Paul Zimmer-Harwood enjoys taking on extreme challenges. In 2016, when he was 24 years old, he swam 18 hours to complete a 26-mile marathon in a swimming pool in Gütersloh, Germany. In 2019, he completed the Marathon des Sables—a six-day, 156-mile ultramarathon across sand dunes and dry riverbeds in the scorching heat of Southern Morocco. Later that year, as Zimmer-Harwood embarked on a doctorate in neuroscience at the University of Oxford in England, he volunteered to get bitten by malaria-infected mosquitoes for a vaccine trial against the life-threatening disease.
In mid-2021, when scientists were recruiting young healthy adults to deliberately expose to SARS-CoV-2, the virus that causes COVID-19, Zimmer-Harwood didn’t hesitate. “In my mind, it was an immediate yes,” he says. And while advancing science was important motivation for him, it didn’t hurt that he would be compensated nearly $6,000 for his time and discomfort.
Though he was unvaccinated at the time of the trial he’d already had Covid. “It made it a little less scary for me, but I’m pretty sure I would have done it either way,” he says.
This University of Oxford study—only one of two approved worldwide for intentionally exposing healthy humans to SARS-CoV-2—could help quantify the level of immunity needed to prevent COVID-19 reinfections and could lead to better vaccines and treatments. The other study led by researchers at the Imperial College London has been exploring why some uninfected and unvaccinated youth get COVID-19 while others seem protected against infection after exposure to the original virus strain. Imperial researchers are also hoping to learn why some people develop symptoms and others remain asymptomatic.
“Such studies might lead to scientific insights into the disease process that will be difficult to obtain through observational studies because the precise timing of infection is known,” says Dan Barouch, an immunologist and virologist at Harvard Medical School who was not involved in research.
No dearth of volunteers
In February 2021, when Christopher Chiu, an infectious disease physician and immunologist at Imperial College London, and his colleagues put out a call for healthy volunteers between 18 and 30 years old, an astounding 26,937 registered, he says. But, he added, “we were very selective about who we’d include in the study.”
That meant excluding anyone with a potential risk of developing severe COVID-19 symptoms, including individuals with comorbidities: a high or low body mass index, and abnormalities in blood or lung tests. In the months that followed, the research team whittled the number of volunteers down to 36 individuals who were then exposed to the virus.
Alastair Fraser-Urquhart had never had COVID-19 but was a volunteer with a group called 1Day Sooner, which was campaigning in 2020 for “challenge trials” to accelerate vaccine development. In 2021, when he was 19, he was selected to participate in the Imperial College study. He said he wanted to participate in the name of science and to honor the millions who had lost their lives to COVID-19.
As clear liquid droplets containing small amounts of the virus hit his nose, Fraser-Urquhart realized it was the scariest thing he’d ever done.
“There’s an inherent risk involved,” he says, but Chiu’s team monitored his infection every 12 hours, drawing blood, swabbing his nose and throat, and running several other tests for at least 14 days as his mild symptoms subsided.
“We’re in the process of doing very in-depth analyses of those samples,” Chiu says. He’s particularly interested in discovering why nearly half of the 36 participants in his study didn’t get sick or develop antibodies against SARS-CoV-2.
In a study likely to launch in a few months, Chui’s team also hopes to infect vaccinated individuals with the Delta variant, which caused a surge in vaccine breakthrough COVID-19 infections last summer, to understand why these happen.
Human challenge trials go way back
Human challenge trials aren’t a COVID-19 pandemic phenomenon. Scientists have conducted such studies for decades to learn more about malaria, influenza, cholera, and other infectious diseases, and to test vaccines against them.
Their use is often not so controversial, “when you have a pathogen you understand well, you understand the course of the disease well, and there is some way a researcher doing the challenge study is able to reliably protect participants against longer term, serious outcomes,” says Seema Shah, a medical ethics expert at Lurie Children's Hospital in Chicago.
