One Man’s Quest to Infect People With Covid-19 for Science
Inside the movement to launch a human challenge trial for Covid-19
During Josh Morrison’s first year at Harvard Law School in 2007, while preparing for exams, he took a break from his studies and turned to the New York Times Magazine. That’s when he read an article that changed the trajectory of his life.
The author, a woman named Sally Satel, recounted her quest to find a kidney donor. Two numbers, in particular, grabbed his attention: In 2005 alone, 60,000 people were waiting for a new kidney. By 2007, the list had grown to 74,000. To Morrison, it amounted to a calling.
“The idea of needing an organ and worrying if anyone cared about you enough to do that — that seems like the loneliest, worst thing ever,” he says, relaying the tale in June while we peered at each other through our computer webcams.
Most people are born with two kidneys, the upshot of millions of years of evolutionary tinkering resulting in humans’ bilateral symmetry: two eyes, two ears, two nostrils. Our kidneys, though, are show-offs. A single kidney operating at three-quarter capacity can still filter bodily fluids, produce red blood cells, activate vitamin D, and perform its handful of other vital functions. Healthy people can survive just fine with one.
So Morrison donated a kidney in 2011, months into his job as a corporate attorney. A few years later he abandoned the law for a more mission-driven career helping people find kidney donors, eventually starting the nonprofit Waitlist Zero in 2014.
In his telling, his parents “really hated” the idea of being a live organ donor. What he’s planning next terrifies them: Morrison wants to give himself Covid-19 for the sake of science.
Half a year has passed since the novel coronavirus began its worldwide hitchhike, infecting millions, separating families, and robbing people of life. Scientists are feverishly trying to find therapeutics to treat Covid-19, the disease caused by the virus. Still others are concocting vaccines to hopefully prevent the disease.
“It’s a real possibility one of us dies.”
That’s where Morrison wants to help. The 35-year-old from Brooklyn is the leader of 1Day Sooner, a grassroots organization he co-founded in the spring with a radical idea: Speed up vaccine testing by giving the coronavirus to willing recruits. Including Morrison and his co-founder, 22-year-old Stanford human biology graduate Sophie Rose, more than 30,000 people from 140 countries are signed up — a pool of applicants offering to enlist in what’s known as a human challenge trial.
“It’s a real possibility one of us dies,” says Morrison, leaving unsaid the grim statistics that back this up: More than 650,000 people, one-quarter of them Americans, are already dead.
Human challenge trials involve deliberately infecting small groups of vaccinated volunteers. In a time of social distancing, mask-wearing, and the public’s general leeriness of contracting Covid-19, some researchers, doctors, and ethicists say challenge trials are worthwhile. Unlike traditional Phase 3 clinical trials, which sign up thousands of participants, inject some with a vaccine and others with a placebo, and then wait for people to encounter the virus in everyday life, there’s no waiting on people to catch a virus in a challenge trial. This means it can be completed in weeks instead of months or years, potentially yielding data on vaccine efficacy much more quickly.
On July 15, human challenge trials for the coronavirus received their biggest endorsement. Adrian Hill, director of the Jenner Institute at the University of Oxford in the U.K., announced that Oxford scientists — already hard at work on a promising coronavirus vaccine — want to launch a challenge trial.
“We’re hoping to be doing challenge trials by the end of the year,” Hill told The Guardian.
In a separate public statement, Hill added, “We see considerable potential in the use of human challenge studies to accelerate Covid-19 vaccine development… and applaud 1Day Sooner’s drive to help make this happen.”
To date, 1Day Sooner has raised about $1 million to fund its advocacy operation, with $300,000 of it earmarked to pay for making the virus strains used in the challenge trial. (The process requires a specialized laboratory with trained scientists.) As the logistics are still being put in place, the Oxford team including Hill declined to comment further, but the two groups plan to collaborate on the costly manufacturing of strains of challenge virus.
For Morrison, it’s a major step forward not only for the group, but also for Covid-19 vaccine development. “We’re hugely thrilled,” he says.
Up until a few weeks ago, the notion of conducting a human challenge trial was more proposition than promise, despite support from leading medical researchers and a history of being used for other diseases. Now questions around testing an unproven vaccine in volunteers intentionally “challenged” with the coronavirus require concrete answers. If challenge trial volunteers get sick and then get well, the trial could bring the pandemic to a halt by moving a vaccine forward. But if a challenge trial fails — if someone dies — it might set back even further the timeline for stopping the virus’s worldwide march.
