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One morning in Baltimore last October, a 26-year-old named Alexander Laurenson strode into a small white room to have his arm preyed upon by mosquitoes. As requested, he had not showered the night before to make his skin more attractive to the pests, drawn as they are to body odor. The mosquitoes, for their part, had been infected with malaria, a disease that kills over 600,000 people every year.
Mr. Laurenson was part of a study at the University of Maryland School of Medicine to test a new monoclonal antibody designed to prevent malaria transmission. Specifically, he had agreed to take part in a human challenge trial, a research method in which volunteers are knowingly infected with a pathogen.
In preparation, the room had been secured to ensure against the mosquitoes’ escape, with a bug zapper installed on the wall and a few electrified paddles added as extra precautions. One by one, over 20 volunteers shuffled inside to serve as prey.
Trials like this one have long underpinned the development of vaccines for deadly scourges like typhoid and cholera. Today, they are typically undertaken only with diseases that already have fast-acting drugs to ensure recovery. But because of the perceived risk involved, and their significant cost, challenge trials remain rare and, in some cases, controversial.
“A lot of people say, ‘Doesn’t this violate the Hippocratic oath?’ or ‘How can a doctor do this?’” said Seema K. Shah, a bioethicist at Lurie Children’s Hospital and professor at Northwestern University in Illinois who studies challenge trials.
Still, challenge trials have become an area of enthusiasm since the Covid-19 pandemic. Funding for trials has poured in. Countries including India, Canada and Australia are beginning to develop the capacity for conducting them. Some researchers have found it easier to recruit volunteers, who are willing to shiver, sweat, puke and ache all in the name of helping others (and earning a little cash).
“I think it would be unreasonable to value my convenience more than other people’s lives,” said Oscar Delaney, a 22-year-old research assistant in artificial intelligence in Oxford, England, who joined a challenge trial last year.
Researchers have found that challenge trials can be used to observe not just immune responses but also transmission and infection. And by the standards of disease research, they are nimble; the whole process can take as little as a few months. This is in contrast to the years it often takes to run a traditional trial requiring thousands of research subjects to naturally become infected with a disease.
And so proponents of human challenge trials ask: If we can reliably speed up the process, and learn more about how pathogens move within and between us, shouldn’t we be doing that?
That October morning in Baltimore, Mr. Laurenson needed to receive five mosquitoes bites. But mosquitoes are surprisingly picky eaters. After several minutes with his forearm held over an insect-filled cup, Mr. Laurenson had only three bites. To speed things up, he smeared his forearm against his sock.
“They really like the sweat and the musk,” said Mr. Laurenson, who is a second-year medical student in immunology at the University of Maryland. The bugs took the bait.
Almost all of the volunteers that day received varying doses of the monoclonal antibody. But a few “control” subjects would instead deal with the effects of malaria and then receive a medication. The principal investigator, Dr. Kirsten E. Lyke, informed them all that it would take at least a week for symptoms to develop. If the monoclonal antibody worked, none would show for the group that received it.
A week on, Mr. Laurenson felt fine. But then, 11 days out, a headache set in. So did nausea. Then, he vomited.
The first vaccine in history was born through a human challenge trial. In 1796, the English scientist Edward Jenner wondered if cowpox, a mild disease, might protect individuals against smallpox, a deadly one. He exposed his gardener’s son, James Phipps, to cowpox via a cow. He then deliberately infected him with smallpox. Luckily, his theory proved correct, and the experiment lives on in his coinage, “vaccine,” which is derived from vacca, the Latin word for cow.
A number of challenge trials arose in the following two centuries, many involving infecting vulnerable groups like prisoners or soldiers without their consent.
In the 20th century, researchers with the wartime regimes of Nazi Germany and imperial Japan infected prisoners with anthrax, chlamydia, cholera and other horrors; the U.S. Public Health Service for decades surreptitiously denied treatment to Black men in Alabama who had a previous syphilis infection, so that researchers could study the disease.
The field of bioethics grew, in large part, out of this ugly past. But as far back as 1900, the U.S. Army physician Walter Reed was pioneering a better way forward when he provided participants in a yellow fever study in Cuba with money and contracts that clearly outlined the risks of the trial. Over time, that model became standard. Acquiring repeated consent became paramount, as did confirming the availability of rescue therapies.
