For much of the latter half of the 20th century, residents of Great Britain could travel to the quiet medieval city of Salisbury to enjoy a free vacation—provided that they were willing to be infected with a virus. These were the days of the U.K.’s Common Cold Unit, a research body that infected volunteers with cold viruses to better understand how the viruses worked and develop treatments for them. It was through one of these “human challenge trials,” or HCTs, that researchers identified the first human coronavirus in 1965. “People were used to going off on a flu camp,” says Peter Openshaw, professor of experimental medicine at Imperial College London. “It wasn’t a foreign concept.”
So it’s no coincidence, Openshaw says, that the first human challenge trial of SARS-CoV-2 was conducted just two hours east of Salisbury, by him and his colleagues at Imperial. In February 2021, scientists at Imperial College London gained approval to conduct an HCT of COVID-19 in a small group of young, healthy volunteers. Like for much of the work in the Common Cold Unit, the goal of the study was to better characterize the trajectory of COVID and its associated immune response. In late March, the scientists reported their first results, in the journal Nature Medicine. They found, among other discoveries, that subjects tended to first test positive by PCR fewer than two days after exposure—much more quickly than many had thought.
The work the Imperial scientists have done—in particular, determining that many people can catch COVID after being exposed to an extremely small dose of it in the lab—is a foundation on which future COVID challenge trials can be built. Scientists at Imperial already have further studies in the works, according to Openshaw. And the protocols that his research established can in principle now be used in COVID human infection studies anywhere.
But principle is far from reality. While some experts emphatically support COVID HCTs and have advocated for them since March 2020, others doubt that the risks currently outweigh the benefits. “I’m still skeptical of whether this study was sufficiently justified,” says Seema Shah, a bioethicist at Lurie Children’s Hospital of Chicago.
Intentionally infecting people with the virus that has disrupted life across the planet for the past two years and killed more than 6 million people worldwide might seem difficult, even impossible, to justify. But newly developed treatments mean that such studies are now more feasible than they have ever been, and, as the pandemic continues to trudge on, they could answer essential questions that might otherwise prove insoluble.
“We really need to understand basic facts about infection, immunity, and transmission, and some of those are just really hard to observe in community epidemics,” says Euzebiusz Jamrozik, postdoctoral fellow in ethics and infectious disease at the University of Oxford. “In a well-circumscribed, controlled laboratory setting, where you know the exact time that people are getting infected, we just get a much better read on those facts.”
When discussion first began to buzz around COVID human challenge trials early in the pandemic, everyone was focused on vaccines. The idea had a strong precedent: Challenge trials have proved instrumental in the development of vaccines for cholera, typhoid, and malaria. Real-world exposure to pathogens is often incredibly uncertain, and studying infectious diseases in a well-controlled laboratory setting allows scientists to collect much more data, and do so much more precisely, than would be possible otherwise. For vaccines, this can mean faster, and cheaper, approval.
COVID HCT advocates argued at the time that even if challenge trials might pose some risks to volunteers, the benefits of that potentially early approval were so astronomical that such trials had to be considered. In this pandemic, “every day is thousands of lives,” says Josh Morrison, president of 1Day Sooner, an organization that advocates for volunteers who want to participate in COVID HCTs. “If you get an earlier answer, even if it’s earlier by just a week, that could be really valuable,” he says.
In the first months of the pandemic, however, those benefits and risks were both incredibly uncertain. Some experts, like Ruth Macklin, professor emerita of epidemiology and public health at Albert Einstein College of Medicine, argued that the lack of a treatment for COVID made such challenge studies categorically different from those used to develop vaccines for treatable diseases like malaria. In the absence of a means to prevent serious consequences for participants, Macklin and others were unwilling to take on the risk.
Nir Eyal, director of the Rutgers University Center for Population-Level Bioethics and an early advocate for COVID challenge studies, thinks this worry was misplaced. “There has been a convention in the realm of challenge trials that you only do them for diseases that are either very mild or perfectly containable,” he says. But this perspective, he argues, ignores the possibility that major benefits can outweigh substantial risks, and that risks can be reduced without a cure.
In particular, for young, healthy volunteers, COVID effectively is a very mild disease, something scientists have known almost since the start of the pandemic. Of course, the risks aren’t zero—but risks are never zero in medical research with human subjects. “In cancer trials, most people think it’s in the interests of cancer patients to participate,” says Jamrozik, but that isn’t the case at all. Many experimental treatments don’t work; they may harm participants through unpleasant side effects, or by forcing them to forgo other treatment options. Those studies are only justified, then, because the treatments could one day end up helping many other people. “Most research is not a net benefit to the participants,” Jamrozik says.
