Two institutions in England have launched COVID-19 human challenge trials, which will deliberately infect participants with the SARS-CoV-2 virus. Despite the approval of these trials by European regulators, debates have continued over whether the ethical justification is sufficient.
The studies, conducted at and the , are in their initial stages and have recruited participants ages 18 to 30 who have no risk factors for severe COVID-19 illness.
But the trials do have one major difference. The Oxford trial will investigate how much protection is needed to avoid reinfection, meaning its participants have already had COVID-19. The trial at Imperial College London, however, will infect people who have not been previously exposed.
Human challenge trials have been highly contested since the start of the pandemic, when they were publicized as studies that could fast-track development and production of vaccines. These types of trials can provide critical insights about a pathogen faster than standardized clinical trials, making the argument for conducting them during a public health emergency attractive.
However, some bioethicists say that using these studies to research COVID-19 is still not justified based on the availability of vaccines to prevent infection, uncertainties about the long-term effects of disease, and the lack of a rescue treatment for participants who fall seriously ill.
Providing Critical Insights
Arthur Caplan, PhD, director of the division of medical ethics at the NYU Grossman School of Medicine in New York City, said that challenge trials are needed to answer certain questions quickly. For example, in regions where there are new outbreaks, these trials could be used to test vaccine efficacy against a new variant, answer questions about mixing vaccine doses, or test new immunizations.
"There are basic insights that we could get about coronaviruses from challenge trials," Seema Shah, JD, a bioethicist at Lurie Children's Hospital of Chicago, told MedPage Today. The trial at Oxford, for example, might give scientists more information about who is protected against COVID-19 reinfection, and how exactly they are protected.
Shah said that gaining knowledge about protection, such as whether it is related to the mucosa in a patient's nasal passage or the antibodies in their bloodstream, could be critical in developing better tests or vaccines. But providing a sound ethical justification is necessary.
A "Checkered" Ethical History
Scientists have used challenge trials to study diseases for hundreds of years. Prior to the COVID-19 pandemic, challenge trials helped researchers learn about and develop vaccines for illnesses such as smallpox, malaria, cholera, and influenza.
But while challenge trials have a place, they haven't always been ethically justified. Daniel Sulmasy, MD, PhD, director of the Kennedy Institute of Ethics at Georgetown University in Washington D.C., told MedPage Today that "challenge trials have a checkered history."
Some trials, he said, have been widely condemned, such as the U.S. in Guatemala after World War II, or the that tested vaccines on children with mental disabilities, which ended only in 1972.
Sulmasy noted that we have come a long way from these experiments, using specific criteria to conduct challenge trials. But in the face of a public health emergency such as the COVID-19 pandemic, "we ought to be careful about playing too fast and loose about those criteria," he said.
Proving Social Value
In a viewpoint published in , Sulmasy said that the ethical justification for the COVID-19 challenge trial at Imperial College London "falls short of the mark." He outlined an ethical framework for conducting challenge trials, which includes considerations such as social and scientific warrant, non-maleficence, and justice.
One of the first ethical questions considered before conducting a human challenge trial is whether or not it has social value -- that is, what kind of information will the study investigate and how will it make a difference?
Sulmasy said that evidence for social value in the Imperial College London trial is not justified. While there is a social and scientific warrant to study a disease such as COVID-19, which has significant morbidity and mortality, he stressed that warrant is diminished by the availability of vaccines.
"We already have a number of effective vaccines available," he noted. "So why it is that we need to rush into a challenge trial, with all of its problems, seems questionable to me."
Additionally, since the trial is being conducted in young and healthy volunteers to minimize the risk of severe illness, results may not be generalizable to an older, higher-risk population, he said.
First Do No Harm
Sulmasy also said it's important to assess risks to participants and whether or not those risks are justified. A major argument against conducting challenge trials, he added, is that risks associated with the disease are still poorly understood.
"In some kinds of challenge trials like malaria, the disease has been around for thousands of years," he noted. However, with COVID-19, we are only scratching the surface in terms of understanding the long-term consequences of illness.
"So we're subjecting people not just to the known risks of death. But we are also not aware of what the long-term consequences might be of being infected," he said.
Additionally, Sulmasy emphasized that we have no rescue therapy, which is ethically necessary.
However, in a recent commentary in , Seán O'Neill McPartlin, Abie Rohrig, and Josh Morrison, representatives from , an advocacy organization for participants of human challenge trials, argued that rescue therapies should not be a prerequisite for a COVID-19 challenge trial. They suggested that there should be no "rescue therapy standard" since rescue therapies do not exist for the flu and respiratory syncytial virus -- which have both been studied in challenge trials.
Justice and Concerns About Financial Incentives
There are many important questions to consider when recruiting participants for challenge trials, Sulmasy said. The Imperial College London trial does not appear to have any overt justice issues, such as performing experiments in vulnerable populations. But it will pay participants £4,500 for their time -- around $6,300.
"I'm just a bit concerned about the amount of money they are giving to people," Sulmasy said. The worry is that a larger financial incentive might attract people experiencing economic adversity, which may overlap with those who would be at a higher risk of illness, he added.
Shah said that it is important for human challenge trials to "make sure that people are paid enough for the time and burden they are taking on." She recognized that there are concerns that a high financial incentive might attract people who would sign up against their better judgment. But she added that suggested that people who are motivated by money were no less likely to consider and understand the risks of a challenge trial compared with those motivated by altruism.
Avoiding Ethical Exceptionalism
Shah said that the challenge trial at Oxford has a different set of ethical considerations than the one at Imperial College London, because infecting people who have already had COVID-19 is probably safer than infecting those who have never been exposed. But the risks of disease, she added, are still too unclear to make a good case for conducting challenge trials.
"The big issue, to me, is that there is still a lot of uncertainty about the risk of COVID," Shah said. "That's what gives me pause."
For Sulmasy, he said sticking to principles and criteria for conducting challenge trials is essential. When difficult and urgent circumstances arise, such as the COVID-19 pandemic, the criteria for these trials allows researchers to know the limits to what they can and cannot do. "I think we ought to be careful of ethical exceptionalism," he said.
"The end doesn't justify any and all means," he added. "We stick to those principles, because this is exactly the kind of situation [in which] we need them."