Human ‘challenge trials’ entail risk but they could be our best protection against the next pandemic

Fifty years ago this month, as the seasonal smallpox epidemic raged to a peak in India, nobody knew it would be the last. Over the course of the outbreak, close to 200,000 smallpox infections were recorded, and more than 30,000 deaths. Remarkably though, in May 1975 the last ever smallpox case in India was diagnosed. And in just three years, smallpox had been eradicated worldwide. 

The origins of this success can be traced to rural Gloucestershire in the late 18th century when English doctor Edward Jenner inoculated his gardener’s nine-year-old son with blister fluid from someone with cowpox. He did this with the aim of protecting the boy against smallpox – beginning the science of what would come to be called vaccination (from vacca ‘cow’). But Jenner’s innovation was not the vaccine itself. Similar ideas about cowpox had been circulating for decades, and the practice of vaccinating people with material from smallpox lesions had been used in various forms in Asia for centuries. 

What Jenner did that was unique was testing the effectiveness of the vaccine by then intentionally exposing the boy to smallpox. When he did not get infected, this provided the necessary scientific evidence to his peers that the cowpox vaccine was protective. Propelled by Jenner’s study, the practice of vaccination rapidly spread and so did the idea that vaccines could be used to ultimately eradicate disease. 

Ethical standards and the scientific method have improved considerably since Jenner’s time. And with it, the idea of using controlled human infection or “human challenge studies” where volunteers are deliberately exposed to an infection, has gained acceptance in the medical research community as a vital scientific tool. 

Over the past 20 years, hundreds of controlled human infection studies with more than 15,000 volunteers have been conducted around the world. In a controlled human infection study, volunteers are inoculated with a precisely quantified and exactingly prepared dose of an infectious agent such as a virus or bacteria. Volunteers are carefully selected to minimise any risk of harm and are often housed in quarantine facilities so they can be closely monitored while experiencing symptoms and to ensure no risk of transmission in the community.

Such studies yield extremely accurate and detailed data about how an infection develops and how the immune system responds to fight it. By measuring the release of virus from an infected person into the air and environment we can also understand better how it is transmitted, and crucially, how to stop this. 

As Jenner showed, human challenge studies also allow for vaccines and therapeutics to be directly experimentally tested in a way that cannot be done in a study of ‘natural infection’. Amongst others, the breakthrough malaria vaccine, and vaccines for cholera and influenza, owe their success to testing in controlled human infection studies during their clinical development.

Pandemic preparedness

For selected infections where the risks of harm are well understood and can be mitigated, controlled human infection studies are well accepted. But how far can this be taken? Is it safe and ethical to do such a study in the early stages of a pandemic with a new virus? 

The potential advantages are clear. Inevitably with infections that are acquired naturally in the community, the exact timing and amount of virus exposure cannot be known. Studies attempt to compensate for this by recruiting many participants but will always be beset by uncertainty. The beauty of a controlled human infection study is that data is obtained with a much smaller number of volunteers, and is much more precise, better underpinning the decision making that follows.

Controlled human infection studies are also often used to select the best candidates that should move forward into large clinical trials. Such trials are costly and may involve thousands of participants. Over the Covid-19 pandemic hundreds of vaccines entered clinical development. Only a small proportion were eventually licensed and just a handful administered at any sort of scale, suggesting that much of this effort could have been better placed. 

But working out how to do a controlled human infection study in the next pandemic means answering several key questions: can an infectious agent that meets the highest quality standards be developed fast enough to impact development of vaccines and treatments? And how should ethics committees and potential study volunteers judge the risk of participating when knowledge about the infection may be incomplete? 

For the first, the solution relies on investing in the laboratory methods and capabilities to more quickly produce the clean and well-tested infectious agent that can be used in human studies. This is a major aim of MusiCC, an international controlled human infection consortium led by Imperial College London that launched recently with funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and the European Commission’s Horizon programme. 

The second appears more complicated to answer when the nature of any future outbreak is unknown. However, the first of its kind SARS-CoV-2 controlled human infection study conducted in the UK in early 2021 in unvaccinated and uninfected volunteers showed that it is possible to do this type of study during a pandemic. That study benefited from the careful consideration of ethicists and experts that occurred from early in the pandemic. Building on this, the ethical framework for how such a study should be assessed during an emergency is now being developed by the World Health Organization (WHO). This includes considering how to communicate to potential volunteers the risks and the areas of uncertainty, robust safety procedures that includes selection of participants at low risk of serious complications by comprehensive health checks, and independent monitoring to minimise any risk of harm, and appropriate compensation. 

But fundamentally, when a healthy volunteer is exposed to some degree of risk (whether from a new medication or an infectious agent) there needs to be a compelling rationale and prospect of benefit to public health. Even with incomplete data, these risks can be estimated and modelled through good quality studies of natural infection and then continually updated as a pandemic evolves and our understanding about an infection improves. This must then be built into a robust informed consent process, so that volunteers can make a reasoned decision to participate based on what is known and unknown in terms of benefits to society and potential risks to themselves. 

If such a study could have started in 2020 rather than 2021, it may have changed the course of the Covid-19 pandemic. While the SARS-CoV-2 vaccines lived up to their promise at reducing severe illness and death, they have been less effective at preventing infection or stopping the continued transmission of SARS-CoV-2. Developing vaccines which block transmission of respiratory viruses is difficult and testing transmission-blocking capacity in a conventional clinical trial is difficult to do. It is therefore imperative that the vaccine which is tested in these trials has the best chance of success. Controlled human infection studies give us the information to select this. 

The rewards of getting this right can be enormous. From their humble origin in a muddy cowshed, the next-generation vaccines being developed today could re-awaken the Jennerian dream of eradicating infectious diseases and stopping a pandemic before it has begun.

• Associate Professor Barnaby Young is Head of Singapore Infectious Disease Clinical Research Network (SCRN) at the National Centre for Infectious Diseases (NCID); Professor Wang Linfa is Director of Emerging Infectious Diseases Research Programme at Singapore’s Duke-NUS Medical School; Professor Chris Chiu is Professor of Infectious Diseases at Imperial College London and principal investigator for MusiCC

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