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Covid-19: Human challenge studies will see people purposefully infected with virus

BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4101 (Published 22 October 2020) Cite this as: BMJ 2020;371:m4101

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Re: Covid-19: Human challenge studies will see people purposefully infected with virus

Dear Editor

The covid-19 pandemic affects all countries in the world, has cost already about 1,150,000 lives and has led to the most serious economic recession since World War II. The social and psychological consequences of the lockdown are not yet fully known [1]. It can be doubted that these severe negative impacts on human societies will stop unless effective vaccines and treatments are available. Thus one tries to accelerate their development as the currently required preclinical and clinical testing typically takes years before they can get approved by drug authorities. With the aim of speeding the evaluation of the effectiveness and safety of vaccines, so-called human challenge studies [2-5] are currently discussed intensively, and now even planned. There has been a worldwide initiative to register volunteers for such a study too [6]. The objective of the following deliberations is to focus on the ethical and scientific problems of human challenge trials.

The concept of a challenge trial is that all participants are first vaccinated with placebo or with the test vaccine and then get intentionally exposed with a sufficiently high dose of SARS-CoV-2, so that all participants can be considered infected. As all participants have been exposed, the efficacy of a vaccine can be assessed with considerably smaller sample sizes and possibly more quickly, as compared to a conventional trial with community participants. Such challenge trials have been performed in the past with infections like hookworms, cholera, and malaria. But challenge trials go along with serious ethical issues [7], and often neglect scientific and practical pitfalls.

First of all a challenge trial does not provide any direct benefit for the participant. A further important ethical issue is that since Hippocrates physicians have been asked to obey to two principles: beneficence and non-maleficence. Both are still indispensable and present an essential part of deontological ethics. Beneficence means that the physician has to take positive steps to contribute to the wellbeing of persons. The principle of nonmaleficence is often abbreviated to the words: ”Above all do no harm.” It is obvious that the intentional infection of persons, even if they are volunteers, means that physicians act in sharp contrast to these two principles that are still today part of the Hippocratic oath. The principal assumption of challenge trials is that harm has to be done to prevent greater harm for the society. There is no doubt, and the proponents of challenge trials admit too, that fatalities may occur in challenge trials.

Thus a sample of volunteers with a very low risk for suffering from serious covid-19 is looked for. Till today, the characteristics of such a distinct group of volunteers without any risk of fatal progression and stressful late complications of covid-19 are not known. Thus there is already a discussion ongoing what rate of fatal cases could be accepted for a challenge trial [8]. A discussion of what it means for the mental wellbeing of a physician when he or she realises that a presumably young healthy volunteer, who has been intentionally infected, has died, is still absent. We know, however, that even relatives who were involved in vital decisions on their family member may suffer long term from serious psychological distress [9]. Thus physicians should not be forced to participate in challenge trials and should provide informed consent too before they can participate.

The relevance of the ethical issues with covid-19 challenge trials could be reduced if a highly effective and safe treatment is available. Up to now such a treatment is not available. The informed consent of the volunteer has to be provided after comprehensive information, with regard to the potential long term consequences of covid-19, being fully understood too. It may be questionable, however, that a person can imagine the consequences for his quality of life when a scarred lung tissue, for instance, impairs his health many years later. In addition, it is a misunderstanding of the commitment of informed consent that it permits medically inappropriate behaviour. Thus it may happen that a physician involved in a covid-19 challenge trial gets prosecuted, convicted and may end in prison or may lose the license, if the patient suffers a severe adverse outcome.

From an ethical point of view, great care needs to be taken to avoid that primarily members of underprivileged and vulnerable groups of a society participate in a challenge trial. It is hard to believe that members of the prosperous parts of society will volunteer for covid-19 challenge trials. There are also practical problems that limit the usefulness of challenge trials. The sample of volunteers will consist most probably of very healthy, young adult women, as these are currently regarded as a group with the lowest risk of suffering from severe covid-19. It cannot be taken for granted, however, that results achieved with such persons can be generalized to elderly, multimorbid men, the high-risk group. There has been evidence that many vaccines, which work well in young and middle-aged persons, do not work in elderly ones [10]. Thus even the medical and social value of a covid-19 challenge trial can be questioned.

The second practical issue is that the dosage of SARS-CoV-2 needed to effectively infect the volunteers is not yet known. Thus prior to the challenge trial itself, dosage assays are needed, which take time and further limit the potential to hasten the evaluation of the vaccine.

Finally there are already 11 covid-19-vaccines being tested in phase III trials without using prior human challenge trials. Thus one can only hope that human challenge trials with SARS-CoV-2 will not be performed as human beings should not become just a means to an end.

References
1. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N, Rubin GJ. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020 Mar 14;395(10227):912-920.
2. Eyal N, Lipsitch M, Smith PG. Human challenge studies to accelerate coronavirus vaccine licensure. J Infect Dis 2020; 221:1752-1756.
3. Shah SK, Miller FG, Darton TC, et al. Ethics of controlled human infection to address COVID-19. Science. 2020;368(6493):832‐834.
4. Jamrozik E, Selgelid MJ. COVID-19 human challenge studies: ethical issues. Lancet Infect Dis. 2020 May 29:S1473-3099(20)30438-2.
5. Rubin R. Challenge Trials-Could Deliberate Coronavirus Exposure Hasten Vaccine Development? JAMA. 2020 Jun 4. doi: 10.1001/jama.2020.9881. Epub ahead of print. PMID: 32496545.
6. https://1daysooner.org accessed 23 October 2020
7. Metzger WG, Ehni H-J, Kremsner PG, Mordmueller BG. Experimental infections in humans – historical and ethical reflections. Trop Med Int Health 2019;24:1384-1390.
8. Binik A. What risks should be permissible in controlled human infection model studies. Bioethics 2020;34:420-430.
9. Wendler D, Rid A. Systematic review: the effect on surrogates of making treatment decisions for others. Ann Intern Med. 2011;154:336-346.
10. Wagner A, Weinberger B. Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives. Front Immunol 2020; 11:717.

The opinion expressed here does not necessarily represent the opinion of the Association of Medical Ethics Committees in Germany (AKEK)

Competing interests: No competing interests

25 October 2020
Joerg Hasford
Professor for Medical Biometry and Epidemiology and President of the Association of Medical Ethics Committees in Germany
Association of Medical Ethics Committees in Germany and Institute for Medical Information Processing, Biometry, and Epidemiology , University of Munich
AKEK Charlottenstr. 42 10117 Berlin, Germany