It was an unusual thing to volunteer, but there they were: a group of young adults waiting to be attacked by mosquitoes carrying a parasite that kills more than 600,000 people each year.
The group had agreed to take part in a medical trial at the Jenner Institute at Oxford University to test a new malaria vaccine.
The vaccine, known as “R21,” was already generating enthusiasm among scientists even in its early stages.
The trial was conducted in 2017, although the institute had already been conducting similar experiments with mosquitoes since 2001.
Each volunteer was led into a laboratory. There, on a table, was a small jar, shaped like a coffee cup, with a gauze pad on top.
Inside were five buzzing mosquitoes, imported from North America, that had been infected with the malaria parasite.
The volunteer placed his arm against the top of the container so that the mosquitoes could get to work, biting through the lid and entering the subject’s skin.
As the insects sucked the blood of their willing victims, the saliva the mosquitoes used to prevent their food from coagulating could carry the malaria parasite into the wound.
The hope was that the vaccine would offer volunteers enough protection to prevent them from developing the disease.
It is a picturesque example of what is known as a “controlled human infection trial,” an experiment in which a volunteer is deliberately exposed to a disease.
It may seem dangerous, perhaps even reckless, to deliberately expose a person to an infection that could make them seriously ill.
But it’s an approach that has become popular in recent decades in medical research and is paying off, with some notable medical victories.
Controlled infection
The R21 vaccine was later shown to be up to 80% effective in preventing malaria and became only the second malaria vaccine in history to be recommended for use by the World Health Organization (WHO).
The first doses of the vaccine were recently administered to infants in Côte d’Ivoire and South Sudan, countries that lose thousands of lives each year to malaria.
And this was made possible, at least in part, scientists say, by people who voluntarily placed their arms over the cups full of mosquitoes.
“There has been a remarkable renaissance of controlled infection trials over the last 20 years,” says Adrian Hill, professor of vaccinology and director of the Jenner Institute.
“Controlled infection models have been used for everything from influenza to Covid-19. That has been really, really important.”
Now, scientists are seeking to deliberately infect volunteers with ever more diseases, all in the hope of developing ever more effective vaccines and treatments.
Pathogens such as Zika, typhoid and cholera have already been used in controlled infection trials. Other viruses, such as hepatitis C, are being discussed as future candidates.
Although there is no central registry of these trials, Hill estimates that they have contributed to at least a dozen vaccines over the past two decades.
A systematic review found 308 controlled infection studies in humans between 1980 and 2021 that had exposed participants to live pathogens.
Proponents of these studies believe that the benefits far outweigh the risks, if conducted under the right conditions.
But some recent trials have pushed the boundaries of medical ethics, and a handful of senior scientists are uncomfortable with the speed at which once-taboo experiments are being carried out.
Dark past
It is impossible to understand the concerns some have about controlled infection trials without going back to some of the darkest moments in medical history.
The most notorious are the experiments conducted by Nazi scientists, in which concentration camp prisoners were forcibly infected with tuberculosis and other pathogens.
Less well known are the actions of American doctors in Guatemala, who in the mid-1940s intentionally infected 1,308 people with syphilis and other sexually transmitted diseases.
In the early 1970s, it emerged that doctors at Willowbrook State School in New York City had exposed more than 50 disabled children to hepatitis during the 1950s and 1960s in an effort to create a vaccine.
Among medical researchers, “Willowbrook” has become synonymous with shoddy research ethics.
But the Willowbrook experiments also contributed to the discovery that there was more than one pathogen responsible for hepatitis.
But all of these examples contributed to a backlash against the idea of intentionally infecting people with pathogens, says Daniel Sulmasy, director of Georgetown University’s Kennedy Institute of Ethics, who served on the U.S. presidential commission that investigated the syphilis trials in Guatemala.
In the late 1960s and 1970s, scientists in high-income countries developed sets of guidelines for medical trials that placed the welfare of volunteers as the primary concern.
The result was that controlled infection trials became much more difficult to conduct.
But gradually, as our approach to medical ethics becomes more nuanced, and in the face of the growing threat of pandemics, scientists are reconsidering controlled infection trials in humans.
Speed is a key motivation. In a traditional vaccine trial, volunteers are given either a vaccine or a placebo and then asked to live as normal.
The hope is that some volunteers will be exposed to the virus during the course of their daily lives, offering a chance to test the vaccines’ effectiveness.
