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
• monitor the performance of approved vaccines and treatments in the real world.

Researchers recruit a group of healthy adult volunteers to take part. They give an in-depth explanation of 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.

Given that current treatment options for Covid-19 are limited, it is important that volunteers are recruited from the lowest-risk groups and are closely monitored throughout the course of the study. The World Health Organization has published ethical guidelines for how studies should be set up and run.   

For example, volunteers should not include people:

• over the age of 30 
• with pre-existing health conditions (like diabetes)
• with respiratory problems.

Covid-19 studies are also 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.

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.  

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 who have already had the disease and have a small level of antibodies, to look at how long immunity against re-infection lasts.

The first ever Covid-19 human infection study will take place in the UK, after receiving ethics approval in February 2021. The study will recruit 90 people aged 18-30.

First, a Covid-19 dose escalation study will confirm the optimal dose of the virus (or challenge agent) that needs to be given to volunteers to cause a mild infection. If successful, and the study design gets regulatory approval, vaccine trials are expected to begin in mid to late 2021.

The study will be delivered by the UK government's Vaccines Taskforce, Imperial College London, the Royal Free London NHS Foundation Trust and hVIVO. 

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, 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.

Another benefit is that the studies produce highly-detailed information. They are performed under controlled conditions, so the timing of infection and the dose of the challenge agent given 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. 

Although developing successful vaccines is a huge step forwards towards ending the pandemic they are not a silver bullet, especially in the face of new variants.

We will need to keep learning more about the virus, as well as monitoring the performance of approved vaccines and treatments in the real world (also known as phase IV studies), and developing new ones.

Human infection studies can help us:

• better understand how long immunity lasts for, and the impact of different Covid-19 strains on our immune system
• test whether approved vaccines and treatments are effective against new strains 
• look at the effectiveness of approved vaccines and treatments across different population groups or geographical areas
• develop and test second and third generation vaccines more quickly – this will be especially useful if natural levels of infection are waning, making phase III trials more difficult
• develop and test new treatments.

There have been many successes using human infection studies. A key achievement is the development of the 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. 

Wellcome is currently funding eight human infection studies in Asia, Africa and South America, covering a variety of diseases. 

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, for example where the infection in the animal model does not mirror the infection in humans. They are usually only used when there’s already some form of treatment for the disease. 

This explainer was originally published in December 2018.