By Hayden P. Nix and Charles Weijer.
Human challenge studies are clinical trials in which researchers intentionally infect research participants with a pathogen. The UK government has announced plans to conduct SARS-CoV-2 challenge studies beginning in January 2021.
SARS-CoV-2 human challenge studies are controversial because of the risks they pose to participants. In order to justify these risks, an analogy has been drawn between participation in a SARS-CoV-2 challenge study and altruistic kidney donation. The analogy arose from their common altruistic nature, and the fact that both COVID-19 in young, healthy patients and altruistic kidney donation have a mortality rate of approximately 3 in 10,000. The analogy has appeared in academic literature, [1, 2] and its intuitive appeal led to pervasive uptake in the mainstream media, appearing in The Washington Post, CNN, The Atlantic, and The Guardian. But is altruistic kidney donation sufficiently analogous to participation in a SARS-CoV-2 challenge study to justify the risks?
Three morally relevant features distinguish challenge studies from altruistic kidney donation: (1) our understanding of adverse effects, (2) the availability of alternatives, and (3) the potential to undermine public trust. These differences undermine the analogy, demonstrating that the ethical acceptability of altruistic organ donation does not justify the risks of SARS-CoV-2 challenge studies.
In addition to mortality, morbidity is an important consideration for both altruistic kidney donation and SARS-CoV-2 challenge studies. The adverse effects of kidney donation are well understood. The risks of acute complications, such as bleeding and anesthesia-related injuries, are well known and have been incorporated into consent materials for altruistic donors. Relative to the general population, kidney donors are not at an increased risk of all-cause mortality, cardiovascular disease, or type 2 diabetes. Donors are, however, at an increased risk of end-stage renal failure and preeclampsia. Equipped with this knowledge, donors and their physicians know what to expect and can attempt to prevent and manage these conditions early in their progression.
In contrast, the adverse effects of COVID-19 remain poorly understood. In addition to respiratory illness, stroke, encephalopathy, and myocarditis, there are reports of COVID-19 causing diabetes, thyroiditis and multi-organ damage months after the initial infection. These reports require further investigation. The uncertainty surrounding potentially serious complications that may befall participants in SARS-CoV-2 challenge studies is importantly distinct from the well-established medical needs of altruistic kidney donors.
End-stage renal disease can be treated with dialysis or a kidney transplant. However, kidney transplantation is preferable over dialysis because it is associated with increased survival benefit and quality of life. Altruistic kidney donations make up a substantial percentage of the kidney donations, meaning that removing this source of organs would increase the morbidity and mortality of patients with end-stage renal disease. For end-stage renal disease, altruistic kidney donation is a necessary and favourable treatment option.
In contrast, SARS-CoV-2 challenge studies are not necessary or preferable to traditional clinical trials. Traditional clinical trials of COVID-19 vaccines are proceeding at unprecedented speeds. The traditional clinical trials testing vaccine candidates from Moderna, AstraZeneca, and Pfizer and BioNTech have yielded preliminary data indicating ≥ 70% efficacy. Pfizer and BioNTech have completed phase 3 trials and submitted an application for regulatory approval for their vaccine candidate. Traditional clinical trials avoid the ethical problem of intentionally infecting participants. They also typically have broader inclusion criteria than challenge studies, making their results more generalizable. Unlike altruistic kidney donation, there is a favourable alternative to conducting SARS-CoV-2 challenge studies.
Public trust in medicine is not eroded by rare deaths or harms that occur during organ donation. Altruistic organ transplantation has been an established medical practice since the transplant in 1954 and the risks are now widely known and accepted. An estimated 85.5% of people favour living organ donation. Public attitudes toward organ donation have improved since the 1990s. While the ethics of paying altruistic donors has been debated, public trust in medicine has not notably declined because of altruistic organ donation. Indeed, it is the widespread acceptability of altruistic organ donation gives the analogy with SARS-CoV-2 challenge studies its intuitive appeal.
In contrast, public trust in medical research, especially vaccine development, is fragile. Vaccine hesitancy is a major threat to global health and the anti-vaccination movement continues to gain followers. After the AstraZeneca vaccine trial was halted due to poorly disclosed adverse effects, experts called out pharmaceutical companies for their lack of transparency. Once public trust in a vaccine is lost, it can be very difficult to recover. Since the fraudulent report linking childhood vaccines to autism spectrum disorder was published, overwhelming evidence has disproven the association. Despite the evidence, an estimated 30% of people continue to hold the false belief that childhood vaccines cause autism. A death or serious adverse event in a SARS-CoV-2 vaccine challenge trial could irreversibly damage public trust SARS-CoV-2 vaccines. No matter how quickly it is developed, a vaccine’s efficacy relies on widespread acceptance. Unlike kidney donation, the risk of challenge studies eroding public trust may undermine the benefit they promise to produce.
The acceptability of altruistic kidney donation does not justify the conduct of SARS-CoV-2 challenge studies. The prevalence of the analogy in the mainstream media demonstrates its intuitive appeal. However, morally relevant differences between the comparators undermine the analogy. Advocates of SARS-CoV-2 challenge studies must look elsewhere to justify the level of risk in these studies.
Authors: Hayden P. Nix1,2 and Charles Weijer3
Affiliations: 1MD Student, Schulich School of Medicine & Dentistry, Western University, Canada; 2MSt Student, University of Oxford, UK. 3Professor Department of Medicine, Epidemiology & Biostatistics, and Philosophy, Western University, Canada.
Competing Interests: HPN has no competing interests to declare. CW receives consulting income from Cardialen, Eli Lilly & Company, and Research Triangle Institute (RTI) International.