Testing new treatments and vaccines can take years, if not decades, to gather enough data, so scientists are resorting to a controversial approach that involves deliberately infecting volunteers with deadly viruses, parasites and bacteria.
It was unusual to volunteer for such a thing.
But here they came - a group of young adults waiting to be attacked by mosquitoes carrying a parasite that kills more than 600.000 people a year.
The group agreed to participate in a medical trial at Oxford University's Jenner Institute to test a new malaria vaccine.
This vaccine - known as "R21" - already caused problems in the early days excitement among scientists.
The test was held in 2017, although the institute has been conducting similar experiments with mosquitoes since 2001.
Each volunteer was introduced to the laboratory.
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There, on the table, was a small container, about the size of a coffee mug, with a gauze cover on top.
Inside were five buzzing mosquitoes imported from North America, infected with the malaria parasite.
The volunteer had to put his hand on top of the container so the mosquitoes could get to work - biting through the lid and piercing the volunteer's skin.
And while the insects were sucking the blood of their willing victims, the saliva that the mosquitoes used to prevent their meal from coagulation could transfer the malaria parasite into the wound.
Scientists hoped that the vaccine would offer volunteers enough protection to prevent them from getting sick from this disease.
It is a vivid example of what is officially known as "human challenge testing" - an experiment in which a volunteer is deliberately exposed to a disease.
It may sound dangerous, perhaps even reckless, to knowingly expose a person to an infection that can make them seriously ill.
But it is an approach that has become popular in recent decades in medical research.
And he began to produce results, among them some notable medical triumphs.
The R21 vaccine was later shown to 80 percent effective in preventing malaria, and she became another malaria vaccine in the history that the World Health Organization (WHO) recommends for use.
Recently, the first doses of the vaccine were given to babies in Ivory Coast i South Sudan - in countries that thousands of people die every year from malaria.
And that was possible - at least in part, scientists say - because of the volunteers who voluntarily placed those containers full of mosquitoes against their hands.
"The past 20 years have seen an incredible renaissance in challenge testing," says Adrian Hill, professor of vaccinology and director of the Jenner Institute.
"Challenge models are used for everything from flu to covid-19. That really turned out to be quite important."
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Now scientists want to deliberately infect volunteers with more and more diseases - in the hope of creating ever more effective vaccines and treatments.
Pathogens such as zika,typhus, kolera they have already been used in challenge testing.
Other viruses such as hepatitis C are mentioned as future candidates.
Although there is no central registry of challenge trials, Hill estimates that they have contributed to at least a dozen vaccines over the past two decades.
One systematic review found 308 studies of human challenges between 1980 and 2021 which exposed participants to live pathogens.
Proponents believe that the benefits of these studies far outweigh their risks, if performed under the right conditions.
But some recent trials have pushed the boundaries of medical ethics - and a handful of the world's top experts are already uneasy about the speed at which experiments that were once considered taboo are being carried out.
It is impossible to fully understand the constant sense of uneasiness that some feel about challenge testing without going back to some of the darker moments in medical history.
The most notorious are the experiments that are performed by Nazi scientists, in which concentration camp prisoners were forcibly injected with tuberculosis and other pathogens.
Less well known are the works of American doctors in Guatemala, who deliberately infected people in the mid-forties 1.308 people with syphilis and other sexually transmitted diseases.
In the early 50s, it was revealed that doctors at Willowbrook State School in New York exposed more than XNUMX disabled children to hepatitis during the XNUMXs and XNUMXs, with the goal of making a vaccine.
Among medical researchers, “resting place" has become synonymous with dubious scientific ethics.
But the Willowbrook experiments also contributed to the discovery that there is more than one pathogen responsible for hepatitis.
Still, these examples all contributed to resistance to the idea of intentionally infecting people with pathogens, says Daniel Sulmasi, director of the Kennedy Institute for Ethics at Georgetown University, who was part of the US presidential commission that investigated the syphilis trials in Guatemala.
In the late 1960s and 1970s, scientists in high-income countries drew up a set of guidelines for medical trials that declared the well-being of volunteers a top priority.
The result was that challenge testing was much more difficult to perform.
But gradually our approach to medical ethics became more complex, and in the face of increasing threats from pandemics, scientists began to turn once more to human challenge testing.
Speed was the key motivation here.
In a traditional vaccine trial, volunteers receive either a vaccine or a placebo and are then asked to lead a normal life.
The hope is that some volunteers will be exposed to the virus during their daily activities, which will provide a chance to test the effectiveness of the vaccines.
But it can be a brutally difficult process.
The average vaccine against an infectious disease can take more than 10 years to develop, with tens of millions of US dollars spent, while thousands - sometimes millions - of people continue to suffer from those diseases.