But it can be a cruelly slow process. Developing a vaccine against a typical infectious disease can take more than 10 years, costing tens of millions of dollars, while thousands (sometimes millions) of people continue to suffer from the disease.
Controlled human infection trials get straight to the point. They eliminate the waiting period by exposing a vaccinated volunteer directly to a virus.
“Timing matters: Sometimes we really need to be much faster,” says Andrea Cox, a professor of medicine at Johns Hopkins University in Baltimore, Maryland.
Early warning systems
For her, controlled infection trials have strong arguments in their favour: they save time, money and, ultimately, human lives.
And they are particularly useful when dealing with rare pathogens like salmonella and shigella, he notes, where a traditional trial could drag on for years because scientists have to wait for volunteers to come into contact with the disease by chance.
“That’s not something that happens commonly, so waiting for that to happen takes a long time,” he says.
According to scientists, if done correctly, controlled infection trials can also act as early warning systems.
They allow researchers to be agile, test the vaccine in different types of people and highlight any potential problems in a vaccine’s chemistry.
In fact, Cox says vaccines sometimes have teething problems when they’re first rolled out, and it’s far better to discover these issues in the comfort of a scientist’s lab, where treatments are readily available.
It points to the Dengvaxia vaccine, launched by the Philippine government starting in 2016 to protect against dengue fever, the mosquito-borne virus that kills thousands of people each year.
The vaccine was given to 800,000 children in the Philippines. But researchers found 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 WHO changed its guidelines and recommended that Dengvaxia not be given to people who had not previously been infected with the dengue virus.
Cox says this is exactly the kind of alarming detail that a controlled infection study might have initially highlighted.
If Dengvaxia had been tested first in a controlled infection trial, he says, researchers could have observed how the vaccine and the virus interacted in the bodies of various patients, including those who had already been infected with dengue and those who had not.
“Knowing that a vaccine causes problems in an environment where there is intense monitoring and medical care available is better than knowing that in an area of the world where there are limited resources,” Cox said.
Diseases without a cure
When discussing controlled infection trials, scientists have long talked about the need for a reliable treatment in case things go wrong.
The Jenner Institute began intentionally exposing people to malaria in 2001, by which time effective treatments for the disease were already available.
And researchers at the institute are using a strain of malaria that is highly sensitive to drug treatment, due to the parasite’s growing drug resistance in many parts of the world.
But some scientists worry that ethical red lines will be blurred once experiments begin on diseases for which there are no available treatments.
In 2022, US researchers administered two strains of the Zika virus to 20 healthy women, none of whom were pregnant or breastfeeding, as part of a trial in which a similar number of men would also be infected with the virus.
Zika causes mild symptoms in most adults, but can cause birth defects in babies born to parents infected during pregnancy.
In rare cases, it is also linked to neurological problems in adults. There is no treatment for the virus.
The women underwent pregnancy tests several times before the trial and were asked to use contraception for two months afterwards.
Although the results have not yet been published, all of the women who received the virus became infected and most developed symptoms including rash and joint pain during a quarantine period, according to details reported at a medical conference in 2023.
Hepatitis C
The study could provide a template for a larger controlled infection trial against Zika virus, according to co-author Anna Durbin, an infectious disease specialist at the Johns Hopkins Bloomberg School of Public Health.
Researchers are recruiting volunteers now for a trial that will test how effective a dengue vaccine is in protecting people when they are deliberately infected with the Zika virus.
Perhaps more controversially, due to the lifelong consequences of the disease, trials of controlled HIV infection have also been discussed, albeit as a distant hypothesis.
More realistic, however, is the prospect of a controlled infection trial with hepatitis C, a virus that is usually, but not always, treatable.
Chronic infections with the virus can cause cirrhosis, liver failure, and death if left untreated.
Researchers at the University of Oxford, for example, have secured funding to test a potential hepatitis C vaccine using a controlled infection trial.
Cox also proposes a controlled infection trial with the virus after his frustrating experience launching a traditional hepatitis C vaccine trial in 2012.
He says it took six years and ultimately failed, a disappointing and emotional process in which, in the meantime, millions of people around the world succumbed to the disease.
A controlled infection trial would be much faster, he argues. And he proposes recruiting fully informed adult volunteers, who would freely 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 clear the virus would be given antivirals.
But even with rigorous security controls, accidents do happen. In 2012, a Jenner Institute volunteer failed to show up for his mandatory medical checkup seven days after being infected with malaria, Hill says.
