Last week, researchers in the UK got the green light to conduct the world’s first COVID-19 human challenge trial, in which healthy volunteers will be deliberately infected with the novel coronavirus.
A challenge trial is one way to test a vaccine or treatment for a particular disease: Participants consent to be infected with the disease, as well as to receive the medical intervention being tested, so that researchers can see how well the vaccine or treatment works. Bioethicists, researchers and other experts have been debating the potential value and harm of COVID challenge trials since the pandemic started. Some believe this research can be performed ethically, and that a risk-benefit analysis tilts in its favor. Others strongly disagree.
“You have a very substantial divide among the people who know all about vaccines and clinical trials and who are ethically very, very sensitive people,” says Dr. William Schaffner, medical director of the National Foundation for Infectious Diseases and professor of preventive medicine and infectious diseases at Vanderbilt University’s School of Medicine in Nashville.
Challenge trials past and present
The practice of intentionally making people sick in the name of science has been a longstanding source of ethical consternation. While past challenge trials have helped expedite vaccine development, there have been instances of participants dying from the disease in question.
Additionally, challenge trials have a spotty record when it comes to informed consent. Ethicists assert that only when participants are fully aware of the potential consequences of being in a study, and freely agree to all parts of the study, can research be deemed usable and ethical. Through the early 1970s, some challenge trials included prisoners, military personnel and people with diminished mental capacity — participants who didn’t necessarily understand the risks of participation or feel they had the choice to opt out.
“Prisoners volunteered for these studies because it got them out of their cells,” Schaffner says. “It was thought that those environments were so coercive that, in a sense, prisoners could not make informed choices. And so it was forbidden to do challenge studies in confined populations.”
During the 1960s, an international medical group created the Declaration of Helsinki to describe how study participants should be treated. The updated version, which has a lengthy section on informed consent, helps guide researchers through ethical concerns today.
The first COVID challenge trial
For the upcoming COVID-19 challenge trial, UK researchers will recruit up to 90 healthy people, aged 18 to 30. They’ll be exposed to SARS-CoV-2, the virus that causes COVID, and will remain in isolation, where they’ll be observed and treated, in case they become ill. The researchers hope to learn about the earliest stages of coronavirus infection, test the effectiveness of new vaccines and see how existing vaccines protect against different COVID variants.
“In this situation, informed consent is absolutely critical so that volunteers can make a fully informed judgment about whether to participate,” says Christopher Chiu, chief investigator of the upcoming challenge trial at Imperial College London. “We are spending a lot of time to make sure they fully understand what the study entails, as well giving them many opportunities to ask questions or indeed withdraw if they are unsure.”
Why COVID challenge trials are controversial
“The UK SARS-CoV-2 human challenge study should not have received ethical approval,” says Charles Weijer, a bioethicist at Western University in London, Ontario, who was a member of the World Health Organization Working Group for Guidance on Human Challenge Studies in COVID-19. “The proposed study breaks with a 50-year history of human challenge studies that put the safety of participants first by only permitting study of well-understood diseases that are either self-limiting or for which a curative rescue medication exists.”
Although young adults are less likely to experience serious illness than older people, volunteers may unknowingly put themselves at risk.
“We know that this virus can strike young, healthy adults and put them in the intensive care unit,” Schaffner says. “[And] we are now gathering more information that young adults, even if they have mild illness, can become long-haulers. So that’s a matter of concern.”
Proponents of challenge trials point out that some people put themselves in medically risky situations that aren’t considered unethical, such as donating a kidney to a loved one.
“Challenge trials certainly have a reputation as supposedly far riskier for participants than conventional field trials are, but conventional field trials also involve risks and uncertainties — for example, from disease severity enhancement,” says Nir Eyal, professor of bioethics at Rutgers University in New Jersey. “It is actually not clear to me that challenge trials are riskier. Although even if they were, they could remain ethical if they help prevent lots of death and injury around the world and are done with fully informed consent.”
Some experts say studying COVID in healthy young adults won’t yield results that are applicable to older adults, those with underlying health conditions, or people who are Black or members of other underserved groups, all of whom are more likely to experience COVID-19 complications. Others believe that challenge trials just aren’t necessary at this stage of the pandemic.
“Given the number of proven effective vaccines that we now have in hand, the scientific justification for SARS-CoV-2 challenge studies is not simply not compelling,” Weijer says.
Still, some experts emphasize the potential value of COVID challenge trials.
“There is nothing wrong in the sheer fact that these researchers are conducting challenge trials,” Eyal says. “If done right — and note the conditional nature of my statement — human challenge trials would be both permissible and an excellent way of answering some of the core questions that remain open about existing and new vaccines, as well as about natural immunity.”
Deliberating the ethics of challenge trials
Because COVID-19 is such a new illness, researchers can’t model challenge trials after previous studies.
“You have the responsibility for being clear in your own mind that you’re not putting the volunteers to undue risk,” Schaffner says. “What’s undue risk? We don’t have a check sheet for that. You have to decide that on your own, weighing all the benefits and the potential liabilities.”
Different factors determine whether a challenge trial is risky or ethical.
“The risk of young people dying from COVID is 0.001 percent or so,” says Dr. Charles Rosen, president of the Association for Medical Ethics and professor at the University of California, Irvine, School of Medicine. “The risk of dying here in Los Angeles on the highway is 1 in 40,000, but that is accepted.”
Why people volunteer for challenge trials
Despite concerns that participating in a COVID-19 challenge trial could lead to serious illness, long-term health problems or death, many people are willing to sign up. Through the advocacy group 1Day Sooner, more than 38,000 people worldwide have expressed interest in volunteering for challenge trials.
“Volunteers are overwhelmingly motivated by altruism — a desire to save lives and help the whole world recover from the COVID-19 pandemic as soon as possible,” says Josh Morrison, 1Day Sooner’s cofounder and executive director.
There are no plans for COVID-19 challenge trials to take place in the US at the moment. Should the occasion arise for you to volunteer, give the matter deep thought, and discuss the opportunity with a trusted friend.
“Consider all the implications as thoroughly as you can,” Eyal says. “Are you ready for a prolonged period in isolation? Are you ready for the remote but ineliminable possibility of serious disease and long-lasting injury or death? Don’t let any earlier declarations you may have made about your willingness to volunteer feel binding. You want to decide this matter in the freest possible manner, thinking fully about the implications, and then making up your mind.”