Lehua Gray, a 32-year-old product manager in Austin, wants to risk her life for a coronavirus vaccine. A cloud of potentially deadly microbes would be spritzed up her nose — if she’s allowed to a participate in what’s called a human challenge trial.
It’s built on a deceptively simple premise: Researchers inject healthy volunteers with an experimental vaccine and then expose them to a pathogen. If the vaccine prevents volunteers from getting sick, the study can accelerate development of a promising formula.
This approach has been used to test malaria and cholera vaccines — and now, in laboratories and conference rooms, preliminary discussions are unfolding about the feasibility of employing it in the quest to find a weapon against the novel coronavirus.
The obstacles are formidable. Infecting healthy people with a potentially lethal virus, with no treatment to save them from severe illness or death, raises some of the most fraught ethical, scientific and philosophical issues in the history of medicine. Exposure to pathogens in challenge trials is usually permitted only for diseases that aren’t fatal or that have treatments available. No such assurances exist for the coronavirus, which has killed more than 425,000 people worldwide.
Francis Collins, director of the National Institutes of Health, said in an interview that challenge trials are “on the table for discussion – not on the table to start designing a plan.”
Large-scale trials of coronavirus vaccine candidates are slated to begin this summer and fall, but they involve more conventional approaches.
When Gray explains to her family her interest in potentially participating in a challenge trial, “it starts out being a conversation about FDA processes and ends up being a conversation about how I’m about to risk my life,” she said.
Despite that risk, Gray and more than 28,000 other volunteers have joined a new online organization, 1Day Sooner, hoping that by placing themselves in the path of the virus, the pandemic will end sooner.
‘An upper limit of risk’
One of the first studies to endorse coronavirus challenge trials was published in March in the Journal of Infectious Diseases. Rutgers University bioethics specialist Nir Eyal and his colleagues proposed using challenge trials to supplement or even supplant a Phase 3 trial, the lengthiest and final step in vaccine creation.
In a typical Phase 3 vaccine trial, which is required for Food and Drug Administration approval, thousands of participants receive an inoculation, either an experimental vaccine or a placebo. To test whether a vaccine prevents infection, researchers wait until subjects have been naturally exposed in their communities. This process can take six months or more. Even as pharmaceutical companies race to make a coronavirus inoculation, the wait may stretch a year or longer for a vaccine to reach the market.
As coronavirus cases decline in the regions hit hardest in the spring, some experts worry a traditional Phase 3 trial may take too long or not gather enough evidence to be conclusive. Because challenge trials guarantee exposure, these studies require as few as 100 subjects and can be completed in two or three months.
A challenge trial may not be able to bypass a Phase 3 trial or efficacy study but can help in other ways. “If you’re looking at 100 vaccines, some of them might turn out be total busts,” said Neal Dickert, a bioethics specialist at Emory University who has studied flu challenge trials. Using that approach with the coronavirus trial could help scientists shelve the busts sooner.
In the months since Eyal and his co-authors published their paper, support for challenge trials has grown among specialists in bioethics. Charles Weijer, a professor at Canada’s Western University, said coronavirus challenge trials presented the hardest question he has faced in 24 years as a bioethics expert.
A paramount tenet of conducting human research, dating to the Nuremberg Code, is informed consent – in which people fully understand the risks and limitations of participating.
“Most ethicists agree there is an upper limit of risk,” said Seema Shah, an ethics professor at Northwestern University’s Feinberg School of Medicine. “It wouldn’t be okay to sacrifice one individual for the benefit of many others.”
When Weijer helped develop guidelines for challenge studies in 2015, a central idea was “that volunteers in human challenge studies in no circumstance will be exposed to diseases that are irreversible, incurable or possibly fatal,” he said. Coronavirus trials violate that concept.
“It makes me very worried that in a COVID-19 challenge study, should we go ahead, that odds are some people are going to be seriously injured and some people are going to die,” Weijer said. “The question for me then is: What can we do to mitigate those risks?”
To answer that, the World Health Organization convened a panel of ethics experts and researchers from around the globe, including Weijer and Shah. They wrote a 19-page document explaining criteria for conducting these studies. The report emphasized informed consent, minimizing risk (people 18 to 30 have the lowest fatal infection rate, the authors noted) and the need for “strong scientific justification.”
Careful site selection is also important. Drawing participants from communities where transmission is high may reduce the relative risk to volunteers because they would be more likely to catch the virus anyway — but this should not exploit populations vulnerable to the virus, ethics experts agreed. “This disease has obvious socioeconomic disparities and racial disparities that we have to be aware of in the context of doing things like challenge studies,” Dickert said.
The WHO panel opened the door for challenge trials to proceed. “Well designed challenge studies might thus not only accelerate COVID-19 vaccine development,” they wrote, “but also make it more likely that the vaccines ultimately deployed are more effective.”
Shah and another group recently published in the journal Science an ethical framework for coronavirus challenge trials. “Moral disagreements about upper limits to risk” exist, they wrote, but risks can be tempered by isolating subjects in inpatient facilities under careful observation.
Challenge trials have been compared with other selfless acts. There’s a flaw in that thinking, Shah said. Firefighters and kidney donors can feel confident their altruism will benefit someone, she said. It’s uncertain any clinical study will make a difference.
“The Ebola experience is one cautionary tale where there were these two massive trials that tried to determine whether vaccines worked,” Shah said. These traditional vaccine trials “couldn’t come to completion. They couldn’t get an answer.” A third trial worked: A “ring” vaccination, in which clusters of people who were friends or relatives of infected people received vaccines.
Shah said she is reasonably confident challenge trials will happen somewhere. “I don’t know if they’ll happen in the United States,” she said.
