Josh Morrison isn’t a doctor or scientist, but as a well-intentioned activist he’s provoked a fierce debate over how to develop a coronavirus vaccine. To speed up testing, he wants to be deliberately infected with the coronavirus. And he’s drawn considerable attention to his cause by starting a nonprofit that already has recruited more than 37,000 volunteers to get infected too—all in the name of science.
What Morrison is advocating is known as a challenge trial. Participants are given a vaccine and then administered the virus to shorten the time it takes to determine a vaccine’s effectiveness. In traditional clinical field trials, scientists have to wait for vaccinated participants to encounter the virus naturally, which can take months.
Morrison’s quest has pushed some of the most elemental ethical questions in medical research into the public arena, raising awareness of a contentious disagreement between scientists whose arguments are typically waged behind the scenes in scientific journals. This debate is now playing out on social media and other platforms as vaccine candidates move through field trials with unprecedented speed.
The questions are many: With no known treatment for COVID-19, is it ethical to inject participants with a virus that’s potentially lethal or might cause lasting organ damage and neurological problems? Can trials likely based on tests in the young and the healthy provide an accurate picture of a vaccine’s effectiveness in the elderly and vulnerable? How can volunteers give informed consent, a federal regulatory requirement for human research trials, when the full impacts of the new virus remain unknown? And would challenge trials really lead to a vaccine more quickly?
Those who support challenge trials tend to disbelieve the rosy scenario presented publicly by the Trump administration that a vaccine could be just around the corner. Vaccine development remains a perilous endeavor. Things can go wrong, a point underscored by the recent temporary halt of AstraZeneca’s clinical field trials after a participant became ill. The record for the speediest vaccine ever developed it still held by the mumps vaccine, approved by the Food and Drug Administration in 1967. That took four years.
Arthur Caplan, a bioethicist at New York University, and Stanley Plotkin, an emeritus professor of vaccinology at the University of Pennsylvania, co-authored a paper supporting challenge trials published in the journal Vaccine. They argued that these tests were essential, in such extraordinary times, as a backup plan.
“What you want to prepare for is having a challenge study ready,” Caplan says. “What if the first vaccine doesn’t recruit enough participants? Let’s say the first three vaccines don’t work. Or they give protection for three months, and you need two doses, which is not practical.”
Those scientists who remain unconvinced point to the lack of a treatment and the unknowns about this still mostly mysterious disease. The death of a challenge trial participant could have profound consequences for public trust in vaccine trials and vaccines themselves.
“I am not against challenge trials,” says Jeffrey Kahn, director of Johns Hopkins Berman Institute of Bioethics in Baltimore. “If you can’t be confident about the risks, there’s no way you can be confident about the risk-benefit balance. That’s where this all falls apart.”
Meanwhile, Morrison presses on with building a fledging movement. In addition to recruiting volunteers to participate in a challenge trial, he has raised more than $1 million. Some of that is intended to fund development of a weakened strain of the new coronavirus, known as SARS-CoV-2, to be used in a challenge trial. He rounded up 125 prominent researchers and ethicists, including 15 Nobel laureates, to sign a July 15 open letter to Francis Collins, director of the National Institutes of Health, urging the government to make “immediate preparations” for human challenge trials.
Anthony Fauci, the immunologist who oversees federal vaccine research, says the NIH is preparing a strain of the virus to be used in a challenge trial if one were deemed necessary, but the nation’s premier medical research center has no plans to conduct one.
The World Health Organization, in draft guidelines issued last May, advised that challenge trials be limited to healthy people ages 18 to 25 because they have the lowest risk for becoming severely ill or dying. But the 19-member advisory panel split roughly in half on several major points, including whether trials should be conducted at all if there’s no treatment for COVID-19.
Morrison is dismayed, but not surprised. He has received a warmer reception in the United Kingdom. He’s working now with Adrian Hill, director of the University of Oxford’s Jenner Institute, named for Edward Jenner, the English physician who created the world’s first vaccine. Hill announced in July he planned to conduct a challenge trial later this year, but Oxford’s communications office has since said there are no current plans for one.
“Imagine a world where we do have unexpected setbacks in vaccines, and it’s January 1, 2021, and there is no end in sight,” Morrison says. “In that world, if we have done preparations so we can do a challenge study, at least then, you can start getting answers within a couple of months.”
