Challenging Circumstances: we need international guidelines for human infection studies
Would you be willing to infect yourself with coronavirus to test a vaccine?
There is no known cure, no proven treatment, and COVID-19 can kill even healthy young adults. Yet online campaigns are already demonstrating that volunteers are willing and pharma companies say they may consider this to accelerate COVID-19 vaccine development.
Controlled human infection studies (also known as challenge studies) are not new or unusual in vaccine development. Edward Jenner, ‘father’ of modern vaccination, tested a vaccine for smallpox this way. Infection studies have also been conducted for cholera, shigella, influenza, malaria, and typhoid vaccines and the number of studies has increased over recent decades. In 2017, a University of Oxford trial on typhoid helped speed the licensing of a new vaccine that is now being rolled out in places where the disease poses a substantial threat.
Similar to other forms of medical experimentation, infection studies have a mixed history as far as ethics are concerned and continue to present ethical challenges even in diseases where treatments are available. The development of vaccines against COVID-19 will likely test the ethical limits of existing trial frameworks. So much so that the World Health Organisation (WHO) has published criteria for the ethical acceptability of COVID-19 human infection studies. The question is whether this could also open the door for more comprehensive global guidance on human infection studies?
Rather than rolling out a new vaccine to thousands of people and relying on uncontrolled natural infections, vaccinating and then intentionally infecting carefully monitored healthy volunteers allows researchers to quickly see how well potential vaccines may work in comparatively safe circumstances. However, there are things that have to be considered before going ahead with potential COVID-19 trials. For one, there is no guarantee that trials will result in successful vaccine rollouts.
Between 1946 and 1989, Britain’s Common Cold Unit infected over 20,000 volunteers with common cold viruses. The trials improved knowledge of respiratory viruses and led to an anti-influenza compound but did not result in a proven vaccine. Even if a successful vaccine is found it is not all straightforward. Trial participants are subject to medical screening to ensure they are healthy before vaccination and infection, wider populations will have varying complicating factors like age, malnutrition, obesity, or additional infectious and non-infectious diseases.
Ethically, COVID-19 infection studies are at the edge of what may be acceptable. Challenge studies require knowledge of the appropriate infectious dosage with which to test a vaccine and usually require a ‘rescue remedy’ if participants fall ill. We currently know of neither of these in the case of COVID-19.
There are also the critical questions of where to conduct trials and how to select participants. In 1796, Edward Jenner tested his cowpox vaccine against the deadly smallpox virus on his gardener’s son, James Phipps, by inoculating him and then exposing him to smallpox scabs. This experiment proved successful and resulted in a new form of vaccination that saved countless lives and paved the way for the eradication of smallpox by 1980.
In the 19th and 20th centuries, imperial powers trialled new vaccines and treatments on colonial subjects. Vulnerable populations in rich countries were also exploited. During the 1940s, US researchers infected four hundred prisoners with malaria to test potential treatments. In Nazi Germany, doctors conducted infection studies on concentration camp inmates. Even after the 1947 Nuremberg Code established the principles of informed consent, voluntary participation, and freedom to leave a study, infection studies in US prisons continued until 1976.
Whether and how to reward participants is an equally difficult question. There are concerns that high financial rewards could unduly influence volunteers to participate in trials due to financial need and whether participants in low-income countries should receive similar payments to those in high-income countries.
Despite their chequered past and these important ethical questions, there currently is no international regulatory framework for human infection studies. In Britain, challenge agents are not considered drugs and studies including no new investigational medicinal product only require local ethics approvals. In the US, trials are subject to oversight by the Food and Drug Administration. In India, concerns about the ‘offshoring’ of clinical trials led to restrictions in 2013 but legalising strictly controlled infection studies is now being considered.
With multiple countries trying to win the prestigious race for the first COVID-19 vaccine and enormous hopes resting on rapid trials, pressure for COVID-19 infection studies is building. In addition to personal hazards for volunteers, there is, however, a risk that rushed, badly designed, or exploitative infection studies could undermine wider trust in resultant vaccines and medical research generally. Past experiences like the 2019 CRISPR-baby scandal show that weak standards in one place can bring disrepute on an entire community.
WHO and other organisations have been working on scientific and regulatory considerations for infection studies since 2014. The eight WHO criteria for COVID-19 studies, which include scientific justification and an ethical assessment based on risks and potential benefits, will hopefully mark the first step towards more comprehensive global guidance for all forms of infection studies.
Authors
Dr Claas Kirchhelle, (@kirchhelle) Oxford Martin Fellow and Lecturer, University College Dublin, and Dr Samantha Vanderslott, (@sjvanders) Social Sciences Researcher.
This opinion piece reflects the views of the author, and does not necessarily reflect the position of the Oxford Martin School or the University of Oxford. Any errors or omissions are those of the author.
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