He was not found for a week. The volunteer was eventually fine, and the incident was reported to an ethics committee. But the consequences could have been much more serious.
“Confusing principle”
And it is the speed at which controlled infection trials are being conducted that makes some scientists like Eleanor Riley, emeritus professor of infection and immunology at the University of Edinburgh in the UK, uncomfortable.
“For diseases that have the potential to cause very serious disruption, and where we don’t have a drug that stops that organism in its tracks, I think… the balance becomes much, much more difficult,” he says.
“When there is a risk that one in every 1,000 people will die [por ejemplo]“You have to convince me that this is something that cannot be learned in any other way.”
Other ethicists are less concerned. Arthur Caplan, a professor of bioethics at New York University’s Grossman School of Medicine, believes the idea that controlled infection trials should only be done with treatable diseases is a “confusing principle.”
“Altruism and the desire to help others is a very legitimate reason for wanting to participate in research,” he says, pointing to experiments conducted to aid space exploration.
In these trials, volunteers are asked to lie on a bed tilted backwards, which causes blood to flow to their brain, to mimic the effects of microgravity.
Volunteers are often paid little to participate in these studies. “They are simply doing it for the public good,” he says. “So there is a precedent for using people in studies who volunteer to face risks without benefits,” he says.
All of these questions came to light in 2021, when Imperial College London announced the world’s first controlled human infection study of Covid-19.
It was greeted with enthusiasm, particularly by 1DaySooner, a US-based group set up in March 2020 in response to the Covid-19 pandemic to push for more controlled infection trials and help recruit volunteers for them.
The study has provided valuable insight into why some people may avoid getting sick even when they have been infected.
He revealed that they have a localized immune response in the lining of their nose that prevents the virus from taking hold in their bodies.
But the study also sparked controversy. Covid-19 has no cure and its long-term effects are unpredictable.
Thirty-six young adults were exposed to the virus through a liquid injected into their nose and were quarantined for 14 days in a London hospital.
“We saw that [los voluntarios] “They had a lot of virus replicating in their nose and throat, and they remained infectious for about 10 days,” said study co-author Anika Singanayagam, a clinical lecturer at Imperial College London.
It also helped demonstrate the accuracy of lateral flow tests, the easy-to-use, at-home Covid tests that were routinely used in many countries at the time.
But Sulmasy, of Georgetown University’s Kennedy Institute of Ethics, believes the Imperial College controlled human infection study failed the ethical test.
“There wasn’t much that could have been learned from that that couldn’t have been learned from an alternative,” he says. “Covid was a novelty. They didn’t really know much about the long-term consequences.”
He adds that several Covid-19 vaccines had already been approved by the time the trial began, reducing the need to take risks.
In a written statement, Imperial College London said that Remdesivir, the antiviral treatment that can reduce the risk of severe illness in patients with Covid-19, was available throughout the study to any volunteers who felt sicker than expected.
“When the study was ethically approved, we were already a year into the pandemic,” said a spokesperson. “At that time, there was a lot of information about the disease in healthy young adults showing a very low risk of severe disease in this group.”
He adds that the study “provided a lot of granular data on the infection [por covid-19] which would not have been obtained with other types of tests.”
Since then, other controlled infection trials with Covid-19 have emerged.
Researchers at Oxford’s Jenner Institute are currently enrolling patients in a trial in which volunteers, who have been vaccinated against Covid-19, will be deliberately infected with the BA.5 omicron subvariant.
The goal is to understand more about how vaccines interact with subvariants of the virus. Participants will receive $400 for their time and travel expenses.
More essays
Sean Cousins, a 33-year-old delivery driver from Southampton, England, received more than $14,280 for participating in three controlled infection trials between 2014 and 2020.
In two of them he contracted influenza, while in the other he contracted respiratory syncytial virus (RSV).
But she says she would have signed up for the trials even without the money. “It was something new to try. [Quería] offer my time […] and, if I could, help humanity…”, he says.
Scientists agree on one thing: We’re likely to see more controlled human infection trials in the future, not fewer.
The list of pathogens used will also increase, including some that are dangerous and untreatable.
This leaves some scientists, like Sulmasy, with a feeling of anxiety that is hard to shake. “I think we are going to push the boundaries and it will only stop when someone gets hurt,” he says.
But others foresee enormous medical opportunities. If proper controls are put in place, they say, controlled human infection trials could allow for faster and better vaccine development for diseases that have plagued humanity for centuries.
This article appeared on BBC Future. You can read the original version in English here.
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