COVID-19 requires the world to consider 'unconventional approaches'
Morrison, 35, found his way to activism in medical science in a roundabout fashion. In 2011, he was a Harvard-educated lawyer starting his climb up the career ladder when, in an act of uncommon generosity, he decided to donate a kidney to a stranger. It not only saved someone else’s life, it dramatically changed his.
“Two things stuck with me,” he says. “One was the idea that you can save someone’s life, and two, that the risks to you were a lot less than benefits to them. That’s a pretty cool superpower.”
He quit his Boston law firm and joined a do-gooder group that advocates for kidney transplants. By 2014, he had relocated to Brooklyn, New York, and founded his own kidney transplant nonprofit, Waitlist Zero. “I had been very privileged growing up and economically secure, with great parents and being lucky in school,” he says. “If all I did with that was make a bunch of money as a corporate lawyer, it seemed that would be a bit of a waste.”
Last March, as the pandemic swept the world and overburdened hospitals halted surgeries, including transplants, Morrison found himself at loose ends. He read a paper published in the Journal of Infectious Diseases that argued challenge trials could accelerate the rollout of safe and effective vaccines. “A novel strain of coronavirus forces us to consider unconventional approaches,” the three authors wrote.
The trio—Nir Eyal, a bioethics professor at Rutgers University, Marc Lipsitch, an epidemiologist at Harvard University, and Peter G. Smith, a tropical epidemiologist at London School of Hygiene & Tropical Medicine—noted that society asks people to take risks “every time we ask volunteer firefighters to rush into burning buildings, relatives to donate a live organ to loved ones.” Morrison was convinced.
What was needed, he concluded, was to create a pool of volunteers to save time. To recruit them, he and Sophie Rose, a recent Stanford University graduate, launched a website called 1 Day Sooner, and by the end of June, volunteers from 162 countries had signed up. More than half were from the United States and Brazil. Many are young, well-informed, and single, says Abie Rohrig, a junior at Swarthmore College who volunteered and now serves as the organization’s communications director.
“Even if it saves one day, it could be really valuable,” Rohrig says. “A month less of what’s going on right now would be incredibly important and is worth quite a bit of effort and sacrifice to achieve. I would be willing to take on those risks if I could be some small part of saving time and bringing the world back to normal a day sooner, a week sooner, a month sooner.”
One of the most sobering features of 1 Day Sooner’s webpage is a tally of the number of lives that could be saved in one day, one week, one month, three months—based on the July average of 5,000 deaths globally per day.
Gavriel Kleinwaks, 23, an engineering graduate student at the University of Colorado, says volunteering for a challenge trial could be the most important thing she ever does. “When you think about it in a clear pros-and-cons method, you are looking at risk you are taking on yourself versus saving tens of thousands of lives. I will take that risk,” she says.
Many of the recruits equate volunteering for challenge trials with volunteering for military service during a war. One recruit even compared the mission to defeat COVID-19 with storming the beaches at Normandy in World War II.
Angela Rasmussen, a virologist at Columbia University who believes it’s too dangerous to do challenge trials involving diseases for which there is no treatment and incomplete historical information, especially dislikes the military analogies.
“Yes, in war there is a risk of death or disability. However, in war soldiers are not used to test new types of weapons or defensive technology. We don’t ask soldiers to put on bulletproof vests and then open fire on them to test those vests,” she says. “It is not helpful to frame signing up for a human challenge trial as similar to doing your patriotic duty, especially when the results from such a study would likely be incremental.”
How challenge trials have evolved from the 18th century
The practice of deliberately infecting healthy people to test vaccines dates to 1796 when Jenner, the English physician, inoculated an eight-year-old boy with cowpox and then tested its effectiveness against smallpox by infecting him with the disease. The boy didn’t develop lesions, and the smallpox vaccine was born. Challenge trials since have been used to test vaccines for typhoid, cholera, malaria, and a host of other diseases.
In the United States, 20th-century challenge trials often were conducted in institutions, such as mental facilities and prisons, where the participants had not truly volunteered. In Maryland, trials were held in the Jessup prison outside Baltimore. From 1955 to 1970, challenge trials to test a vaccine for hepatitis were conducted on children at the Willowbrook State School on Staten Island, New York, where developmentally disabled children and adults lived in overcrowded conditions later described as a “snake pit.” The trials hastened development of a hepatitis B vaccine, but at the time other researchers were also closing in on a viable vaccine and there long has been debate over whether it was right to infect children.
