Jimmy Bernot watched with interest as the nurse carefully transferred a small amount of liquid containing dozens of hookworm larvae onto a piece of gauze, and then placed it on his wrist. Bernot couldn’t see the larvae — at just about half a millimeter long, they are all but invisible — but he could soon feel them: a tingling, itchy sensation as the worm larvae wriggled through his skin and into his bloodstream.
From there, Bernot knew, the hookworms would travel to his lungs. Eventually, they would make their way up from his lungs, slip down his esophagus, pass through his stomach, attach themselves to the lining of his small intestine, and begin to suck his blood.
Hookworms infect more than half a billion people worldwide. In severe cases, they can cause anemia in adults and stunt growth and mental development in children. But in March 2020, Bernot, an evolutionary biologist who was then a graduate student in genomics and bioinformatics at George Washington University, was infected with some voluntarily — part of a trial to test an experimental hookworm vaccine.
Bernot was participating in a human challenge trial: a kind of study in which researchers infect participants with a pathogen, often for the purpose of testing a new vaccine or treatment. Over the years, challenge trial volunteers have been bitten by malaria-infected mosquitoes, drunk water contaminated with typhoid-causing bacteria, and inhaled various strains of influenza. They have been given whooping cough, cholera, parasitic worms, and even gonorrhea.
Now, after months of debate, Covid-19 has joined that list. On Feb. 17, the United Kingdom approved the world’s first Covid-19 human challenge trial. Researchers will expose up to 90 young, healthy people to the virus in order to study how it affects the human body; as of March 25, the first three volunteers have been exposed. As novel variants arise, some experts say, future human challenge trials could hasten development of new vaccines and treatments for a disease that has killed more than 2 million people worldwide. But critics caution that there are ethical pitfalls to any research that intentionally sickens healthy people — and that even the best-planned trials may involve a small risk of serious complications.
Human challenge trials do have a troubling history. In the past, many involved coercion or deception of patients. Sometimes, participants died. Even in their current, highly-regulated form, proposed trials for emerging diseases like Zika or Covid-19 have been controversial.
In general, challenge trials are conducted with diseases that are well understood and have established cures. In cases where no cure exists, as with dengue virus, scientists use a weakened form of the virus that is intended to cause only mild symptoms.
That’s why the Covid-19 challenge trials are so contentious. “In Covid, there’s much less known,” says Sean Murphy, medical director of the Malaria Human Challenge Center at Seattle Children’s Research Institute. The full effects of Covid-19 on the body remain mysterious, and there are still no known drugs that reliably treat severe cases. “We’re on a thinner amount of evidence than we are for some of the long-standing challenge trials,” Murphy says.
Ultimately, researchers and ethicists are not the ones putting their bodies on the line. The experiences of human challenge trial volunteers like Bernot offer unique insights into the ethical issues at stake, including acceptable levels of risk, the potential influence of high payment for trials, and the personal agency of participants.
In typical clinical trials, participants receive an experimental vaccine or treatment, but nobody actually gives them a disease. In some cases, though, researchers say that challenging participants with a pathogen offers advantages over a traditional trial.
For example, challenge trials can “be done with much smaller numbers of people in a much more controlled way than standard vaccine trials,” says Euzebiusz Jamrozik, a bioethicist at the University of Oxford who has published extensively on the ethics of human challenge trials. Standard vaccine trials “require tens of thousands of people,” he says. For comparison, human challenge vaccine trials may involve only around 100, or even fewer, participants.
Challenge trials also allow researchers to study a vaccine in places where the disease does not generally occur. That’s why the hookworms ended up in Bernot’s arm, in a lab in Washington, D.C., far from hookworm hotspots.
After undergoing health screening and receiving three injections of the trial vaccine or the placebo — he still doesn’t know which — Bernot received a modest dose of 50 hookworm larvae, too little to cause a serious infection. The worms remained his companions for the following six months, during which the research team collected symptom reports, vital signs, and blood samples. They also regularly collected his poop to monitor it for hookworm eggs.
At the end of the study period, the researchers cured Bernot with an anti-worm medication. Besides an itchy rash where the worms had crawled through his skin, he says he didn’t feel any different than usual.
Other human challenge trial participants haven’t been so lucky. When Andrew Prendergast, then a graduate student at the University of Washington, volunteered for a malaria human challenge trial there in 2012, he says, it was “probably the sickest I’ve ever been in my life.”
