Understanding the causes and spread of disease is crucial to improving human (and animal) health. The results of experiments involving volunteers are essential in the ongoing hunt for new vaccines and treatments, but have to be conducted responsibly with safety being the top priority.
Researchers studying various infectious diseases around the world collect samples and test medical interventions as and where new outbreaks occur. But such studies have large gaps: they can’t always answer all the scientific questions. This gap can be filled by infection studies, which allow researchers to dig deeper into the human biology of infections.
Following on from our post about the history of volunteer infection studies, we take a look at modern-day studies – why they are important and what measures are in place to protect people who take part in human research.
The pros and cons of volunteer infection studies
As the name suggests, a volunteer infection study involves people volunteering to take part in research that intentionally exposes them to a disease-causing microbe (including bacteria, viruses, and parasites) in a controlled way. Doctors and scientists can then investigate how the infection takes hold and develops, and test new vaccines and treatments.
There are lots of advantages of studying infections this way instead of carrying out research on natural outbreaks of disease. Professor Peter Openshaw, Director of HIC-Vac, explains why volunteer infection studies are useful.
“We constantly need to develop new treatments and vaccines to reduce the global impact of disease. Controlled studies involving volunteers greatly accelerate their development,” says Openshaw.
Volunteer infection studies have been pivotal for new vaccines against typhoid, cholera, and potential malaria vaccines (which are being tested in larger clinical trials).
According to Openshaw, volunteer infection studies can help in two main ways. First, understanding more about the early immune response to infections can reveal important clues that lead to the discovery of new vaccines and treatments. Then later in the process, volunteer studies can help researchers test how well vaccines work.
“It’s often very difficult to study natural outbreaks of infection. Their timing and location can be unpredictable and it’s not always easy for researchers to get themselves and their equipment to the location of an outbreak quickly, and that’s if ethical approval, staff and funding is already in place.”
Carrying out infection studies in a controlled way also helps answer scientific questions more quickly too. Dr John Tregoning from Imperial College London tells us why.
“In an infection study, researchers know the exact strain, dose and timing of the infection, so they can answer questions about whether different strains trigger different immune responses, or how long the incubation period is before symptoms appear.
“Doctors can take more samples from each person than they could during a natural outbreak to track the course of the infections, plus they know if there are other important factors in play – like another underlying disease – that can muddy the results.”
But there are challenges in studying infectious diseases in this way and the biggest concern is always that of volunteer safety, and the ethics of purposefully exposing people to an infection.
During volunteer infection studies, doctors intentionally cause unpleasant symptoms, disease, and discomfort in people who don’t stand to directly benefit themselves from taking part – this, on the face of it, breaks an ancient oath of medicine, ‘first, do no harm’.
But can it be considered unethical not to carry out studies involving volunteers? There is the value to society that must be weighed up against the potential discomfort to volunteers.
“Infection studies can lead to medical interventions that prevent millions of lives being lost worldwide,” says Openshaw. “Researchers need to fully justify each study by demonstrating the potential benefits. We have to convince ourselves, our colleagues, the regulators and the volunteers that there is no other way to get the same information, and that the information we can get is really important.”
Safety is the top priority
Volunteer infection studies have to be very carefully managed to protect people’s safety and well-being. They always involve supportive healthcare, and ideally there is a drug on hand to halt the infection at a set point (or if unexpected reactions occur).
While studies involving people can never be totally risk-free, there are robust ethical guidelines in place to ensure people are very unlikely to experience unacceptable symptoms or irreversible consequences.
The first step to protecting people’s safety is deciding who can take part. Researchers set ‘exclusion criteria’ before the study begins recruiting – for example, volunteers must be between set age limits, and in most cases otherwise healthy. The eligible volunteers undergo screening tests (for example blood tests and a heart check) to make sure there are no underlying health problems. These steps make sure that people who might be more susceptible to experience serious consequences of an infection aren’t put in harm’s way.
Because studies involve natural human diseases, researchers have a very good idea of the likely symptoms that people taking part will experience. This means doctors can plan to manage the symptoms and set specific points at which to treat people.
