models do not show the same level of protection or benefit in people once tested in well-designed clinical trials. HIV vaccine development is widely recognised as an area where this challenge is particularly clear: NIAID’s overview of HIV vaccine development explains the importance of preclinical testing in animals, while maintaining that clinical testing remains vital to determine whether the observed immune responses translate into human protection.   
This is also why modern infectious disease research increasingly relies on complementary methods. Human-relevant tools such as organoids and advanced tissue models can help answer specific mechanistic questions in human cells, while still lacking key features of whole-organism infection, such as systemic immune responses and transmission dynamics. The use of lung organoids in SARS-CoV-2 research illustrates how these systems can be valuable for studying infection and host response in human-derived tissue contexts.   
Ultimately, clinical confirmation is, again, decisive. Vaccines and medicines are not authorised on the basis of animal data alone; regulators require evidence from human clinical trials to determine safety and efficacy in people. The European Medicines Agency (EMA)’s overview of clinical trials in human medicines outlines how clinical trial results from all over the world inform regulatory decision-making in Europe on the uptake of new therapeutics.   
Recognising limitations of all models is part of responsible, transparent science. In infectious diseases, the strongest evidence typically comes from combining animal models with human-relevant methods and subsequent rigorous clinical evaluation, so that conclusions are robust and uncertainty is handled appropriately.   
How are animals cared for?
The use of animals in infectious disease research is tightly regulated to ensure that such studies are justified and that a non-animal method cannot be used to achieve the same results. In the EU, researchers must follow the 3Rs principle of replacement, reduction, refinement, with EU Directive 2010/63 ensuring that a high standard of animal welfare takes place and ethical considerations are addressed, while alternative methods to complement, and in some cases replace, animal research are being developed, where possible.  
 
In the case of animal welfare, an improved range of aspects are important to maximise the well-being of animals, and the accuracy and reliability of experiments, from good experimental design to housing enrichment to harm-benefit analysis (whether the harms that animals are expected to experience justify the benefits of the research).  
Many experimental procedures done for infectious disease research require Animal Biosafety Level 3 ABSL-3 Facilities, which need to be specifically regulated and verified. Enhanced practices are in place for handling laboratory animals infected with agents that can cause serious or lethal disease, including those with potential for aerosol transmission. It requires restricted access, specific training, supervision and the use of biosafety cabinets or other containment equipment for procedures involving infectious materials. 

New approach methodologies in infectious diseases research

Increasingly, as in other areas of research, new approach methodologies, including non-animal approaches, are emerging that have the capacity to replace, reduce or refine the use of animals in some infectious disease studies (3Rs). Although we are still not at a point where these methods can fully replace animals in studying and treating infections and diseases – owing to limitations in research and development, and regulatory approval – alternatives are nonetheless proving valuable for complementing aspects of animal research and providing insights.  
Organoids created from human cells and tissue, and that can be grown and cultured in the lab, are useful for studying certain processes and testing the effect of drugs by mimicking what happens in specific organs in the body. For example, a study at the University of California, Irvine, USA, created a tonsil organoid that was successfully used to model respiratory infections, such as Covid-19 and the flu, and study the development of immunity in response to vaccination.  
Human cells can also be used through organ-on-chip technology, where natural or engineered tissues are grown on a microfluidic chip. These also provide a way to simulate the body and to better understand what happens to organs when they are infected and inflamed, for instance. A variety of organs that are susceptible to infection can be mimicked, including the lungs, kidney and bowels. However, before any studies based on these findings can progress to humans, animals still need to be used to assess the safety and effectiveness on a living organism.  
Meanwhile, computer modelling can forecast diseases using existing data on factors such as transmission and symptoms, to provide estimates on how widespread or deadly a disease could be. Computation has also helped to model the dynamics of infections within hosts and between hosts for diseases like malaria and influenza.   
Useful sources 
One Health, World Health Organization
Antimicrobial resistance, World Health Organization
European Centre for Disease Prevention and Control
World Organisation for Animal Health