Human challenge studies in the study of infectious diseases

What are human challenge studies?

Human challenge studies are clinical trials in which researchers intentionally expose healthy volunteers to a pathogen (such as a virus, fungus or bacteria). These studies enable researchers to better understand the disease that these pathogens cause. They can also be used to test the effectiveness of drug treatments and vaccines.

Human challenge studies have been used since the late 1800s. Since then, human challenge studies have been refined to study infectious disease in controlled settings. People are typically given a small dose of a pathogen through oral ingestion, inhalation, or injection. Medical professionals then closely monitor participants to observe how the body responds and whether treatment is effective in managing or preventing disease.

Examples of human challenge studies

Researchers have used human challenge studies to evaluate the safety, immune response, and effectiveness of new treatments and vaccines against many pathogens, including malaria, influenza, typhoid and cholera. This experimental approach drew recent attention during the Covid-19 pandemic, when human challenge studies were used to learn about SARS-CoV-2.

Typhoid Fever (Salmonella typhi)

Typhoid fever is a highly contagious infection caused by Salmonella typhi, a bacterium which infects over 9 million people per year. It is more prevalent in countries with poor sanitation and limited access to safe drinking water. Without treatment, an estimated 1 in 5 infected people will die.

In 2017, 112 healthy adult volunteers were randomly assigned to receive either a new typhoid vaccine or a placebo. After vaccination, participants were exposed to a strain of Salmonella typhi, and researchers monitored the incidence of typhoid fever in both groups. The vaccine was highly effective, with significantly fewer cases of typhoid fever amongst the vaccinated group. There was also evidence that, where vaccinated participants still became infected, their symptoms were less severe.

Cholera (Vibrio cholerae)

Cholera is an illness caused by infection of the small intestine, usually spread through contaminated water. Like typhoid, it is also linked to inadequate sanitation. Cholera infects up to 4 million people per year, resulting in up to 143,000 deaths.

In the 1960s, the first cholera vaccine was licensed following human challenge studies conducted in Bangladesh, India, and the Philippines, albeit with 60% efficacy and poorly tolerated side effects. In the same decade, human challenge studies were used to estimate levels of bacteria required in the body to cause clinical cholera disease. More developed models of human challenge studies are still being used to test and approve more effective oral vaccines against cholera.

Covid-19

The UK-based Human Challenge Programme conducted the first Covid-19 human challenge study in the world. 36 healthy young volunteers were injected with SARS-CoV-2, and 18 of them developed Covid-19 infection confirmed by blood tests. Over 28 days, participants provided daily nose and throat swab samples, in addition to blood samples, to allow researchers to monitor changes in viral levels and symptoms over time.

The findings showed that even low doses of the virus can cause Covid-19 infection, and that young adults are more likely to experience mild or asymptomatic cases. The study also validated that lateral flow tests are a good indicator of infection. Researchers have planned a one-year follow-up to monitor for prolonged symptoms, including smell disturbance and neurological dysfunction.

Benefits of human challenge studies

Methodological approach

Human challenge studies can supplement the findings of conventional research focused on incidental infections. Conventional studies can be retrospective, as scientists may find people who have been infected with a disease earlier in their life and evaluate the longer-term health impacts. They may also be prospective, where scientists follow a cohort of patients who are infected, or go on to be infected, with a disease of interest.

In contrast, human challenge studies involve deliberate infection, and allow researchers to precisely track disease manifestation, recovery, and treatment in controlled settings. For example, researchers can accurately control the level of exposure for a specific strain of an infectious disease. This also provides an exact timepoint of exposure, which enables researchers to understand the time course for different stages of infection and recovery.

Human challenges studies can also reduce the time and cost of clinical trials, as they require fewer participants and a shorter follow-up period compared to conventional studies based on incidental infection.

Transmission rates

Deliberate infection allows researchers to study diseases even when there are low levels of population infection. This is helpful for studying pathogens that infect people in seasonal peaks and troughs (such as influenza viruses). Therefore, human challenge studies can advance understanding of a disease even in low transmission periods. This can improve preparedness for high transmission seasons.

Disease mechanisms

Human challenge studies inform researchers on how pathogens infect the body and help scientists to identify which parts of the virus to target with treatments or vaccines. For example, the INFLAMMAGE trial is investigating Respiratory Syncytial Virus (RSV), which commonly causes chest infections in young babies and the elderly. The study will improve understanding on how the immune system responds to RSV infection in older people. This can help scientists to identify which parts of the virus to target with treatments or vaccines.

Human challenge studies can provide more precise insights than incidental infection studies, which may not be able to identify the specific time of infection (or how infection occurred) outside a controlled setting.

Testing new vaccines and treatments

Human challenge studies offer a controlled environment, which enables researchers to directly test the effectiveness of newly developed treatments, whilst keeping all other confounding factors that may affect treatment performance (such as exposure and environment during infection and recovery) the same. Typically, different groups of participants receive alternative treatments (or either a treatment or a placebo) so that their symptoms and recovery responses can be directly compared in the same setting. As a result, researchers can make more precise comparisons, due to accurate time-tracking and the ability to closely monitor the disease process.