Before Covid-19, before asseverations about masks and fights over haircut availability, before the germ theory of disease, before vaccines were even invented, there was the boy and the cow.
In 1790s England, the standard protective measure against the fever and pus-filled blisters of smallpox was variolation: Dried scabs from a person who had the disease were either blown up the nose or inserted through punctures in the skin. Like other doctors of the period, Edward Jenner was well-versed in the technique. Still, he suspected there was another way to render protection that didn’t involve giving someone a mild form of smallpox. He found his answer in cowpox, a weak virus that sometimes jumped to milkmaids, leaving pocks on their hands. Cowpox usually resolved in a few days without much trouble. Even better: People who caught it didn’t catch smallpox.
In what might be considered the earliest challenge trial, Jenner tested the notion in 1796. A milkmaid near his country hometown of Berkeley contracted cowpox from Blossom, a lovely local dairy bovine. Jenner collected cowpox pus from a lesion on the woman’s hand, and then selected James Phipps for his experiment. The son of Jenner’s gardener, Phipps was an eight-year-old boy, who, crucially, never had smallpox. Jenner rubbed the cowpox sample into small scratches he made on the boy’s arm. Two months later, he variolated Phipps with smallpox scabs. The boy never developed the disease, then or subsequently in life.
For his work, Jenner is credited as the grandfather of vaccination. Fittingly, he’s the namesake of Oxford’s Jenner Institute. But the experiment he carried out speaks to the stickiest question to emerge from the debate over whether to conduct a challenge trial for the coronavirus: Is it right to risk the health of dozens of people, or even just one person, for the potential benefit of many others?
One renowned medical ethicist, the late Harvard anesthesiologist Henry K. Beecher, states it plainly. Writing in the New England Journal of Medicine in 1966, Beecher concludes: “The gain anticipated from an experiment must be commensurate with the risk involved.”
The trouble with the novel coronavirus is obvious: Because the virus is so new, doctors don’t yet know all the risks. What is the full spectrum of illness? What are its long-term effects? It was only a few months ago that people couldn’t even get tested for the coronavirus unless they had a fever, a cough, or shortness of breath. Now some people who have recovered deal with lingering symptoms: persistent fatigue, pain in their joints and head, heart inflammation, lost smell or taste, delirium, even intermittent coughing that won’t subside. Not to mention the fact that effective therapeutics to treat people who participate in a challenge trial are still being developed or studied.
“If you did a human challenge and somebody got really sick, you want to be able to do something about it,” says Beth Kirkpatrick, MD, director of the Vaccine Testing Center at the University of Vermont’s Larner College of Medicine. “The trouble with coronavirus is you don’t have anything yet. That is a huge safety concern.”
Unlike human challenge trials previously carried out for malaria, typhoid, and cholera, no one knows how to control runaway Covid-19.
Then there’s the insidious danger, also obvious: volunteers developing the severe or fatal disease. New research from July shows that the coronavirus kills between five and 10 people for every 1,000 people it infects, with the rate varying by who is infected and their access to health care. In the U.S., according to data compiled by the Johns Hopkins University, the case-fatality rate is about 3.5%; in the U.K., it’s 15.2%.
The World Health Organization has not explicitly voiced its support for conducting human challenge trials for the coronavirus, but it did convene an advisory group to assess their feasibility. In a draft report published in June, the international health body recommended that the viral dose given in any challenge trial should induce only mild to moderate illness in people.
Yet if there is one element of the pandemic that is known for certain, it’s that the coronavirus is maddeningly vexing. Sometimes it resembles a mild flu. Sometimes it’s devilish enough to remind us that all modern life’s glamorous trappings could be shredded in a moment, like a ship in the night raked across rocks on a darkened shore.
Unlike human challenge trials previously carried out for malaria, typhoid, and cholera, no one knows how to control runaway Covid-19. It’s why human challenge trials are also called controlled infection studies: The salient aspect is being able to effectively manage an illness. When Kirkpatrick’s center recruited human volunteers to test Vaxchora, the only vaccine approved by the Food and Drug Administration (FDA) for cholera, doctors knew they could stabilize people, if they had to, by giving them intravenous fluid.