The question, then, is whether the benefits of any given study outweigh its risks. Such calculations are by no means limited to human challenge trials; in fact, they are intrinsic to any medical study that uses human subjects. But because the potential harms to participants are so obvious in challenge studies, they are perhaps the context where that sort of analysis comes out in the starkest relief.
This calculus is devilishly complex, but one place to start is by looking at cases that medical ethicists have already deemed acceptable. Like participation in a challenge study, living organ donations is an altruistic act that involves risk to the volunteer—and it’s widely considered to be ethical—so it has become a common way of evaluating the risks of COVID HCTs. And based on the best available calculations of the risks to young, healthy participants, COVID HCTs appear to be hundreds of times safer than routine liver donations.
For Eyal, this is a decisive piece of evidence in favor of challenge studies, which also may have much greater benefits than a single liver donation. “We certainly wouldn’t let the injuries alone dissuade us from saving a single life through [liver] donation,” Eyal says. “We shouldn’t let the somewhat vague prospect of long COVID alone dissuade us from saving an incalculable number of lives by improving a pandemic that takes so many lives globally, every day.”
The Imperial researchers are still working to analyze the immunological data from their HCT, so it’s not yet possible to take a full retrospective look at the study’s benefits. What we do know are the negative consequences for the participants. The researchers stipulated that only young, healthy individuals could participate in the study, since such people are extremely unlikely to experience serious consequences from a COVID infection, and that assumption was borne out by the study: The participants experienced only mild to moderate symptoms.
Several subjects, however, did lose their senses of taste and smell; one still had an impaired sense of smell six months later. “Those are somewhat substantial long-term risks,” Shah says. With uncertainty still swirling around the long-term consequences of COVID, she says, there should be a high threshold for intentionally exposing people to the disease.
Participants in challenge trials today, though, will have access to better treatments than those in the Imperial trial—and new antivirals and antibody treatments will make future challenge trials even safer. But now, the original impetus for COVID challenge studies is moot, since COVID vaccines were developed far faster than anyone anticipated and shots were going into arms months before the Imperial study was announced. So some ethicists contend that there is no need for further challenge trials. “We developed faster vaccines than we’ve ever developed in the history of humankind, better vaccines than we’ve developed in the history of humankind, and very rapidly developed treatments that are effective—without having to resort to a human challenge trial,” says Daniel Sulmasy, director of the Kennedy Institute of Ethics at Georgetown University.
But others argue that these advancements are not enough. The past year has made clear that the existence of a vaccine does not guarantee protection for everyone, and Jamrozik says that human challenge studies could help researchers quickly determine which vaccines are effective against new variants and how they should be optimally administered. In many resource-poor countries, vaccination rates remain below 10 percent, and vaccine development is very much still a critical issue. “Challenges can reduce the cost of vaccine development,” Morrison says, “which is particularly helpful in contexts where there’s not as much of a market for the vaccine,” like in lower-income countries.
And some information about COVID cannot possibly be obtained from a standard trial. Imperial College researchers were only able to determine that people tend to test positive fewer than two days after COVID exposure because they knew exactly when their participants had been exposed and because they were testing them twice a day. Such information, Jamrozik says, could help optimize quarantine procedures, and future challenge studies could allow scientists to nail down the effectiveness of prevention measures such as masks and air purifiers. “A mannequin study of aerosols is not the way to study masks,” Jamrozik says. “The way to study masks is to do it in human beings in real-life situations”—to expose people with and without masks to COVID-positive individuals and see how much better off the mask-wearers really are.
There’s one more tantalizing piece of knowledge that challenge studies are particularly well positioned to discover: correlates of protection. When someone mounts a successful immune response to a pathogen and prevents it from taking hold in their body, their immune system typically shows a characteristic response such as the presence of certain antibodies or types of white blood cell. If scientists identify these so-called correlates of protection for COVID, they can test new vaccines without ever exposing subjects to the coronavirus, naturally or otherwise. They will be able to infer successful protection just by studying a person’s immune response in the days following inoculation.
The U.S. Food and Drug Administration already authorizes pediatric COVID vaccines on the basis of “immunobridging” studies, in which antibody production in children is compared with antibody production in adults from the same vaccine, because the rarity of symptomatic COVID infection in children makes the vaccines difficult to test otherwise. But these studies are viewed as adequate evidence only because the same vaccines have already been proved effective in adults through more conventional means. Richer and more general data about the correlates of protection from COVID could allow this approach to be used much more widely, and HCTs could enable that shift. “Everybody agrees the best way of getting at [correlates of protection] is through challenge trials,” says Eyal. Those correlates could then allow new vaccines, and new vaccine administration protocols, to be approved far faster than is currently possible—without ever having to expose anyone to COVID at all. COVID human challenge trials, if successful, have within them the seeds of their own obsolescence.
Future Tense is a partnership of Slate, New America, and Arizona State University that examines emerging technologies, public policy, and society.