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When the Covid-19 pandemic first hit, Christopher Chiu and other researchers asked: Should other healthy people be injected with the virus that caused the pandemic?
The concept is counterintuitive, but by painstakingly giving Americans SARS-CoV-2 in a controlled environment, as Chiu had done for more than a decade with seasonal flu and RSV, scientists can examine how the virus affects the body. and notice what points may provide protective benefits.
These types of studies, called human challenge trials, could help fast-track understanding of the deadly virus devastating the world, experts claimed. Others, though, questioned whether the potential benefits were worth the risk, particularly given the host of unknowns surrounding Covid-19, and the lack of available treatments at the time.
After months of deliberations among doctors, scientists, ethicists and regulators, the world’s first study on the human provocation of Covid-19 finally saw the light of day in early 2021. And Chiu, a doctor specializing in infectious diseases and immunologist at Imperial College. of London, was the lead researcher: “In a way we identified that there was still a lot we didn’t know about how the disease develops.
Early insights helped guide U.K. public policy on isolation times. Nearly four years later, more results are starting to emerge: One recent study published in eClinicalMedicine, one of the Lancet’s open-access journals, suggests individuals who got infected performed worse on cognitive tests than those who didn’t—a finding that may speak to long Covid and the cognitive effects of infection but that has received pushback from other experts. Another 2024 study points to a protein that might help protect against Covid-19. And the most recent study found that certain blood biomarkers may help researchers stratify patients for different treatments.
For Chiu, these studies were a success. And researchers continue to conduct challenge trials with the goal of developing better vaccines than the ones on the market and now want to expand trials to other countries.
However, some skeptics say that none of those challenge trials were provocative and that many effects may have simply been obtained through other types of studies. The challenge trials, for example, did not directly indicate the progression of vaccines or treatments, raising questions about whether those dangers were justified.
“Have we learned?” said Marc Veldhoen, an immunologist at the University of Lisbon and the Gulbenkian Institute of Molecular Medicine. “Not so much. “
Human challenge trials have been going on in some form since the 1700s—and they’ve long been controversial. In recent decades, the trials have become more scientifically rigorous but have continued to spark ethical concerns surrounding potential risk and subject exploitation.
However, several key advantages persisted.
For one thing, because researchers control the type of virus and the dose, they can identify more characteristic causes and effects. “If a patient does something strange or has a unique response, you never know exactly why. Is it due to comorbidities? Is it because this user was exposed to a large dose? said Rik Lindeboom, an immunologist at the Dutch Cancer Institute in Amsterdam. “With those challenge studies, you can control all of that, which makes them very, very unique. “
Scientists can also control the time of exposure, allowing them to pinpoint how long it takes for someone to become infectious and develop symptoms. Indeed, one of the first Covid-19 challenge trial papers, published in 2022, found that individuals started to shed SARS-CoV-2 after just two days of infection and that they could remain contagious for another ten. Participants with a negative Covid-19 test were not shedding virus, they also found.
At the time, this data had a direct effect on public health decision-making in the United Kingdom, Chiu said, and led to the recommended ten-day isolation period: “Thanks to this set of studies we were able to very clearly define When You may have simply emerged from isolation. Other studies have found that some people naturally shed large amounts of viruses and that their bodies fight infections by expanding an immune pathway called the interferon response, offering a possible mechanism. goal to help reduce transmission and disease.
More recently, challenge trials have provided information about a unique population that may otherwise simply not be studied: those who do not swell after exposure. In a Nature study published in June 2024, Chiu and colleagues exposed 16 participants to SARS-CoV-2, but only six developed widespread infection. Lindeboom then studied the immune cells of those participants and found that the other people who had avoided infection shared higher expression of a gene that researchers believe could potentially protect against infection, Lindeboom said.
Meanwhile, the recent eClinicalMedicine study compared inflamed and non-inflamed participants on a series of cognitive tests. The 18 inflamed participants performed worse than the 16 who were not inflamed, especially on tests measuring reminiscence and executive function. These adjustments persisted for at least a year. , suggesting that the virus would possibly have lasting effects on cognitive function.
That study, though, has received some criticism. Veldhoen, the immunologist in Lisbon, pointed out that the differences between the groups were variable and modest. “If you look at all the tests individually, I think there’s only one or two where there is indeed a difference—the difference is quite small,” said Veldhoen, noting that when it comes down to whether the work was necessary, he is “still not completely convinced.”
In fact, not everyone agreed that provocation tests were worth the risk. For example, U. S. institutions decided not to approve such trials, in part because doctors did not have effective treatment for severe cases at the time, which is often a key factor in conducting provocation tests. And while none of the studies to date have reported serious adverse events, such as hospitalizations, some experts question whether more challenge trials are worth conducting, especially given the question marks surrounding long Covid.
The decision to infect someone with a pathogen will have to be balanced by transparent and apparent benefits, said Angela Huttner, an infectious disease physician at Geneva University Hospital in Switzerland. “If you’re going to sacrifice one person, it better be for the good of many people,” he said. Before the studies were conducted, she and others thought that Covid-19 did not meet those criteria. Today, the absence of significant effects confirms their concerns.
Meanwhile, some experts say challenge testing may not be mandatory given the prevalence of Covid-19. In the United States, “we were required to conduct massive phase 3 trials with 30,000 to 40,000 vaccine-matched participants,” Kirsten Lyke, an infectious disease specialist at the University of Maryland, wrote in an email to Undark.
By comparison, challenge trial studies typically attract fewer than 100 subjects. The 2022 Nature study, for example, included just 36 young and healthy volunteers. Veldhoen noted that the small sample size limits the research’s statistical power and generalizability: “It’s super difficult to get the bigger picture from those studies,” he said. Huttner agrees: “You can glean some information, but it may be clinically very limited.”
The findings also did not result in a new vaccine or treatment, as some experts have pointed out. “I’m not convinced that Covid-19 human challenge models turned out to be critical to the effort to develop biologics, vaccines and therapeutics,” Lyke wrote in her email.
Chiu, meanwhile, argues that although current vaccines effectively prevent serious disease and death, they are subpar in stopping the spread. Challenge trials, he said, can help develop better vaccines.
In fact, Chiu is leading a new initiative that aims to do just that: The Mucosal Immunity in Human Coronavirus Challenge, or MusiCC, project awarded $57 million to scale up experimental vaccines to block transmission. The global consortium also aims to build the capacity to conduct challenge tests around the world, Chiu said.
Chiu and a group of collaborators at the University of Oxford led by infectious disease doctor Helen McShane are also recruiting people for their next challenge trial in which they will infect participants with the Omicron strain. Meanwhile, a study organization in Singapore is recently recruiting for a study. on the Delta variant.
While some experts have ignored the kinds of provocation trials of recent years — “We weren’t told anything that we wouldn’t have been told otherwise,” Veldhoen said — the justification for the trials turns out to be another for Chiu.
“It is subjective how much you think scientific findings are worth and their value and their potential impact for the future. So, again, it’s always a conversation to be had, and I would never sort of stop people from criticizing,” he said. “Each new study is a new discussion, and you have to weigh things up again.”
This article was originally published on Undark. Read the original article.
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