“If you cannot control the infection,” she says, “you can’t really ethically do a human challenge model.”
Whether infection could be controlled continues to hold back institutions like the FDA — which would have to authorize a challenge study — from offering any more than open-ended opinions on the merits of a coronavirus challenge. A top FDA official overseeing vaccine approval likened such a challenge to “ethical heartburn.”
A spokesperson at the National Institute of Allergy and Infectious Diseases (NIAID) said, in a statement to Elemental, that the institute is investigating “the technical and ethical considerations of conducting human challenge studies.” In June, NIAID director Anthony Fauci, MD, said the U.S. is producing challenge doses for a potential trial, but also mentioned he hoped “we won’t have to use” one.
The problematic nature of a coronavirus challenge trial also extends beyond the medical conundrum of how to manage the risk for people who participate. There’s a very real question of whether conducting a human trial on an unproven vaccine with a confounding virus violates public trust.
Seema Shah, JD, an associate professor at Lurie Children’s Hospital of Chicago and Northwestern University, says the stakes are even higher in a pandemic when failure — especially when the entire world is watching — could feed further distrust in people relying on governments and health care workers to corral the coronavirus.
“We do accept, in research in general, that people take on some amount of risk in order to benefit others in society. The question is: How much risk is okay?”
“Researchers have to make sure they’re worthy of the trust that the public gives to them before they decide to do a study like that — even if there are a lot of people who would be willing to step up and put their lives on the line,” she says.
In an article examining the ethics of human challenge trials, published by the Journal of Medical Ethics in 2004, bioethicists at Oxford and Cambridge universities summed up the quandary: “If significant numbers of people were to die as a result of taking part in medical research, then this would be likely to have the effect of bringing such research into disrepute […] The fact that doctors are involved in designing the research may lead to a reaction against not only medical research but against medicine more generally.”
A challenge trial in which a number of volunteers get sick may only embolden people already determined not to take any coronavirus vaccine, pandemic be damned.
“We do accept, in research in general, that people take on some amount of risk in order to benefit others in society,” Shah says. “The question is: How much risk is okay?”
At the end of March, like many other Americans, Morrison was under lockdown. Hunkered in his Brooklyn apartment, and with nothing to do since kidney-transplant surgeries had ground to a halt, he was alone, bored, and feeling “just so miserable,” he recalls. He occupied his time reading about the pandemic, which is when he stumbled on an article published at the very end of the month that broached the subject of doing human challenge trials for the coronavirus.
Suddenly, he had an idea for a new project, although the risk calculations he made at the time were more akin to a back-of-the-envelope analysis.
“To me, it looked like the risks were greater than kidney donation,” he says. “And it’s like, I’m in a position — being fairly young, being 34, being in good health, I don’t have any kids — where I could do that. Why not me? Why shouldn’t I do it?”
By early April, he established 1Day Sooner and launched a website to collect the names of other people also interested in signing up for human challenge trials.
The article Morrison read was co-authored by epidemiologists Peter Smith and Marc Lipsitch, PhD, and bioethicist Nir Eyal, PhD. Writing in the Journal of Infectious Diseases, the trio contended that a trial could not only “potentially cut the wait time for the rollout of an efficacious vaccine,” but also be relatively safe — as long as the ages of people chosen to participate would be such that “the risk of death or serious complications following infection is substantially lower.”
Smith, an epidemiology professor at the London School of Hygiene and Tropical Medicine, says that now, four months later, he might recommend further restricting the age limit to adults between 18 and 30, and without preexisting conditions. But the trio’s support for the underlying premise, however, remains unchanged today: We should prepare for the possibility of human challenge trials for the coronavirus, even if they end up being unnecessary.
“There is a risk we will not be able to get prompt answers with a classic Phase 3 [trial],” says Lipsitch, a professor at Harvard’s T.H. Chan School of Public Health. “That risk remains, and although many countries still have raging epidemics, we have a long way to go before there are enough good vaccines for the world.”
Yet what age qualifies people for a challenge trial — while not entirely a mystery — is still in dispute. Oxford’s Hill has said the risk of death “is extremely low in young people… so low that it’s difficult to measure.” An analysis of the coronavirus mortality risk of people in their twenties that 1Day Sooner likes referencing is the infection-fatality rate that pegs it at one in about 3,300, similar, they say, to something with which Morrison is quite familiar: live kidney donation. That age range would eliminate Morrison from participating in a trial, but it’s a reference point the group uses because the WHO proposed a range of 18 to 25 in its June report.