Challenge testing gets straight to the point.
It eliminates the "waiting to see what happens" period by directly exposing the vaccinated volunteer to the virus.
"Time is of the essence—sometimes we really have to be a lot faster," says Andrea Cox, a professor of medicine at Johns Hopkins University in Baltimore, Maryland.
For her, the case for challenge testing is strong: it saves time, money and, ultimately, people's lives.
And it's especially useful when dealing with rare pathogens like salmonella and shigella, she says, where traditional testing could take years because scientists have to wait for volunteers to come into contact with the disease by chance.
"It's not something that happens often, so waiting for it to happen takes a very long time," she says.
When done right, challenge testing can also serve as an early warning system, scientists say.
It allows scientists to be agile, testing the vaccine on different types of people and discovering a potential flaw in the vaccine's chemistry.
Instead, Cox says vaccines occasionally go through childhood illnesses when they're first released — and it's much better to discover those problems in the comfort of a science lab, where treatment is readily available.
She gives the example of the Dengvaxia vaccine, which has been administered by the Philippine government since 2016 to protect people from dengue fever, a mosquito-borne virus that kills thousands of people every year.
800.000 children in the Philippines received the vaccine.
But the researchers noticed a problem: while the vaccine worked well for children who had already had dengue, it was potentially dangerous for children who had not been previously infected.
In 2017, the World Health Organization changed its own guidelines, suggesting that dengue vaccination should not be given to people who have not previously been infected with the dengue virus.
This is exactly the kind of troubling detail that a challenge study could have caught much earlier, Cox says.
If the dengue vaccine had been tested first in a challenge study, she says, researchers could have studied how the vaccine and the virus interacted in the bodies of different patients -- including those who had already been infected with dengue and those who had not.
"Finding that a vaccine causes problems in an environment where there is intense surveillance and medical care is readily available is better than finding it in a part of the world with limited resources," says Cox.
When discussing challenge testing, scientists have long talked about the need for reliable treatment in case something goes wrong.
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The Jenner Institute began deliberately exposing people to malaria in 2001, at a time when effective anti-malarial treatments for the disease already existed.
And researchers from this institute take care to use a strain of malaria that is extremely sensitive to drug treatment, due to the ever-increasing growth of drug resistance in this parasite in many parts of the world.
But some scientists worry that the ethical red line becomes blurred once diseases without available treatments begin to be used.
In 2022, researchers in the US infected 20 healthy women with two strains of the Zika virus, none of whom were pregnant or breastfeeding, in a test that infects a similar number of men with the virus.
Zika causes mild symptoms in most adults, but it can alsocauses defects in babies born to parents infected during pregnancy.
In rare cases, it is also associated with neurological problems in adults.
There is no cure for this virus.
The women were tested for pregnancy several times before the study and asked to use contraception for two months afterwards.
Although the results have yet to be released, all of the women who received the virus contracted it, and most developed symptoms such as rashes and joint pain during the quarantine period, according to details presented at a 2023 medical conference.
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The study could serve as a template for larger Zika challenge testing, according to co-author Anna Darbin, an infectious disease specialist at Johns Hopkins University's Bloomberg School of Public Health.
Researchers are now recruiting for a trial that will test how effective the dengue vaccine is at protecting people when they are intentionally infected with the Zika virus.
Perhaps more controversial given the lifelong consequences of the disease, challenge tests using HIV have also been the subject of discussion—albeit highly hypothetical.
More realistic, however, is the possibility of challenge testing for hepatitis C, a virus that is usually, but not always, curable.
Chronic infections with the virus can cause cirrhosis, liver failure and death if left untreated.
Researchers at the University of Oxford, for example, secured funding to test a potential hepatitis C vaccine using challenge testing.
Cox is also proposing a challenge test with this virus after her unpleasant experience with a traditional hepatitis C vaccine trial in 2012.
She says it took six years and ultimately failed - a disappointing and emotional process that has since left millions of people around the world succumbing to the disease.
And testing the challenge would be much faster, she claims.
She suggests recruiting fully informed adult volunteers, who would willingly agree to participate, but would also be paid for their time.
After being vaccinated, they would be deliberately exposed to the virus and then monitored for several weeks or months.
Those who do not get rid of the virus would be given antiviral drugs.
But even with strict safety measures, accidents happen.
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In 2012, a Jenner Institute volunteer failed to show up for a mandatory medical exam seven days after contracting malaria, Hill says.
He was not found for a week.
In the end, the volunteer was fine, and the incident was reported to the ethics committee.
But the consequences could have been much more serious.
And it is precisely the speed with which the challenge is being tested that makes some scientists nervous, like Eleanor Riley, professor emeritus of infection and immunology at Britain's University of Edinburgh.