In 2015, for example, a research group exposed 46 healthy participants to the influenza virus to determine the amount of virus necessary to produce a mild to moderate influenza infection in at least 60 percent of the participants. Such knowledge has helped scientists test experimental vaccines after exposing participants to the infection-inducing viral dose. Identifying a safe yet effective quantity of pathogen that can induce infection is often the first step, says Kathleen Neuzil, a vaccinologist at the University of Maryland.
In 2016, for instance, to test if a single-dose oral vaccine called Vaxchora prevented a cholera infection in healthy adults, U.S. scientists exposed study participants to the cholera bacteria either 10 days or three months after vaccinating them. The study showed that Vaxchora reduced the likelihood of severe diarrhea in vaccinated individuals by between 80 and 90 percent. Because cholera is a rare disease in the United States, “you can’t really do a big field trial,” says Neuzil. The study results led the Food and Drug Administration to approve the only cholera vaccine available in the U.S. for adults aged 18 through 64 years who are traveling to cholera-affected regions of the world.
In their study, Chiu and his colleagues were surprised to find how little SARS-CoV-2 was needed to infect nearly half of their previously uninfected and unvaccinated participants. “Based on our understanding of similar studies with other viruses, we were expecting at least 10-fold or more virus to achieve the same sorts of infection rate,” he says. “But it’s a combination of the fact that people didn’t have immunity and also the highly infectious nature of the virus.”
Some scientists argued that despite using a low dose of the virus and targeting a less vulnerable demographic, human COVID-19 challenge studies weren’t justified because a reliable rescue therapy wasn’t available at the time of the initial experiments in early 2021. “It's still controversial, whether those trials were actually ethically justified at the time that they were conducted,” Shah says. “It was a hard decision for that ethics committee—it was a lot of back and forth.”
So, why continue these COVID-19 human challenge studies in 2022?
Compared to early 2021, many people are now vaccinated, lowering their chances of developing severe COVID-19. On the off chance that occurs, a handful of treatments are available that may help. But breakthrough infections with new variants are becoming increasingly common among those vaccinated and boosted.
Human challenge trials, albeit with their obvious risks, may be better suited to understand how long a previous COVID-19 infection or vaccine shot provides immunity and if indicators other than antibodies, which are currently used to assess the efficacy of vaccines and other treatments, may be more relevant to measure success, says Nir Eyal, a bioethicist at Rutgers University.
Results from conducting similar experiments in animals may not accurately reflect human responses to a disease or treatments. The other advantage with challenge trials is that scientists can get a snapshot of the immune system before and after infections. This helps identify elements of the immune system that may prevent someone from getting infected or developing symptoms after exposure to the virus.
“With a challenge study you can do that because you can get [blood, tissue, respiratory] samples before infection and continue to sample following the infection,” Neuzil says, as the patients remain under observation in the controlled environment of a hospital while they continue to shed the virus and when they return for checkups over following months. Here, asymptomatic infections are also identified.
However, obtaining clearances and laying the groundwork for such studies can take months, but “it becomes particularly tricky for coronaviruses and influenza viruses that keep changing,” Neuzil says. By the time an experiment reveals a safe and effective viral dose to expose challenge study participants to, another variant comes along and requires researchers to determine a new dose for challenge trials that might involve the new variant. “That’s absolutely one of the biggest challenges,” she says.
But because such studies don’t require hundreds of thousands of participants as traditional clinical trials do to work, they could speed up the development and testing of new vaccines and treatments, and possibly cut research costs.
Barouch, however, argues that such studies are not a substitute for large-scale clinical trials. “A human challenge study is, by definition, a small, highly selected population, almost certainly of young and healthy people,” he says. “It would not capture the breadth and diversity of the human species.”
Currently, COVID-19 challenge studies are only approved in the U.K. “I could now see making the risk-benefit case for doing these in the U.S,” Neuzil says. Although the possibility of young healthy participants developing long COVID cannot be discounted.
“That was my only real concern,” Zimmer-Harwood says, “but it was a risk I was willing to take.”