Abie Rohrig had just turned 18 when he told his mom he would be donating a kidney to save a stranger’s life. Her answer: No you’re not. He did it anyway – the organ went to a man about his age – and his mom was so inspired she went and donated a kidney herself.
So Rohrig expected her to understand when he told her that, for the benefit of humanity, he may volunteer to become infected with Covid-19.
It turns out “she’s more worried than she was about the kidney thing,” said Rohrig, now a 20-year-old college student who lives with his parents in a New York City apartment.
“She was like, ‘What? What? I don’t know,’” he said. “She’s skeptical.”
Rohrig is one of more than 16,000 people – most of them young adults – who have signaled their support for a controversial method of speeding up the development of a vaccine by intentionally infecting dozens of volunteers. The signees of the online registry – a new website called 1 Day Sooner – have all checked a box next to the statement: “I am interested in being exposed to the coronavirus to speed up vaccine development.”
The practice is called a human-challenge study – or controlled human infection study – and it can truncate a conventional vaccine study by several months. The reason: Rather than waiting for months to assess what percentage thousands of vaccine-trial volunteers get infected with the disease in question while leading their day-to-day lives, a challenge trial is much simpler, in that it exposes about 100 volunteers directly to the pathogen – via syringe, cocktail, mosquito bite or nasal spray after an experimental vaccine or placebo is administered. (If the Covid-19 study comes to fruition, experts say it would likely be administered by nose drop.)
But if it’s high reward, it’s also high risk: Although Covid-19 is a much more deadly disease for the elderly and the compromised than healthy young adults, it is an unpredictable pathogen that has put star athletes in the hospital. What’s more, should something go wrong, treatment options are limited.
However, with the disease still raging after having killed more than 82,000 Americans and 291,000 people worldwide since it first appeared in China late last year, some say a riskier-than-normal study is justified.
Challenge studies offer high reward, but also high risks
The notion of a human-challenge trial for Covid-19 was jump-started by a March 31 article in the Journal of Infectious Diseases, which made the case that the nature of the global emergency warrants consideration of unconventional approaches.
Co-authored by Nir Eyal of Rutgers, Marc Lipsitch of Harvard, and Peter Smith of the London School of Hygiene & Tropical Medicine, the piece concluded that while a human challenge study would not be without risks, “every week that vaccine rollout is delayed will be accompanied by many thousands of deaths globally.”
“It’s an idea that is controversial when people hear about it for the first time,” Eyal, a bioethicist, told CNN. “However, we show that if you select people in the right way and conduct the trial in the right way, it’s surprisingly low risk and certainly within the bounds of what we already approve.”
Such a study would ultimately need the blessing of the US Food and Drug Administration.
But the researchers’ call for a challenge study has since been propelled by the popular support of those who have indicated on 1 Day Sooner – which is incorporating as a nonprofit organization – that they’d be willing guinea pigs. (This is just an informal expression of interest, not a binding contract.)
The site, which was inspired by the scholarly article, launched in mid-April and is premised on the claim that shaving even one day from the long-distance race for a Covid-19 vaccine could save up to 7,120 lives.
What a human challenge study for coronavirus could look like
At some point, should a group of researchers decide to seriously explore the matter, the site would ask prospective volunteers to fill out pre-qualification questionnaires that would divulge more of their medical history, region of residence and other information that would help determine eligibility, said 1 Day Sooner’s co-founder Josh Morrison.
The researchers would then screen those forms for the most eligible applicants and would eventually seek approval from a research or medical center to host the study, he said.
Morrison is a former corporate lawyer who gave up life in the fast lane to start a nonprofit organization called Waitlist Zero, which matches prospective kidney donors with recipients. Because business is at a near-standstill in the kidney-transplant world, Morrison found himself with a lot of spare time.
“I was like sitting at home in my apartment in New York City, just kind of depressed,” he said.
Morrison came across the Journal article while noodling around on the internet.
“And I thought, ‘Well, would I want to do this?’” he said. “I’m pretty young, 34, and in good health. And so I thought, ‘Yeah, I think I would.’”
The notion seems to be gaining traction in expert circles. On May 6, the World Health Organization released a report outlining “key criteria for the ethical acceptability of Covid-19 human challenge studies.”
An FDA spokesperson told CNN that the agency would work with those who are interested in conducting human challenge trials to help them evaluate ethical and other issues.
“A formal determination about any specific human challenge trial proposal would be made by the FDA in the context of all the information that is available at that time,” Michael Felberbaum wrote in an email.
Conventional vaccine trials typically consist of three phases – the first, in which fewer than 100 participants are dosed to determine the safety; the second, in which the number of participants ramps up into the hundreds; and the third, in which the study is broadened to include thousands of people.