The researchers gave Prendergast malaria the old-fashioned way: via mosquito. “They had infected mosquitoes, and they put them into this little, like, ice cream tub with a wire mesh over it,” Prendergast recalls. “You would come in and put your arm on top of it and just get bitten up by mosquitoes for, I think, like two or three minutes, which was very unpleasant. You’d leave the trial center just itching like crazy.”
Bill Wood, who was also a University of Washington graduate student, participated in a different malaria trial, testing an experimental vaccine, at around the same time. He remembers feeling “exhausted, feverish, out of it.” Wood and Prendergast both said their symptoms quickly disappeared after researchers gave them an established anti-malarial medication.
The risks of unpleasant side effects depend on the trial, but also, to some extent, individual luck. In 2016, Nick Crang, then a graduate student at the University of Oxford, volunteered for a typhoid challenge trial there. After a thorough health screening, some volunteers received an experimental typhoid vaccine. But not Crang. Although he didn’t know it at the time, Crang was in a placebo group that received a meningitis vaccine, which, while good to have, offers no protection against typhoid.
After the vaccination, it was time for the challenge. Volunteers first drank a baking soda solution to neutralize their stomach acid. “That solution was disgusting, just incredibly bitter,” says Crang. By comparison, the typhoid bacteria Crang and the other volunteers drank afterwards went down easy. “You know the aftertaste, that you have in yogurt? It was a little bit like that,” says Crang. “Not nearly so bad as you’d have thought.”
While typhoid can be effectively treated with antibiotics, the disease still kills over 100,000 people per year, and even milder cases can involve fever, stomach pain, and diarrhea. Many volunteers in the placebo group experienced the unpleasant effects of the typhoid bacteria, but, Crang says, he stayed healthy. He figures he’s among the small group of people who have a natural resistance to typhoid.
The trial, which had been funded by the Bill and Melinda Gates Foundation, was a success. The vaccine significantly reduced the likelihood of developing the disease. Soon after, the World Health Organization recommended it for use in regions where typhoid is prevalent.
In interviews, former challenge trial participants described motives for their participation that ranged from the light-hearted — several imagined it would be a fun story to tell at scientific conferences and parties — to the serious. Some spoke of altruistic motives, often shaped by personal experiences. “I spent a couple years in Africa; I was in the Peace Corps,” says Amelia Priesthoff, who was in Seattle completing prerequisite coursework required to apply for medical school when she participated in the same malaria trial as Prendergast. While abroad, she had many friends who suffered from regular and debilitating bouts of the disease. “I think for me, seeing that firsthand, and knowing that there might be some way that maybe I can be a part of figuring out whether or not we can make a vaccine for malaria,” she says, “definitely played a big part in it for me.”
“I thought it would be an interesting tale to tell as a parasitologist,” says Bernot, who studies parasitic crustaceans. But, he says, he was also aware of the harm hookworms cause. “Five-hundred million people are infected with these things, not by choice, in very uncontrolled circumstances. So, if there’s something that I can do willingly to potentially help hundreds of millions of people,” he says, “sure, I’ll give it a try.”
Other kinds of medical trials involve unpleasant procedures and health risks, and, sometimes, serious accidents occur. In 2006, for example, six healthy people in London volunteered to be the first humans to receive a drug called theralizumab, which researchers thought might be useful for treating certain kinds of lymphoma or autoimmune disease. Within hours, all six had gone into multiorgan failure and had to be hospitalized, although all survived.
But even if typical trials carry some degree of risk, the idea of doctors intentionally infecting participants with pathogens can make medical ethicists squirm. The potential influence of money often adds to that discomfort. Challenge trial participants are paid, and some ethicists and researchers worry that compensation might have an undue influence on individuals’ decisions to participate or remain in a trial.
“People worry that high payment might distort people’s judgment,” says bioethicist Jamrozik. “Some people say it might interfere with their personal assessment of the risk,” he adds, although he’s not sure there is sufficient evidence that this actually happens. Ethicists also worry that people who need the money might lie about medical conditions or certain behaviors in order to participate in the trial, which could ultimately put them at greater risk.
At the same time, Jamrozik says, many bioethicists would likely agree that it makes sense to compensate participants, since the trials are time intensive. “Even if you just pay people minimum wage for their time, it potentially adds up to thousands of dollars,” says Jamrozik.