Reforms followed in the 1970s, including the National Research Act in 1974 that established protections for participants in human research trials. Today, all human trials require review by Institutional Review Boards, as well as government approval.
In field trials, participants live at home as scientists wait for them to encounter the virus naturally. The trials usually are conducted in regions where the pathogen is active. Challenge trials are conducted in enclosed medical units where participants are isolated during testing. Depending on the pathogens involved, challenge trials could require biosafety level protection. A COVID-19 challenge trial would require a biosafety level 3 protection.
The Center for Vaccine Development and Global Health at the University of Maryland School of Medicine operates a 48-bed unit in Baltimore where challenge studies are routinely conducted to create vaccines for diseases such as malaria, influenza, and a slate of bacteria-related illnesses caused by consumption of contaminated food or water, such as shigella.
Wilbur Chen, a specialist in vaccinology and chief of the Adult Clinical Studies section, gave a tour recently of the unit where challenge trial participants stay while they are waiting out effects of the infections they’ve been given. It includes a recreation room, with pool table and TV, and small rooms where patients can read or work. Repeat volunteers are common, he says, and he noted that writers especially say they appreciate the isolation.
Before trials can proceed, they require an FDA-approved model and a strain of the virus that is strong enough to test the vaccine, but weak enough not to kill or disable the volunteer.
“The assumption is a challenge trial is faster. Well, probably not,” Chen says. “You have to understand what dose you want to use to elicit illness. You have to march up, low dose to the target dose, in what we call escalation studies. The whole process can take up to 16 months.”
The big difference between the center’s research studies and a challenge study for COVID-19 is that all the vaccines tested by Chen and his team are for diseases that have treatments. When the participants in the bacterial studies get ill, they’re given antibiotics, no harm done.
Chen and Kahn, the head of the Johns Hopkins bioethics institute, are preparing a paper that will argue against challenge trials for diseases that lack treatment.
“We reviewed the literature and come down on the side that you cannot substantiate the ethics behind a COVID challenge,” Chen says. “It’s not true that it’s completely safe for young adults. If you had chronic complications that are life-long as a consequence, or the risk of death, that is something that has to be very seriously considered.”
What is not as prominent in the discussion about the ethics of challenge studies, but looms over the issue is public trust. Recent polling by the Kaiser Family Foundation shows public confidence in the government’s handling of the pandemic declining, with fewer than half of Americans surveyed saying they would get vaccinated if a vaccine became available before November. Chen says the public wariness would make challenge trials virtually impossible to conduct.
“Let’s say the government said we’re going to do challenge studies and infect people. It would sow even more distrust at this time,” he says. “It sounds in line with thinking that there is some sort of conspiracy or maladapted intention behind the whole situation.”
Challenge trials may yet have a crucial role to play
Even if one of the frontrunners gains approval by early next year, that would be only the first milestone in vaccine development for COVID-19. The world will need multiple vaccines to inoculate everybody, and the early versions are likely to have some drawbacks. Moderna’s vaccine, for example, requires a storage temperature of negative 4 degrees Fahrenheit and two doses given a month apart. The BioNTech and Pfizer vaccines will require storage at negative 94 degrees Fahrenheit. Such dosing and storage requirements create distribution problems that may be solvable in the United States, but not in sub-Saharan Africa.
If history is a guide, the next generation of improved vaccines will be even more difficult to develop. Funding for research and volunteers for lengthy field trials could become harder to find. As populations are vaccinated, the infection rate will drop, making field trials more difficult.
Chen envisions that challenge trials could play a key role in testing better vaccines and also learning more about how the coronavirus interacts with its human host.
“You can get samples multiple times a day so we can really look in depth at those sorts of scientific questions. We can look at the immune response, we can look at T cells and B cells, blood samples, spit, respiratory samples,” he says. “We can do that systematically and carefully in a standardized way and get a collection of data that can only be done in the context of a challenge study.”
But without a therapy to treat coronavirus, he says, those studies will have to wait.
“There is a role for challenge studies to play, and the timing for that will be when we are over the pandemic, or get to a point where it’s something still widespread but under better control and we have things in place that we feel safe,” he says. “Maybe in six months or 12 months we will have learned enough to be comfortable proceeding. At this time I don’t feel comfortable.”
If that delay disappoints the eager recruits of 1 Day Sooner, Chen urges patience. They may yet get their chance to help: “We will want to learn as much about this virus as we can to prepare for future pandemics.”