"For diseases that have the potential to cause very severe disease and where we don't have a drug that will stop the body, I think the balance becomes much, much more difficult."
"Where there's a risk of one in 1.000 people dying, for example, you have to convince me you have something I can't find out any other way."
And the list of pathogens used will also grow - among them some that are dangerous and incurable
Other ethicists are not so concerned.
Arthur Kaplan, professor of bioethics at New York University's Grossman School of Medicine, thinks the idea that challenge testing should only be done with treatable diseases is a "false morality."
"Altruism and the desire to help others is a very legitimate reason for wanting to participate in these researches," he says.
He points to experiments being conducted in support of space exploration.
In these tests, volunteers are asked to lie on a bed that tilts backwards and causes blood to flow into the brain to mimic the effects of microgravity.
Often, volunteers receive very little compensation for participating in these trials, he says; they are simply doing it for the public good.
"So the precedent for using people in studies who volunteer to put themselves at risk without compensation exists," he says.
All these questions came to the fore in 2021, when Imperial College London released the world's first study of the challenges of covid-19.
She was greeted with great excitement, especially by 1DaySooner, an American activist group founded in March 2020 in response to the Covid-19 pandemic to demand more challenge testing and help recruit people for it.
The study provided useful insights into why some people manage to avoid getting sick despite being infected.
She showed that they had a localized immune reaction in the nasal mucosa that prevented the virus from taking root in their body.
But the study also sparked controversy.
There is no cure for covid-19 and it has unpredictable long-term effects.
Thirty-six adults were exposed to the virus through a liquid dripped into their noses and quarantined for 14 days in a London hospital.
"We saw that the volunteers had a lot of virus multiplying in their noses and throats, and they remained infectious for 10 days," says study co-author Anika Singanajagam, a clinical lecturer at Imperial College London.
It also helped prove the accuracy of lateral flow tests - rapid, easy-to-use tests for Covid that were routinely used at home in many countries at the time.
But Sulmasi, of the Kennedy Institute for Ethics at Georgetown University, thinks the Imperial Human Challenges Study did not pass the ethical test.
"Not much was learned from it that could not be learned from the alternatives," he says.
"Covid was something new. They didn't know much about the long-term consequences."
He points out that several Covid-19 vaccines had already been approved by the time the trial began - reducing the need for unnecessary risk.
In a written statement, Imperial College London said remdesivir - an antiviral drug that can reduce the risk of severe disease in patients infected with Covid-19 - was available throughout the study for any volunteer who did worse than expected.
"When the study was ethically approved, the pandemic had already lasted a year," says the spokesperson.
"At that time, there was already a lot of information available about the disease in young healthy adults that showed a very low risk of severe disease in this group."
They added that the study "provided a wealth of granular data on Covid-19 infection that would not be possible with other types of trials."
Meanwhile, other challenge tests for covid-19 have only continued to multiply.
Researchers from the Oxford Jenner Institute are currently conducting patient trials in which volunteers who have been vaccinated against covid-19 with the omicron BA.5 subvariant will be infected.
The goal is to better understand how vaccines interact with subvariants of the virus.
Participants will be paid $6.400 for their time and travel expenses.
Clinicians deliberately infected a small number of healthy young people with Covid-19 in a study to better understand the virus
The issue of payment, however, is another sticking point.
Ethics commissions in high-income countries generally recommend that volunteers be compensated for their time, but that the payment should not be high enough to serve as a financial incentive in itself.
This is a delicate balance designed to ensure that volunteers sign up for the right reasons (such as a love of medicine as a science or simply out of altruism), rather than because they need a quick buck.
Still, Riley is surprised by how many people sign up for the cholera challenge test, which can give volunteers a severe form of diarrhea.
She wonders if money still plays a role.
"I'm happy to have enough money to live on," she says.
“You wouldn't get me to sign up for a cholera test for $6.500 or $13.000. But for someone else, that sum might change their life."
Sean Cousins, a 33-year-old delivery courier in Southampton, UK, was paid more than $14.000 to take part in three challenge tests between 2014 and 2020.
On two he was infected with influenza, while on the third it was respiratory syncytial virus (RSV).
But he claims that he would apply even without the money.
"It was just something new I wanted to try. I wanted to spare time and help humanity as much as I can," he says.
Scientists do agree on one thing: We're more likely to see more challenge testing in the future than less.
The list of pathogens to be used will also grow - among them some that are dangerous and incurable.
Because of this, some scientists, like Sulmasi, have a feeling of anxiety that is difficult to get rid of.
"I think we're going to keep pushing the boundaries and it's only going to stop when someone gets hurt," he says.
But others foresee a huge medical opportunity.
With the right controls in place, they say, challenge testing could lead to faster and better vaccines for diseases that have plagued humanity for centuries.
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