Some challenge trial participants acknowledge that money shaped their decision to participate. “It felt like I was doing something to further scientific knowledge,” says Prendergast, one of the malaria trial participants, noting the disease’s devastating global toll. But, he added, “I can’t deny that there was a huge financial motivation for us to do that.”
At the time, he was completing his Ph.D., receiving only a small stipend for long hours of work in the lab. “We were grad students. We were really poor. They pay you, like, $3,000 to get malaria,” he says. “When you’re making $25,000 a year, it’s really hard to say no to that.”
Crang recalls that graduate students seemed to make up a substantial portion of the volunteers in his typhoid trial. Oxford, he notes, has a high cost of living, especially relative to graduate students’ stipends. “We definitely appreciated the fact that our participation would help improve people[‘s] lives further down the line, but the money was the key to getting us to take the plunge,” he wrote in a follow-up email.
In a survey of 16 human challenge volunteers, published in 2018, most said they were at least partially motivated by the compensation provided. While only one participant said that the payment helped them overlook some of the risks of the trial, most participants thought it was possible that people would lie to qualify for the study, especially about things like drug and alcohol use, if they needed the money.
“I think there’s some concern with these human challenge trials as to what kind of subjects you’re going to get if you’re offering financial incentives,” says Prendergast. “You really are sort of putting this burden on people who really need that money.”
But other former participants questioned whether people should be protected from making an informed choice about a risk. Nick Escobar, who participated in a malaria challenge study in 2014 and now works as a nurse manager in Seattle, points out that society allows people to make many choices that could end in harm: “If we let people volunteer to go to wars, you know, it seems strange that we wouldn’t let people volunteer to do a medical trial.”
Research institutions require researchers to inform participants of the procedures and risks involved in any trial. And, in interviews with six challenge trial volunteers, all said that the informed consent process was very thorough.
Even researchers who regularly run human challenge trials say that the ethics of a Covid-19 human challenge trial aren’t necessarily clear-cut.
“With Covid, you have to balance the risk that you’re exposing someone to a virus that we don’t understand very well, versus the benefit of using the challenge,” says Kirsten Lyke, director of the Malaria Vaccine and Challenge Unit at the University of Maryland. She notes that the relatively quick development of Covid-19 vaccines demonstrated that progress on vaccines, at least, is possible without human challenge trials.
Whether something is ethical or not isn’t just up to experts, says Jamrozik, who has argued in favor of Covid-19 challenge trials. The community in which the research is being conducted — and especially those community members who participate in the trial — must also find the trials to be ethically acceptable, he adds.
The government-funded U.K. challenge trial will study the coronavirus’ effects on the body from the first moments of infection, rather than test a specific vaccine. Like the ethicists who have debated this topic, previous challenge trial volunteers are conflicted about the initiative.
Escobar believes that as long as the risks to participants are clearly explained, people should be free to make their own choices. “I saw my experience in the malaria trial as being for the good of humanity, and I find restrictions on people’s choices from paternalistic experts to be insulting,” he wrote in an email. “‘Experts’ shouldn’t get in the way of people volunteering to take on risk for the good of humanity.”
Others are more hesitant. Bernot says that he was comfortable taking part in the hookworm study, in part, because he knew that there was an established cure. If the disease had progressed, “I could have been cured in days with a single dose,” he wrote in a follow-up Twitter message. “Clearly, that is not the case for a Covid challenge, and so the ethical considerations there are much more complex.”
Prendergast is concerned that the pandemic-related financial insecurity many people are experiencing could impact people’s decision to participate in such a trial. “The financial incentive of it kind of perverts the idea of informed consent a little bit,” he says. “Especially in a world that’s being ravaged by pandemic, a lot of people are unemployed, and then you go to someone, like, ‘Hey, I’ll pay you, whatever, $5,000, $10,000 to get Covid.’ Are you really making an informed and fully consensual decision at that point? You’re under financial duress.” (The U.K. volunteers will receive 4,500 pounds — around $6,240 — for their participation.)
But, Prendergast says, he sees research trials as an important tool. And he was happy to be a data point in research aimed at reducing the global burden of disease. “I’m glad to participate in that way,” says Prendergast. “Mostly I feel proud that I could contribute in this small way.”