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Human challenge studies with coronavirus: towards effective vaccines

 

Coronavirus (COVID-19) has been sweeping across the globe and caused more than 1 million deaths. It is spread mainly by droplets produced when someone infected with the virus coughs, sneezes, talks, or even breathes, which means it spreads easily between people in close contact.

Clinical trials have helped find treatments that help more people survive, including steroids such as dexamethasone. But there is no guaranteed cure, and it would be better if we could prevent people from needing hospital care or getting ill in the first place.

The best way to protect peoples’ health is an effective vaccine. Scientists are working with urgency to find the best vaccines that offer people the highest level of protection.

Finding a vaccine

New vaccines require careful testing to make sure they are safe and that they protect people from the disease they aim to prevent. Lab experiments and research involving animals can provide some of this information, but a new vaccine must be tested in people too before it can used in a national vaccine programme.

The usual way of testing if a vaccine works is a “field study”, where healthy volunteers are vaccinated as part of a clinical trial. Researchers compare how many of the vaccinated volunteers catch the infection when going about their everyday lives to the number of unvaccinated people who become infected.  

But this method requires large numbers (thousands) of volunteers and relies on enough people being exposed to an infection naturally. This means it can take a long time to understand whether it works (often years – particularly if the number of cases in the community is low).   

Human challenge studies – how are they different and how can they support new vaccines?

Human challenge studies (where carefully selected, healthy volunteers are deliberately exposed to an infection for medical research) have a long history of being used to understand and fight diseases including flu, typhoid, cholera, malaria, and even the humble common cold

The first human challenge study with the COVID-19 coronavirus would be to determine if it is safe and to find the lowest dose of virus that can be used to cause an infection in people (a “dose-escalation study”). The volunteers wouldn’t have any immunity, either from a vaccine or prior exposure to the virus.

Once shown to be safe, human challenge studies can speed up vaccine development by giving an early indication of whether a vaccine protects people. It is easier to measure how effective a vaccine is compared to field studies, because volunteers are exposed to the same dose of virus at a known point in time, rather than waiting for natural exposure. A human challenge study takes months rather than years and involves fewer volunteers (50-100). These rapid results help researchers focus on the most promising vaccines and not waste time on less effective options.

However, purposefully giving a healthy volunteer an infection is ethically complex and the potential benefits must outweigh the risks. There are widely accepted international principles that are used to help expert independent committees decide if a proposed challenge study is ethically acceptable and can go ahead.

Now, with coronavirus causing a global emergency, researchers around the world are asking the question – would it be acceptable to deliberately expose volunteers to coronavirus (COVID-19), with the goal of speeding up effective vaccines?

A human challenge study with coronavirus: the risks

The main risk with deliberately exposing volunteers to this coronavirus is to their health. Coronavirus infections can be very different for different people – some people have no symptoms, some a flu-like illness that resolves in a few weeks, some become so unwell they are hospitalised, and in the very worst cases die.

Having lived with the virus for over half a year, researchers now have a much better understanding of who is at higher risk of more serious disease. To minimise the risk to volunteers, it would only be acceptable to allow those with the very lowest risk to take part, for example young, healthy non-smokers. But until there is a guaranteed cure, there is still a small risk of a volunteer becoming seriously unwell or dying.

In addition to the immediate symptoms caused by the virus, there are the less-well understood “Long Covid” symptoms that could affect volunteers. Because coronavirus is still relatively new to the world, there isn’t a lot known about the long-term effects – what they are, what causes them, who is likely to get them, or how to treat them.

However, there are lots of things that we choose to do which carry an element of risk, be that for work or pleasure. From an ethical perspective, if people were to volunteer for a human challenge study with coronavirus, it’s essential that they can fully understand the risks and make a choice to accept them. Doctors would provide and thoroughly explain all the information known about the risks prior to the study starting.  

Once exposed to the virus, there is the additional risk that a volunteer could transmit it to people outside of the study. To minimise that risk, the study would take place in a specialised clinical isolation unit so that volunteers are not in contact with other people whilst infectious. Staff running the study, including doctors, nurses, cleaners and porters, would also need the correct PPE to protect them. 

Lastly, there is a chance that a vaccine that shows promise in a human challenge study might not be as effective in more vulnerable groups, such as older people or those with other health conditions (who are the very people most in need of an effective vaccine). However, the safety of the volunteers comes first, so it is normal for human challenge studies only to accept young healthy people at the lowest risk of illness or complications.

A human challenge study with coronavirus: the benefits

The main potential benefit of human challenge studies with coronavirus is providing a powerful way for doctors to test new vaccines. Speeding up the development of vaccines could save many lives, both from the virus itself and by reducing deaths caused by the negative effects the virus has had on society and the economy (for example poverty and delays in routine healthcare).

There are over 200 new vaccines currently in development, so being able to quickly work out which ones are best would save time, resources, and potentially more lives. A vaccine that shows promise in a human challenge study is more likely to be successful in the broader population, so researchers can focus on them over vaccines that don’t work as well in young, healthy volunteers.

Another benefit to carrying out a human challenge study is that researchers can collect lots of samples from the young, healthy volunteers to better understand how a vaccine works at a biological level. Once they have measured the immunity created by a vaccine in the study volunteers, they can test to see if the vaccine triggers the same immunity in more vulnerable groups. This gives an early indication that a vaccine would protect vulnerable groups from disease too.  

In addition to testing new vaccines, researchers can get detailed information about the disease and early immune response to it. This could help answer scientific questions, such as why some people get ill while others have no symptoms at all. Researchers could also study how the virus is transmitted – for example why some people shed little virus and others are “super-spreaders” – which could help inform public health advice and preventive measures like social distancing.

There are also possible benefits for the volunteers. Given that the virus is circulating naturally in society, there is a chance that they would be exposed naturally anyway. By taking part in a human challenge study they would receive a low dose of the virus in a unit where they are monitored by doctors and have healthcare support. Although we don’t yet fully understand if someone can be infected more than once, being exposed could offer the volunteers some level of immunity against future coronavirus infections.

Who decides?

The job of deciding if carrying out a human challenge study with coronavirus is ethically acceptable (meaning that the benefits outweigh the risks) will ultimately fall to an independent committee made up of experts and members of the public.

They would be asked to consider all the details of a study until they were satisfied that every measure possible was in place to minimise the risks, and that the risks are acceptable when judged against the possible benefits.

It will not be a decision they will take lightly – no one wants to risk a volunteer coming to any undue harm. But at the same time, hundreds of thousands of people are losing their lives to COVID-19 or due to the other devastating impacts the virus is having on people’s lives, and speeding up vaccine development would have huge wider societal benefit.

 

Article based upon:

WHO ethics https://www.who.int/ethics/publications/key-criteria-ethical-acceptability-of-covid-19-human-challenge/en/

WHO frameworks https://www.who.int/publications/m/item/feasibility-potential-value-and-limitations-of-establishing-a-closely-monitored-challenge-model-of-experimental-covid-19-infection-and-illness-in-healthy-young-adult-volunteers