For example, one study showed more rapid RSV clearance, greater reduction in viral load, and improvements in the severity of clinical disease, in people who received a new treatment (ALS-008176) compared to a placebo. This treatment was then tested in a clinical trial with infants admitted to hospital with RSV.

Human challenge studies can also accelerate vaccine development, as deliberate infection can be used to optimise vaccine dosages and schedules to improve their effectiveness. For example, one influenza study showed that two lower doses of the vaccine resulted in the greatest increase in antibody creation, compared to one or two higher doses. By measuring antibody responses regularly, researchers can measure when the antibody levels begin to fall, which can indicate whether a booster might be needed.

Challenges and additional considerations

Some stakeholders have raised ethical concerns for human challenge studies, particularly regarding risk to participants and potential for exploitation.

Managing risks to participants

One main concern is the safety of participants, particularly when there is no known effective ‘rescue treatments’ for the disease being studied. This was originally the case for SARS-CoV-2 and Zika virus human challenge studies, for example.

Human challenge studies involve deliberate exposure to harm. Usually, deliberate exposure to harm is considered a contravention of the Hippocratic Oath (the ethical code for medical practitioners). There may be multiple risks of harm if volunteers are deliberately exposed to both a pathogen, and an experimental treatment in which effectiveness and/or side effects may be uncertain.

However, risks of harm may be ethically justified if they are outweighed by benefits. For example, side-effects from chemotherapy when treating cancer. However, risks and benefits can be harder to determine for an emerging disease, as there may be uncertainties on how prevalent the disease will become or how effective research treatments will be.

There are specific challenges for comparing risks and benefits in human challenge studies, as these studies tend to provide delayed benefits to wider society (such as effective treatment development), rather than direct benefits to the volunteers themselves. In some cases, volunteers may not benefit from effective vaccines or treatments developed as a result of their participation (for example, if the approved treatment is targeted at elderly or clinically vulnerable people).

Informed consent

Participants must provide informed consent before taking part in human challenge studies. However, some critics argue that people cannot give true ‘informed consent’ for studies of emerging diseases, as the immediate and long-term risks may not yet be fully understood. For example, there are concerns about the risks of long-Covid to volunteers. Recent imaging studies have shown that SARS-CoV-2 infection can lead to changes in the regions of the brain responsible for smell, indicating there may be permanent consequences of infection.

Risks of exploitation

Human challenge studies can be conducted in regions of endemic disease to provide relevant insights on the populations affected.

These areas often include low- or middle-income countries where there may be increased financial motivation for taking part. Consequently, adverse effects of human challenge studies may disproportionately affect certain groups, and there is a risk of exploitation if financial incentives are offered or people do not fully understand the risks. There is also evidence that this is occurring in the UK, with media outlets advertising human challenge studies as potential solutions to the cost-of-living crisis.

There is a further risk that people in low- or middle-income countries may be less likely to benefit from knowledge or innovations developed from the research (such as vaccines or treatments), due to barriers to access and affordability.

Overall representativeness

Most human challenge studies recruit young, healthy volunteers, as the risks of complications are lower than in older people or comorbid populations where people have additional medical conditions. However, this may reduce the usefulness of findings when applied to the general population. For example, most patients admitted to hospital with Covid-19 were older and had additional comorbidities, whereas the first Covid-19 human challenge study consisted of healthy young people.

UK support and regulatory oversight

Funding

In October 2020, the Government announced £33.6 million in funding to support UK human challenge studies. This funding was used to conduct the world’s first Covid-19 human challenge study.

Human challenge studies can also be funded by research councils, as well as private foundations or industry partners. For example, the Medical Research Council (MRC) funded the Common Cold Unit, which ran human challenge studies for over 40 years and led to the discovery of the first human coronavirus in the 1960s.

In 2021, the Wellcome Trust announced £15 million of funding to support Covid-19 infection studies over two years. This included a human challenge study investigating the immune response to re-infection.

Regulatory oversight

In the UK, plans for all clinical studies are considered and approved by regulators including the Medicines and Healthcare products Regulatory Agency (MHRA) and the NHS Health Research Authority before the research starts. Ethics committees ensure that clinical trials involving human participants are meeting ethical and scientific quality requirements.

In February 2021, the World Health Organisation (WHO) published a report from its Advisory Group on human challenge studies with recommendations for ethics and regulation, following their increased use throughout the Covid-19 pandemic.

Parliamentary interest

In December 2022, the House of Commons Science & Technology Select Committee launched an inquiry into emerging diseases and learnings from Covid-19. This followed a joint report with the House of Commons Health and Social Care Committee, Coronavirus: lessons learned to date‘. The inquiry included written evidence on how human challenge studies can be useful for future pandemic preparedness, based on the Ethical Framework report from the UKRI-funded UK Pandemic Ethics Accelerator Project.

Following consultation with wider stakeholders, non-profit organisation 1Day Sooner proposed that it is essential to establish clearer guidelines, ethical frameworks, infrastructure and regulatory pathways to deploy human challenge studies quickly. They argued that such measures will be critical in initiatives such as the G7 100 Day Mission, which aims to make diagnostics, therapeutics and vaccines available within the first 100 days of future pandemics.

Acknowledgements

POST would like to thank Dr Ruchi Baxi and Dr Selena Stellman from the Nuffield Council on Bioethics, who acted as external peer reviewers in preparation of this article.

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