Why is infecting humans called a challenge?
The concept is simple — one of the best ways of finding out if a vaccine works for an infectious disease is to vaccinate someone and then expose them to the infectious microbe and see if they become sick. Most often, this is done naturally, and COVID is a good example of this in action. While the vaccines looked like they would be effective at preventing the disease in clinical trials, it took wide-scale monitoring at population level to understand their true effect on preventing disease and bringing the pandemic under control.
When new vaccines (or other drugs) are in development, they are firstly tested in phase 1 and 2 studies, which evaluate safety and check dosing levels in small numbers of clinical trial volunteers. In phase 2 studies of vaccines, researchers measure effects on the immune system and try and predict what level of immune system response might work to prevent someone developing the disease.
However, researchers can never be completely sure what the effect of a vaccine will be in the real world, so the next stage is to conduct a phase 3 study with hundreds or thousands of volunteers and monitor its effectiveness, often when the disease is circulating in the population. These types of studies are difficult to manage, are very time-consuming and extremely expensive. They also don’t work well for infectious diseases that do not circulate in a community, but might emerge as an epidemic, such as Zika virus or a new strain of flu.
To bridge the gap between phase 2, phase 3 and real-world effectiveness studies, an increasing number of clinical trials are being conducted that deliberately expose volunteers to an infection to evaluate the effect of a new vaccine or treatment. This type of study is not new and they have formed the basis of the development of many vaccines and treatments that we take for granted today. However, while they have been used to great benefit, they have also been responsible for some of the greatest harm inflicted by doctors and researchers on patients, volunteers, and, in some cases, prisoners.
I will explore these issues in future posts, but to start off, here I am looking at what this type of research study is called. While the concept behind the research is fairly easy to understand, over the years, several different names have been used to describe these studies. In 2018 The Wellcome Trust, one of the world’s largest funders of research science, including clinical trials, released a report aiming to try and clarify and standardise these names.
Most of the names used when reporting these studies are descriptive and usually involve the concept of “infection” as well as “human” and “volunteer” (e.g. human infection study, volunteer infection study). Sometimes they are described as “experimental” to differentiate them from “natural” infection in the community (e.g. experimental volunteer infection study). The other term used to describe deliberate exposure to an infectious microbe is a “challenge”, i.e. the clinical trial volunteers are challenged with the infectious agent to see if they develop the disease (e.g. human challenge study). Alongside this, some studies are also described as “controlled”, emphasising that this exposure is undertaken in tightly regulated, clinical environments with a focus on safety (e.g. controlled human infection study).
When describing the “model” (e.g. challenge study model, controlled human infection model, or CHIM) researchers are most often referring to the methodological construct of the trial. This will include the organism used, which will have well known characteristics relating to pathogenicity or drug sensitivity, expectations around how many volunteers will get sick after exposure, and what the outcome of any treatment may be. When researchers describe “model development” they are often referring to developing a new way of deliberately exposing volunteers to an infectious pathogen, for example, the new method described for a Streptococcus pyogenes (group A strep) infection model developed in Australia.
For simplicity and clarity, the Wellcome Trust recommended that these studies be called “human infection studies”, but the other commonly used names remain widespread. When writing on this topic, I will broadly aim to use human infection studies (HIS) to describe the overall field of research and controlled human infection model (CHIM) to describe the underlying methodology. No doubt I will stray into calling some challenge studies, as this description most accurately describes the experience of deliberately exposing a volunteer to an infection. But hopefully, we’ll all be on the same page.