“For example, during a flu study doctors would expect that people experience a fever, headache and cough, and can make sure people get pain relief and are kept hydrated to manage these symptoms,” says Openshaw. “If someone has symptoms that are unacceptable, for example a really high fever or signs of lung problems, then we would treat them with antivirals as quickly as possible.”
In addition to having plans in place to manage symptoms and halt the infection, the disease itself can’t pose unacceptable dangers. Volunteers must not be exposed to infections that have a high fatality rate (for example Ebola) or that can’t be treated or clear up themselves during the study (for example HIV). For these reasons, researchers sometimes turn to weakened versions of the infectious agent, or study similar strains that don’t cause disease in people.
Safety versus relevance
The safety principles of only exposing people at the lowest risk of experiencing severe symptoms combined with limits on the risks posed by the infection itself makes studies involving volunteers as safe as possible.
But maximising safety can pose its own dilemma – it can come at the cost of how accurately the study reflects natural disease. For example, weakened strains might not generate the same immune reaction as natural infection, and a vaccine that works well against a weakened strain might not be so effective against normal disease. And excluding people at higher risk could leave gaps in our knowledge about the people most likely to become severely ill or even die during a natural outbreak.
“We badly need to know more about how infections behave in vulnerable populations such as children, older adults, or those who are already suffering from a disease like diabetes or asthma. Doing studies in such groups is often impossible for safety reasons, but this excludes the very population we need to help the most,” says Openshaw.
Trying to measure what risk a study poses to volunteers, whether the level of risk is acceptable and weighing it up against the potential benefits is hugely complicated. But the difficult decision of whether a volunteer infection study is safe and ethically acceptable isn’t just left to the researchers – there are independent expert checks in place too.
The UK system of checks and balances
In the UK, when a researcher puts together a detailed plan for a volunteer infection study they want to carry out, experts within the host university, hospital or institute (the ‘study sponsor’) go through the plans with a fine-tooth comb. And this isn’t just a box-ticking exercise – the study sponsor is legally responsible and will be held accountable if anything goes wrong, so they will not approve any study they have safety concerns about.
Studies involving members of the public that take place in NHS centres need to be approved by the Health Research Authority. As part of this process, the plan for the study will be appraised by a Research Ethics Committee (REC), who give a decision on whether the research is ethically acceptable. The committees are entirely independent of the researchers carrying out the study, and made up of experts and members of the public. If they don’t approve, the study cannot go ahead.
Lastly, purposefully infecting people with a contagious disease can pose risks to the environment and people outside of the study. When there is a possibility of the infection being transmitted or escaping into the wild, researchers must follow legislation and put measures in place to prevent this from happening. For instance, in some studies volunteers might have to stay in isolation in a health care facility during the study, or use chemical toilets, and staff might need protective equipment to stop them catching and spreading the infection themselves.
Making an informed choice
While every step is taken to minimise the possible harms of volunteer infection studies, there are always risks involved. That’s why it’s so important that researchers make sure people who are considering joining have high quality information, fully understand what the study involves and why it’s being done, and can make an informed decision about taking part.
Full understanding and willing participation is one of the core ethical principles that researchers must follow. People must also feel free to change their minds and withdraw at any time (with the caveat of if they pose a threat to others or the environment during the study, they need to stay isolated until the infection is resolved).
Supporting the research community
Volunteer infection studies play an important role in understanding disease, and developing new effective vaccines to reduce the global burden of infectious disease.
Due to the thorough international ethical guidelines researchers stick to, modern-day infection studies are very safe.
But there are always risks involved when people volunteer to take part in an experimental study – for example the severe reactions people experienced when given a test drug (TGN1412) at Northwick Park (note – this was not an infection study). A safety problem on this scale is very rare, but it reinforces the need to have strict guidelines in place to protect people, to learn lessons and continuously seek to improve these guidelines, and ensure people are aware of potential risks.
Our role as a Network is to help support volunteer infection studies, and part of this role is bringing the research community together to try and ensure that volunteer infection studies are as safe and as ethical as possible. It’s also important that studies are carried out to the highest standards to ensure that they are of maximum scientific value.
Carrying out high-quality volunteer infection studies will help researchers to understand disease so much better, and to make progress in developing new and improved vaccines against infectious diseases.