The risk of death
In April, dozens of members of the House of Representatives sent a letter to Health and Human Services Secretary Alex Azar and FDA Commissioner Stephen Hahn urging them to consider implementing challenge trials.
The risk of death looms large. “If this went all wrong, and some healthy volunteer died as a result, that would be impossible to forgive ourselves,” Collins, the NIH director, said.
Collins and other leaders of the U.S. vaccine effort wrote in Science in May that such experiments would have to be carefully considered by an independent panel of specialists in ethics, clinical trials and vaccines.
“Some vaccine makers have communicated to us that they would be interested if FDA let them do it,” Eyal said, though he declined to name them.
Johnson & Johnson chief scientist Paul Stoffels said in an interview that the company was not currently considering challenge trials and was focused on a traditional large-scale trial slated to begin in mid-September.
“We don’t think, at the moment, it will help in the speed to results,” Stoffels said, noting that important scientific work would have to be done to develop a model for challenge experiments and a medication would have to exist to treat people who became ill.
But if countries are successful at controlling their outbreaks, it will pose an obstacle to vaccine researchers who in traditional trials give half the participants a dummy shot and depend on enough people becoming infected to see whether their vaccines are protective.
“If the disease gets to a very low level, maybe challenge studies will have to be considered,” Pascal Soriot, chief executive of AstraZeneca, said at a briefing with other pharmaceutical executives.
Other manufacturers are apprehensive. Leaders from Moderna and Inovio Pharmaceuticals, two biotechnology companies with vaccines in early human trials, have said the risks of challenge studies outweigh the benefits.
A joint effort to develop a vaccine by Sanofi and GlaxoSmithKline will not use human infection trials because “we have sufficient knowledge of the vaccine technology we’re using, as it is based on a technology we are using for another vaccine,” said Sanofi spokesman Nicolas Kressmann.
Pfizer is not considering challenge trials at this time, except in animal experiments, a spokeswoman said.
Some sponsors of influenza challenge trials, such as the Bill & Melinda Gates Foundation, are worried that if the covid-19 challenge trials proceed and people die, the field will suffer.
Another objection is the scientific interpretation. If young, healthy people who participate don’t develop severe disease or have only mild illness, what would it mean? A sizable fraction of people — particularly those at low risk — who are infected do not develop severe disease or even symptoms.
“People we’re really worried about — the elderly and with chronic diseases — would not be volunteering,” Collins said. “And can you really extrapolate from saying this 22-year-old recruit from the military did fine, that 72-year-olds and people with [chronic obstructive pulmonary disease] would do well and be protected?”
Kathleen Neuzil, director of the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine, is experienced running challenge trials involving potential vaccines for diseases that have treatments. “We’ve done them for malaria, influenza, shigella. What makes me personally cautious about doing them for SARS-CoV-2 is, at the moment, we don’t have a rescue medication,” Neuzil said, meaning a way to save an infected person’s life.
If challenge trials were to proceed, she said, “this is going to take some very careful thought and very careful planning.”
Challenge trials need to be run in facilities with extensive infection control, where participants may have to live for weeks under close supervision – explaining why many bioethics experts conclude challenge trial volunteers should be paid. Only a few organizations, such as NIH, operate these high-level biosecurity facilities.
Researchers will need to cultivate, at scale, the virus in a laboratory; one option is to use a weakened strain less likely to cause severe sickness. And after the virus is grown, scientists must determine the proper amounts to give volunteers.
A sense of purpose
Two months ago, Josh Morrison, a 34-year-old attorney and activist who represents kidney donors, read Eyal’s paper. Inspired, he and friends founded a website called TheCovidChallenge.org. Sign-ups snowballed — by mid-May, as many as 1,500 new people were joining daily — and the organization was renamed 1Day Sooner.
1Day Sooner now employs Morrison and three other people. It has more than 28,000 volunteers and a German-language chapter in Austria. “Our job is advocating for or representing people. We want people to sign up,” Morrison said.
The organization is collecting donations, which Morrison said will be used to pay for a $50,000 research survey on volunteers. The organization is also trying to hire a vendor to manufacture the microbe.
Most members of 1Day Sooner are young, but Morrison said some who have joined are in their 80s. Many have backgrounds in public health or science. Yet signing up with the organization is no guarantee members will get to participate in a challenge trial.
Volunteers say the trials could provide a sense of purpose in a time of chaos and helplessness.
“Being able to do something constructive and useful, that meant a lot to me,” said Morrison, who in 2011 donated a kidney to a stranger. “The risks are very meaningful and significant, but also roughly on par with childbirth or kidney donation.” The risk of death for kidney donors is about 1 in 3,000 people, which mirrors the coronavirus infection fatality ratio among people in China in their 20s.
Eyal, who has been in contact with 1Day Sooner, said he held the volunteers in high esteem. “They certainly can’t be dismissed as people who misunderstood what this is about,” he said. They “actually comprehend the risk and still want to participate.”
There is little precedent for the creation of this organization – akin to a Screen Actors Guild for human subjects – let alone one established for study participants before studies exist.
Human subjects are often viewed as “people to worry about” or guinea pigs, Shah said. “So I have a lot of respect for the idea of bringing together research participants.”
Gray said she draws motivation to participate in a challenge trial from her grandmother, who is vulnerable to respiratory disease because of lung problems. Gray’s girlfriend and parents have been supportive. A close friend is not.
“Whenever she reads something about long-term damage, that’s what she’s worried about,” Gray said. “It’s possible that I wouldn’t die, but I would have permanent lung scarring or something like that.”
Gray said she was among the first 1,000 people to join after reading about the project on Facebook. “If I can save lives with very little risk to myself,” she said, “I almost feel like: How could I not?”