Typically, in that third phase, the participants return to their daily lives, and researchers – over a period of months – compare rates of infection between the placebo and test groups.
A human-challenge trial can replace a third phase, the Journal article says, short-circuiting the timeline by several months because researchers don’t have to wait for participants to get infected the organic way – by interacting with people at work, at school, in houses of worship or in homes. Instead, they expose the volunteers to the pathogen right then and there, in the lab.
A challenge trial can also serve as a bridge to a Phase 3 study, helping researchers determine which vaccine candidates are most promising; or it can pave the way for provisional licensure in emergency situations.
For a Covid-19 trial of the sort that 1 Day Sooner is advocating, the setup would likely entail first injecting an experimental vaccine into the arms of about 50 volunteers and a placebo into 50 others, challenge-trial experts told CNN. Two to four weeks later, all 100 would be exposed to the virus – perhaps via nose-drop.
Ethical, safety concerns about knowns and unknowns
Human-challenge studies aren’t new. They have played a key role in the development of several vaccines, including ones for malaria, flu and dengue.
Without human-challenge studies, a new vaccine for typhoid couldn’t have been brought to Zimbabwe on a provisional basis last year, human-challenge experts told CNN.
The “FDA approved a cholera vaccine simply on the basis of a human challenge,” said Dr. Robert Read, an infectious-disease expert in the UK.
The difference is that those diseases came with fewer unknowns than Covid-19, and clinicians running the trials were able to offer medical treatments – such as antibiotics or antivirals – to infected patients exhibiting symptoms.
The closest thing to a treatment for Covid-19 is remdesivir, which has yet to be approved and whose effects are modest though significant.
And although the idea of conducting a human-challenge trial for Covid-19 is catching on in the science community, some experts have raised serious concerns about safety.
Read, head of clinical and experimental sciences at University of Southampton, points out that Covid-19 remains a mysterious pathogen, and researchers can’t give volunteers an accurate sense of the risk associated with getting intentionally infected.
“You do have to be able to describe what you know of what could happen to them if they undertake a controlled infection, with complete clarity and honesty,” said Read, who has himself conducted challenge trials – he recently infected dozens of volunteers with whooping cough in search of a more effective vaccine. “And I think lots of volunteers, when faced with the information, would probably not consent to it.”
An article published last week in Science – the peer-reviewed journal of the American Association for the Advancement of Science – puts the mortality risk for adults ages 20-44 who are infected with the virus that causes Covid-19 at less than 0.2 percent. But the piece says that and other statistics on Covid-19 are derived from incomplete data points and small sample sizes.
Generally, Covid-19 is much more lethal for people of all ages with preexisting health problems such as hypertension or diabetes, but some exceptions are especially alarming. Doctors have said that Covid-19 seems to be linked to a surge in strokes suffered by otherwise healthy adults in their 30s and 40s.
Dr. Anna Durbin, a professor of international health at the Johns Hopkins Bloomberg School of Public Health – who has led a human-challenge trial for dengue and worked on another for malaria – said she would be interested to hear how some prospective volunteers would respond to these reports of “cerebral vascular accidents.”
“Millennials don’t think they are going to get sick from this,” said Durbin, who, like Read, is open to the idea of human challenge trials for Covid-19, but stresses that it is incumbent upon researchers to fully evaluate the risks of such a model and to share them to the fullest extent possible with prospective participants. “We see lots of young people in the hospital on ventilators.”
Volunteers have different reasons for signing up – some altruistic, some pragmatic
Rohrig said the frightening spate of young Covid-19 patients having strokes was news to him.
“That’s jarring,” he said. “I know there is a non-trivial risk.”
And yet, Rohrig said he’s almost certainly up for it.
“I know that there are risks, and if I were to do this, and it were to go poorly, then that would be terrible, my family would be really sad,” Rohrig said. But “someone has to step up. It seems like this just needs to happen.”
Coincidentally, the mortality risk of donating a kidney – about 3 in 10,000 – is about the same as the mortality risk for healthy people in their 20s who contract Covid-19, said Eyal of Rutgers.
“That’s heartening,” said Rohrig, who met the recipient of his donated kidney on Good Morning America last summer.
Not all of the prospective volunteers are in their 20s.
John Gentle, an entrepreneur in Alabama, turns 41 on Thursday. He has a wife and four kids. Like Rohrig, Gentle believes a challenge study would afford him a chance to make a societal contribution to the vaccine effort. But as the owner of a business that has him visiting warehouses and flying regularly, he figures he’ll inevitably get infected – so he might as well get it over with.
“I feel if I did it under a controlled environment, and I had an adverse reaction, my chances are much better in a controlled environment than I didn’t know I had it for a week until something had deteriorated to the point I realized,” Gentle said.
