What are human infection studies and why do we need them?

Human infection studies are clinical trials that involve deliberately exposing volunteers to infectious diseases. 

The results can help researchers to:

• understand more about how the body’s immune system responds to a disease
• work out how to prevent the disease or improve its treatment 
• test the effectiveness of potential new vaccines and treatments.

Researchers recruit a group of healthy adult volunteers to take part. They explain the process and the risks involved, and they monitor the volunteers’ health throughout the study.

The study could involve testing:

• vaccines – doctors give the volunteers a dose of the vaccine, then administer a controlled dose of the relevant challenge agent, for example a virus
• treatments – doctors administer the challenge agent, then give volunteers a treatment.

There are strict guidelines in place to protect the people taking part, and they are financially reimbursed for their time.

If volunteers get ill, help is close at hand. Doctors can give them existing treatments that are known to work, and provide other care as needed. If they don’t become ill, it means the vaccine or treatment works.

The process of setting up a human infection study is long and rigorous – taking up to a year and involving many stages to meet high safety and ethical standards. Several key things need to be in place before they can begin, including the development of a suitable challenge agent (which is the dose of the virus that is given to volunteers), volunteer recruitment, site preparation, and having an effective treatment that is known to work. A Covid-19 human infection study will follow a similar process, but there will be some differences.

One difference is that Covid-19 human infection studies are being considered by some governments and funders in the absence of an effective treatment. Even though these studies would be subject to even stricter regulation and monitoring, Wellcome will only support a Covid-19 study if and when an effective treatment is found. 

Volunteers normally take part in human infection studies for around 15 days. This will be the same for Covid-19 studies, but the follow-up, at least for the first few studies, will be much longer to gain information on the duration of antibody response and to confirm there are no long-term side effects.  

Another difference is that, compared with other studies such as for malaria, Covid-19 studies are only likely to take place in high-income settings – like the UK and the US – where facilities can meet the stricter quarantine standards required. Dedicated quarantine facilities will need to be upgraded for Covid-19 studies, for example to allow for controlled air flow. Suitable Covid-19 quarantine facilities will usually be isolation wards attached to hospitals.

The profile of the volunteers who take part may also be different. To maximise safety, volunteers will not include people who are at risk for severe cases of Covid-19, such as people:

• over the age of 50
• with pre-existing health conditions (for example, diabetes)
• with respiratory problems
• from a Black, Asian and minority ethnic population.

Traditionally, studies involve volunteers who have no antibodies to the pathogen they are going to be infected with. However, Covid-19 studies may also include volunteers with a small level of antibodies to look at how long immunity against re-infection lasts.

Currently both the UK and US governments are exploring using human infection studies as a part of Covid-19 vaccine development. 

We foresee that the first Covid-19 studies will begin at the end of 2020 or early 2021. This will initially involve confirming the optimal dose of the challenge agent that needs to be given to a volunteer to cause a mild infection. 

With a rigorous set-up and optimisation process needing to be followed, Covid-19 human infection studies will only begin testing vaccines in volunteers from mid- to late 2021 at the earliest. 

The process of developing and testing new vaccines involves preclinical stages (carried out in lab assays and on animals) and clinical trials (on human subjects). It’s a slow process that can take as long as ten years. This process has been streamlined for Covid-19 vaccine research and development. 

Few test vaccines make the transition from the preclinical stages to clinical trials. And even for those that get to the first round of clinical trials, a test vaccine that performs well in animals doesn’t always predict protection in humans. Using animals to reflect human disease can be unreliable because their biology is different from ours and many infectious organisms are specific to humans. 

Human infection studies have the potential to make vaccine and treatment trials faster, cheaper and more effective. Just as we need multiple options to tackle diseases, we need multiple options for how we conduct trials.

Because the studies use humans in preliminary testing, they give a much earlier indication of whether a vaccine or treatment will work. This could be of particular use for a Covid-19 vaccine, where there are more than 320 possible vaccine candidates in development(opens in a new tab), using a wide variety of methods and technologies. A Covid-19 study could help us to narrow down the field of potential candidates much faster than through traditional clinical trials. 

The studies complement Phase II and III clinical trials – which require hundreds to thousands of participants who are infected naturally with a disease – particularly if these trials take longer to deliver than planned.  

For example, if Covid-19 starts to decline around the world, the number of people naturally infected will decrease which could prove problematic for clinical trials. Human infection studies can make sure that there are enough people to test vaccines and treatments on in a safe and controlled environment.

Human infection studies can take place anywhere. They can focus on a particular population where a disease is endemic, helping to test and develop effective vaccines and treatments for the communities most at risk.   

Another benefit is that the studies produce highly-detailed information. They are performed under controlled conditions, so the timing of infection is known. The volunteer’s health is monitored to see how the disease is progressing and how their body is responding to the treatment or vaccine being tested. The studies might also be used to investigate optimal dosing, how long immunity lasts for, and to compare the efficacy of different successful vaccines and treatments.

There have been many successes using human infection studies. A key achievement is the development of the new typhoid conjugate vaccine Vi-TT (Vi-tetanus toxoid conjugate vaccine). 

During testing in humans, the vaccine showed efficacy of 87.1%. As a result, the World Health Organization recommended it as the preferred vaccine for all ages. 

No, but they have a very wide application. Human infection studies are currently being used to develop vaccines and treatments for diseases such as malaria, typhoid, influenza and dengue. 

They are most appropriate for diseases where no suitable animal models exist. They are usually only used when there’s already some form of treatment for the disease. 

Before taking part, volunteers are given an in-depth explanation of what will be involved. Recruiting and screening volunteers often takes weeks, so that they have time to fully consider their decision to take part. The volunteers are required to give their written and spoken consent repeatedly during the study.

Throughout the testing, volunteers have access to doctors and support workers who can answer any questions and provide necessary treatment. 

Wellcome and other major funders of human infection studies are committed to making sure that studies of this kind are conducted ethically. The World Health Organization has also published guidance for the set-up and running of any Covid-19 human infection studies.

This explainer was originally published in December 2018, and updated on 25 September 2020.