“I think people like me should be eligible,” says Morrison, adding that if it were 1Day Sooner’s decision, the range would be 18 to 40 years. (In June, the group sent a letter to the WHO arguing that even people up to 40 years old should be able to volunteer for a challenge trial.)
Grappling with this question of risk has been a months-long project for Eyal, director of Rutgers University’s Center for Population-Level Bioethics.
“I hear anecdotally from people on the front lines that these long-term complications seem to be much rarer among young people,” he says. “I think you’re right that it complicates the calculation, but for me, it doesn’t very fundamentally change the final conclusion.”
In a subsequent paper published in May, Eyal defended the idea of conducting a coronavirus challenge trial despite the risk of severe infection. It’s a complex weighing of various factors, difficult to talk through fully in an hour-long phone conversation. Part of the calculation lies in the makeup of the challenge itself. While the probability of getting infected in a trial is higher, the probability of either dying or developing a long-term disability as a result is lower, he says: Teams of doctors and nurses would be on hand to scrupulously monitor volunteers throughout the course of infection.
“To conduct the study and to do so ethically, you need to minimize risk. And part of minimizing risk is giving you fantastic critical care,” Eyal tells me.
The other part depends on participant selection. One of the risk calculations he made in the paper with Lipsitch and Smith points out that, in the absence of any vaccine, “a high proportion of the general population is likely to be infected with [coronavirus] at some point, including those who might participate in a challenge study; by volunteering to be artificially infected they may be just hastening an event that is likely to occur in later months anyhow.”
Eyal, in his May paper, goes a step further: He argues volunteers should come from areas with ongoing or expected high transmission rates.
Choosing that volunteer group is the all-important question. Probably no more than 100 people of the 30,000 people who added their names to the list compiled by 1Day Sooner would be picked for a single challenge trial. If the point is testing speed, the participant pool, by nature, must be small.
But among a population of healthy young adults, who gets picked? For starters, a person should be prepared to spend several weeks in isolation in order to be infected, be monitored, and then give their body enough time to clear the virus.
The demographic makeup of the trial, aside from age, also matters. Data shows that people of color are twice as likely to die from Covid-19, but trial diversity is nonetheless important: Therapeutics and vaccines don’t always induce the same effect across ethnic groups.
“If Black people have been the victims of Covid-19, we’re going to be the key to unlocking the mystery of Covid-19,” Rev. Anthony Evans, president of the National Black Church Initiative, told the Los Angeles Times.
What’s more, the 30,000 people are not just a group of names to be picked at random out of a hat. Before any trial volunteers are selected, there must be a robust informed consent process — something Shah says was missing when Jenner conducted his cowpox experiment.
“It’s not clear there was good informed consent. It’s not clear why it had to be done with a child, and the child of his gardener, no less,” she says.
The history of medical experimentation on unconsenting people is an ugly one. Nazi atrocities during World War II included vile human experiments, like when some prisoners at concentration camps were submerged naked in freezing water and then strapped down outside in cold weather. The U.S. has its own troubling past with unethical medical research, perhaps none more famous than the 40-year Tuskegee Study, in which hundreds of Black men in rural Alabama who had syphilis were denied treatment. In 1974, two years after a whistleblower exposed the study, the U.S. passed the National Research Act. One outgrowth of that legislation is the use of Institutional Review Boards, independent bodies that evaluate the ethics of human trials.
The coronavirus challenge trials would be conducted only with healthy, consenting adult volunteers. Even so, the informed consent process will still be difficult. It’s not enough for a volunteer to simply throw their hand in the air and say they’re fine participating. On this point, Beecher is again instructive. “The statement that consent has been obtained,” he wrote in 1966, “has little meaning unless the subject or his guardian is capable of understanding what is to be undertaken and unless all hazards are made clear.”
Eyal makes the same point when he says that informed consent is not enough. “Consent shouldn’t just be formal consent,” he says. “It must be with examinations of comprehension and of the risks.”