Challenge trials began to move away from “the periphery of medical research” and toward more mainstream acceptance, said Dr. Joshua Osowicki, a pediatric infectious-disease physician at the Murdoch Children’s Research Institute in Melbourne, Australia. Though volunteers still became sick, they were never brought close to death or serious harm.
That general scientific acceptance was tested during the pandemic. In the spring of 2020, as the world scrambled for a coronavirus vaccine, some scientists began to call for a broader approach that they said should include such trials. That June, three prominent scientists argued in the Journal of Infectious Diseases that they might help speed up the development of a vaccine.
A fiery debate broke out among the public health community. In April 2020, 35 U.S. congressional members wrote a letter calling on regulators to permit challenge trials for Covid-19 vaccines. Three months later, 177 prominent scientists, including 15 Nobel laureates, joined their call. But opponents argued that the risks of infecting volunteers with a poorly understood virus were too great. The National Institutes of Health, Food and Drug Administration and Centers for Disease Control and Prevention all refused to allow them. At least one trial, in the Netherlands, was scuttled because of the perceived risk.
And yet, instead of torpedoing the field, the pandemic “revitalized” it, said Dr. Christopher Chiu, an immunologist at Imperial College London. In 2021, after months of deliberation, the world’s first Covid-19 challenge trial began at Imperial College London — one of two that took place between 2021 and 2022 for Covid-19 — and interest grew from there.
In 2020, while locked down in his Brooklyn apartment, a former corporate lawyer named Joshua Morrison stumbled upon an early draft of the Journal of Infectious Diseases article arguing for Covid challenge trials. That March, Mr. Morrison and two others founded an advocacy group in Washington, D.C., as a place to organize potential volunteers for Covid-19 challenge trials. As a nod to the speed of challenge trials, they called it 1Day Sooner. Within months, the organization had tens of thousands of sign-ups.
1Day Sooner went on to promote challenge trials for maladies including norovirus, hepatitis-C and shigella, a bacteria that can cause dysentery. Its message inspired people like Mr. Delaney, the research assistant in England. In October 2024, he began his first trial, also on malaria.
He has since had bone marrow extracted from his pelvis as part of the study, and received the malaria parasite via infected blood through a cannula into his arm. Nine days later, his body alternated between sweating and shivering. He could hardly eat and felt lethargic. Finally, he was given tablets of an anti-malarial drug and recovered.
In total, he will receive around $11,000, which he said he planned to donate to a worthy cause. Mostly, he said, he’s happy to potentially be making a difference.
“The risk and inconvenience to me is small, but the possible benefit to the world is large,” Mr. Delaney said. Trial volunteers often express altruistic motivations. One survey of participants of a recent challenge trial in the Netherlands found that a large majority hoped to contribute to science, help people in developing countries or both. Six in 10 participants said the prospect of earning money didn’t hurt, either.
In recent years, more money has been made available to build the costly facilities that successfully contain dangerous pathogens. The University of Melbourne recently opened the first one dedicated to human challenge trials in the Southern Hemisphere. In Antwerp, Belgium, a facility with 30 beds was completed as part of a $57 million project to develop the next generation of Covid vaccines through challenge trial research.
The aim of the next-generation Covid-19 vaccine is to completely prevent transmission — something previous Covid vaccines have so far failed to do. That hope echoes throughout the challenge trials world. They’re also being used to develop a vaccine for Zika, a virus that is notoriously difficult to study in the field. And in Australia, Dr. Osowicki is pioneering challenge trials to evaluate vaccine candidates for streptococcus A, one of the deadliest bacterial infections in the world.
The potential of such trials is not lost on Mr. Laurenson, the University of Maryland medical student. After being introduced to the concept by his mentor, he now hopes to run challenge trials one day, too.
But 11 days after the mosquitoes bit him, Mr. Laurenson was more focused on the nausea and headache he was experiencing. Before his infection, he had received the highest dosage of the monoclonal antibody used in the trial. Had the experimental product failed?
At Dr. Lyke’s lab, a test came back negative for malaria. Mr. Laurenson simply had a stomach bug. At least for him, the antibody had worked after all.
Mr. Laurenson’s exposure to malaria will preclude him from future trials involving that specific disease. But he wants to take part in another trial soon.
He is surveying the options: shigella or influenza? He is leaning toward the flu.
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