Challenge studies for COVID-19: Now is not the time

By Landon J Getz and Francoise Baylis

hVIVO, a for-profit clinical research organization in London, in collaboration with Imperial College London, has initiated a human challenge study in youth between the ages of 18 and 30 to determine the dose at which individuals become infected with SARS-CoV-2, the virus that causes COVID-19. The dose-ranging study, which began in March 2021, is the first in a planned series of human challenge trials where healthy volunteers will be intentionally exposed to the novel coronavirus.

While there is some enthusiasm for this study among potential volunteers, there is reason to question the ethics of this research which involves intentionally putting youth in harms way.

 

Risk of Serious Harm or Death

While our knowledge of SARS-CoV-2 has increased exponentially in the past year, critical knowledge gaps remain. Of particular relevance to the planned challenge studies is the fact that we cannot reliably predict who among young healthy volunteers might experience mild to severe illness from exposure to even a small dose of the virus. Nor can we reliably predict who among those who get sick will suffer from “Long COVID”, a persistent infection that can last for months. This is a serious problem given that there are no efficacious treatments for COVID-19 that “can be administered at an appropriate juncture in disease development to prevent significant morbidity (and eliminate mortality)”. There is Emergency Use Authorization for the simultaneous intravenous infusion of casirivimab and imdevimab, but we know some people who receive these monoclonal antibodies still require medical attention or hospitalization.

Other pathogens for which human challenge studies typically are performed, either cause self-limiting illness or there are rescue therapies that make it possible to minimize the risk of serious harm.

 

Absence of a clear favourable harm-benefit ratio

For all research involving humans there is an ethical obligation to ensure a favourable harm benefit ratio. The age range for this challenge study (18-30 years) aims to minimize the overall risk of harm by limiting enrolment to those less likely to experience serious harm from infection. But in so doing, the potential for benefit – described as an increase in our “understanding of how the virus affects people” – is also significantly decreased owing to the problem of extrapolation.

The knowledge gained from infecting volunteers 18-30 years of age may not apply to people who are younger or older. The knowledge gained from infecting healthy volunteers may not apply to those with co-morbidities. As well, some ethnic groups appear to be at increased risk of illness from SARS-CoV-2. If they too are excluded from the study as part of the strategy to minimize the overall risk of harm, the knowledge gained from infecting one ethnic group may not benefit members of the excluded ethnic groups. Lastly, the GMP virus being used in the dose-ranging study is the virus that has been circulating since March 2020. The knowledge gained about this virus may be less helpful with the new variants that are more transmissible and more deadly.  For example, the B.1.1.7. variant (the UK variant) is up to 75% more transmissible.

If the findings of the dose-ranging study cannot be generalized, it could well be that this study involves exposing research participants to a risk of serious harm without the countervailing benefit of producing broadly useful knowledge.

 

Informed Choice

Among the elements of informed choice are full disclosure and voluntariness. Currently, recruitment through the UkCovidChallenge website provides no details about the planned COVID-19 human challenge studies. Only general information about the human challenge model is conveyed alongside visuals of attractive young people relaxed in a hospital bed reading, on their phones/laptops, smiling, ultimately happy. If anything, this might reasonably be described as misleading information.

At this time, the study protocol and consent form are not in the public domain and there is no information about the ethics approval process other than disclosure of the fact of review and approval by a Research Ethics Committee. As such, details about the trial design, the outcome measures and the planned analysis are unknown.  Also unknown is exactly what information prospective participants will be given about the trial and, more specifically, about the risks associated with COVID infection including the risks of long-term fatigue, breathlessness, headaches, chest pains, palpitations, and dizziness associated with “Long COVID”.

As regards voluntariness, there is the risk of undue inducement as well as the risk of exploitation – the first risk having to do with autonomy and the second risk having to do with agency. For two weeks in isolation and a series of follow-up appointments over the ensuing 12 months, volunteers in the dose-ranging study will be paid £4,500. Is this too much? What is the risk of undue financial inducement perhaps especially among those who are unemployed or underemployed? As of September 2020, 20% of people in the United Kingdom between the ages of 18 and 24 were unemployed. It is likely that at least some of those applying to participate in the challenge study will be among the unemployed and possibly in dire straits (unless some kind of means test will be part of the selection process). Alternatively, is the payment too little – a paltry sum given the (admittedly small) risk of death or (slightly greater) risk of catastrophic illness associated with Long COVID?

 

Haven’t we Asked Enough?

 While many are quick to note other contexts in which we accept the idea that some should take risks for the benefit of others – as happens with those who work in the armed forces, law enforcement, firefighting and so on –  there are important ways in which these jobs are not analogous to the situation of volunteer research participants who do not have any of the benefits or protections that come with career employment and advancement.

From another perspective, it is important to assess the ethics of the ask.  At issue is whether there are things that just should not be asked of others, despite (or in spite of) their willingness to acquiesce?

Civic-minded young people have shown themselves willing to volunteer for COVID-19 human challenge studies. But maybe this is something that they should never have been asked to volunteer for. As our colleague Letitia Meynell writes “This generation of young adults will inherit a world burdened with a manifestly unjust economic system, rising political instability, the extinction crisis, and catastrophic climate change. These are the predictable results of various poor decisions driven by the moral and political failings of the older generation that they are now being called on to protect.”

 

Conclusion

Ethical issues regarding serious risk of harm, trial design, informed choice, and justice plague COVID-19 human challenge studies, and ought to preclude their progression.

 

Authors: Landon J Getz, Francoise Baylis

Affiliations: 

Landon J. Getz is a Ph.D. Candidate, Vanier Scholar and Killam Laureate in the Thomas Lab, Department of Microbiology and Immunology at Dalhousie University

Françoise Baylis is University Research Professor at Dalhousie University in Halifax. She is a member of the Order of Canada and the Order of Nova Scotia, as well as a fellow of the Royal Society of Canada and of the Canadian Academy of Health Sciences. Baylis is the author of Altered Inheritance: CRISPR and the Ethics of Human Genome Editing.

Social media accounts of post authors:

Twitter: @landongetz @francoisebaylis

Competing interests: None declared

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