Oxford University and 1Day Sooner haven’t made formal plans on whether participants will be recruited from the pool of 30,000 names collected by Morrison’s group. But 1Day Sooner is taking initial steps to vet people (while trying to convey that low-risk does not mean no risk). They plan to issue multiple comprehension tests to potential volunteers and worked with Shah, who also serves as the associate director of research ethics at Lurie Children’s Hospital, to put together a survey of volunteer motives. The survey should provide some answers on volunteers’ level of knowledge of the coronavirus, what they think human challenge trials are designed to do — and whether they’re aware of the potential risk involved.
However exciting the University of Oxford news was for 1Day Sooner, virtually little of it matters if logistical hurdles aren’t cleared.
“There are an enormous number of practical issues that we have to overcome to make this useful,” says Matt Memoli, MD, who works at the NIAID directing the Laboratory of Infectious Diseases Clinical Studies Unit.
For 15 years he has studied respiratory viruses. A majority of that work in the last decade was focused on running human challenge trials for influenza, with the goal of using that research to prepare for a worldwide flu outbreak. “All of us thought the next respiratory virus pandemic would be influenza,” he says with a touch of ruefulness in his voice. “None of us thought it was going to be a coronavirus.”
In early March, he sent a note to his boss — NIAID director Fauci — proposing a human challenge for the coronavirus, and urging that groundwork needed to be laid early. Just like the timeline for the coronavirus vaccines is being incredibly truncated, so, too, must the timeline for a challenge trial, if one is to happen before the end of this year. (For comparison: Memoli started preparing his last challenge in early 2019. That trial, for low-pathogenic avian flu, a step toward developing trials to test the universality of influenza vaccines, would have started in March if not for the pandemic.)
Sufficient quantities of a challenge virus need to be safely and reliably produced, work that must happen in biosafety level 3 laboratories. Hill’s lab at Oxford is still working with 1Day Sooner to identify companies that can manufacture challenge strains, most likely from viral isolates of the coronavirus and according to “good manufacturing practices.” So far only one, Los Angeles-based biotechnology startup Curative, was chosen.
Once enough challenge-strain virus is made, an infectious dosing study has to happen. Think of it as a miniature challenge trial: Between five and 10 people would be vaccinated and then infected. This is where the true assessment of the feasibility of a larger challenge trial takes place. Is the challenge virus safe for volunteers? Does it induce infection, or is a larger dose required? Do the attending doctors and nurses have enough personal protective equipment? Is the trial using an excessive amount of health care resources that might be better spent tending to patients in hospitals?
Per the WHO’s advisory report, people who enlist in challenge trials need to be housed in “high-level isolation units” to ensure they don’t infect other people. Memoli says there are only a few locations around the U.S., including where he houses his challenge studies, that meet that criterion. And, of course, the designs for the trials have to go through ethical and scientific review; in the U.S., that means examination by the FDA and an Independent Review Board.
Generally speaking, Morrison says a challenge study would be ready by September or October “in the best-case scenario.” His estimate aligns with what the WHO outlined in June: At least two months are needed to manufacture the virus and determine the proper dose.
Even assuming a trial begins sooner than later, there’s nothing to learn about whether a vaccine reduces or prevents illness in older people or people with health problems. After all, challenge volunteers must be young and healthy enough to withstand infection.
And several potential vaccines are already in the crucial, final stage of phase 3 efficacy testing. Massachusetts-based Moderna, which developed its vaccine in collaboration with the NIAID, begins phase 3 trials this month. Meanwhile, the vaccine developed by Oxford University’s Jenner Institute is in phase 3 trials in Brazil, South Africa, and the U.K., and a phase 3 trial in the U.S., for which Oxford hopes to enroll upward of 30,000 people, is slated to begin in August.
Given the steps involved just to get a challenge trial up and running, there’s no guarantee it speeds up what has already been a rapid vaccine development process.
Still, the world remains several months, if not longer, from a vaccine, despite the U.S. government’s Warp Speed initiative to deliver hundreds of millions of doses by late this year or early next. That leaves an opening for a human challenge trial to be deployed, albeit in a slightly different context than initially envisioned.
Nadine Rouphael, MD, an associate professor of infectious diseases at Emory University School of Medicine, and one of the investigators testing Moderna’s Covid-19 vaccine, cautions that the first vaccine licensed might not be the best one — or that multiple vaccines will be required to fulfill a global need.