Indeed, human challenge studies occur in tightly controlled settings. The report in the Journal of Infectious Diseases advises keeping the subjects in isolation for several weeks and guaranteeing them access to the state-of-the-art facilities of the health system, should the need arise.
“As a part of being in the trial they would be guaranteed excellent care if they needed it,” Lipsitch, a Harvard epidemiologist, told CNN. “Of course, you would expect nobody in the trial on average would need it, but averages don’t always play out.”
Dr. Thomas Darton, an infectious disease expert at the University of Sheffield Medical School, conducted the human-challenge trials that led to the new typhoid vaccine.
Over the years, he said, he has infected some 600 students with the disease. They typically ingest the disease via a sodium-bicarbonate drink resembling Alka-Seltzer and go home. There, they await the symptoms of typhoid – for the study participants they include headache, fever and constipation – which generally kick in within four or five days. At this point, he said, the volunteers with symptoms are given a regimen of antibiotics, which clear up the symptoms in a couple of days.
“We have extensive follow-up data and have not had any long-term problems identified,” Darton said in an email. “The model is safe and reproducible and is a model of mild symptomatic illness only.”
Not all requests for human-challenge studies are granted. In 2017, an ethics panel convened by the National Institutes of Health recommended against a proposal for the development of a Zika human challenge model. (Another panel reversed the recommendation in 2018, and clinical protocol for Zika human challenge development is under review by the FDA.)
Human challenge studies have a checkered history
Human challenge studies date all the way back to the first vaccine, for the highly lethal smallpox disease. The vaccine was developed in the late 18th century by physician Edward Jenner, who aimed to put a piece of folklore to the test: that milkmaids seemed to contract a milder form of the disease, called cowpox.
In an experiment that today would warrant steep criminal charges, Jenner took pus from the scab of a milkmaid and inserted it into an incision on the arm of an 8-year-old boy. The child, James Phipps, developed a headache, chills and other mild symptoms, but when directly exposed to smallpox – again through incisions on the arm – he proved impervious.
A century later, in Cuba, US Army surgeon Major Walter Reed headed up a study to prove that the yellow-fever pathogen that was killing American soldiers during the Spanish-American War was borne by mosquitoes. In the third phase of the study, three of the 10 participants who were bitten by infected mosquitoes died, but Reed was credited for proving the link. Building on that knowledge half a century later, in 1951, virologist Max Theiler won the Nobel Prize for developing a yellow fever vaccine.
In one particularly egregious study, American researchers testing medications for sexually transmitted diseases in the 1940s sent syphilis-infected sex workers into a Guatemalan prison to cavort with unsuspecting inmates. More than 1,300 people were exposed to syphilis and other STDs.
Today’s standards for human-challenge trials are rigorous. Durbin of Johns Hopkins points out that it takes a minimum of six months of prep work to responsibly carry out a human-challenge trial.
This is in part because a suitable strain of the virus – and the proper dosage – must be developed in a lab outfitted with high biosafety standards. Also, researchers must find medical centers that are willing to house the participants in isolation for the duration of the study and provide first-rate care to anyone who falls seriously ill.
“I think it’s very important that you plan for these studies now … and you get it right,” Durbin said. “Yes, it may take time for a good human challenge model to be developed, but if we wait too long to develop it, then I think the moment has passed.”
Caring for volunteers can get tricky
One of the trickier aspects of a challenge study is compensation. Pay too little, and the study may fail to attract candidates; pay too much, and people could be enticed by the money without thinking of their safety.
The latter scenario played out with the yellow-fever trials, in which a participant who was hoping to start a farm in Cuba said it was a “cold-blooded business decision.” The May 7 article in Science – which concludes that the extraordinary nature of the Covid-19 pandemic warrants laying the groundwork for controlled human-infection trials – recommends “several thousand dollars.”
Seema Shah, a bioethicist and associate professor at Northwestern University’s Feinberg School of Medicine – and an author of the Science article – said participants of a recent 40-day human-challenge study for malaria were paid about $2,300.
“Some were very motivated by the money, but others were also interested in the experience, and still others have strong motivations to help others,” she said, adding that some participants personally knew sufferers of malaria and some even donated some of their earnings to charities.
The article in the Journal of Infectious Diseases likens the act of volunteering for a human-challenge trial to other public-service endeavors – such as volunteer firefighting or organ donation.
“People are willing to take on life-threatening risk for other people’s benefit and often not just as a job but as a form of altruistic behavior,” Lipsitch said. “We not only encourage that, but we completely depend on that in many sectors of our lives.”
Still, the onus is on the researchers to ensure that the participants stay safe.
“What keeps me up at night,” said Durbin, “is if I administer a challenge agent to somebody, and that person gets seriously ill or dies – that’s on me.”