“A challenge study might be able to do a rapid screening of vaccine candidates,” she says. “It might also help us understand transmission and what level of antibodies is necessary for protection.”
Understanding how vaccines confer protection is part of the reason why Memoli, despite being aware of the practical problems involved in organizing a human challenge, urged his office to start assembling the model for a coronavirus challenge trial early.
“Right now, we’re guessing. We’re developing vaccines with the notion that we think the mechanism of action of the vaccine is going to work to protect us,” he says. “But the big question is: Why did it work or why didn’t it work? We need to know that. That helps us figure out if our other vaccines are going down the right path.”
In the controlled setting of a trial, researchers — who have already taken blood from volunteers to know what their preexisting immunity looks like before vaccination — know exactly when someone was infected, which means they can track over time how the body reacts to the virus. In flu trials, this kind of precise tracking is invaluable; Memoli says in just the first 24 hours, gene expressions help scientists predict how sick someone will get as the disease progresses. Now imagine having that information for the coronavirus, with detailed data on antibodies, T cells, and other elements of the immune response.
“In a natural study, you give people a vaccine, but you have no idea if or when those people are going to be exposed to the virus,” he says. “And so trying to understand if they had proper protective responses at the time they were exposed is going to be very hard.”
At the University of Oxford, preparations are just beginning to establish a human challenge trial. While the plan is to have it start by the end of this year, whether it runs alongside Oxford’s phase 3 trials or just afterward is still being decided.
“We shouldn’t think that as soon as we have a vaccine, that’s it, we give up doing any work. We will need to continue to study this virus.”
“This might be in parallel or might be after the phase three trial is completed,” Jenner said this month. “They’re not competing options, they’re complementary.”
In other words, the one institution on record saying it hopes to conduct a human challenge study isn’t substituting its phase 3 trials. If anything, it will use human trials as a complement to larger-scale clinical trials — possibly as a way to study optimal dosing for vaccines, possibly as a way to test how long immunity to the coronavirus lasts after being vaccinated or exposed.
“We shouldn’t think that as soon as we have a vaccine, that’s it, we give up doing any work,” Memoli says. “We will need to continue to study this virus.”
As the months have gone on, this is the new message that 1Day Sooner is pushing: Human trials will help researchers study how the body fights off the virus. The group also predicts that challenge studies will help researchers compare the efficacy of one vaccine to another.
“It is very possible that challenge studies won’t be ready for that first wave of vaccine candidates,” Morrison says. “But you’re going to need multiple vaccines, probably, so even if studies aren’t there for the first wave, they will be there for the second wave.”
For now, 1Day Sooner continues to build a chorus of support. In April, 35 U.S. congresspeople lobbied the FDA and other federal regulators for human challenge trials. The editorial board of the Washington Post recently opined that it “makes sense to build the regulatory, medical, and ethical infrastructure to support challenge trials now.” Even Morrison’s parents, once terrified by the prospect of their son being enrolled in such a trial, have tempered their horror.
“It is not easy to lie awake night after night and worry about your child,” wrote Morrison’s mother, Robin, in a letter shared with Elemental. “But it is an unbelievable feeling to know you helped to raise a person who looks at the world as these volunteers do.”
On July 15, the same day Oxford’s Jenner Institute announced a plan for the coronavirus challenge trials, Morrison’s group published an open letter addressed to Francis Collins, MD, PhD, director of the U.S. National Institutes of Health, calling on the various arms of the U.S. government involved in the country’s pandemic response to make preparations for human challenge trials. The document was signed by more than 100 scientists and researchers, including Nir Eyal, Marc Lipsitch, Peter Smith, Nadine Rouphael, and Adrian Hill. Co-founders Morrison and Rose also signed their names to the letter.
“The danger is higher at the moment because there’s no effective treatment for Covid-19, but the circumstances are also unique,” Morrison says. “We could functionally save one month or more and billions of dollars in manufacturing time.”
Four spots down from where Morrison signed was another familiar name, at least to him: Sally Satel. Satel, in fact, has become an advocate in her own right for human challenge trials: Not only did she help draft the open letter, but she also recruited some of its signers. It seems a fitting juxtaposition. It was her article that inspired Morrison, leading him to give up corporate law and found Waitlist Zero — which eventually led him here, pushing another plan, hoping to help.