An unusual statue stands in the courtyard of the San Fernando Medical School in Lima, Peru. It commemorates a student named Daniel Alcides Carrión, who died in 1885 after he deliberately exposed himself to bartonellosis, a bacterial disease spread by the bites of infected sand flies. Carrión was trying to prove that the disease was also responsible for distinctive lesions that erupted from the skin of people in the region. He did so — but only after dying when he injected himself with material taken from one such lesion on a patient.

Carrión's risky self-experiment was very much of its time. But a new generation of scientists have revived and updated the principle, and are once again purposely exposing, if not themselves, then other human volunteers to harmful diseases. The good people of Southampton, U.K., are being asked to inhale a bad bug that is driving a lethal, international revival of infant whooping cough. Fifteen strong-willed men and women in 2010 endured a week of stomach cramps and diarrhea at the University of Vermont after they knowingly swallowed a food-poisoning agent found in raw milk. And in the last few decades hundreds of men in the southern United States have come forward to be inoculated with gonorrhea, well, you know where.

Supporters of these types of experiments — called human challenge trials or controlled human infection models — argue that they are the quickest and cheapest way to develop new vaccines, test medicines, and study the basic progression of some of humanity's most enduring infectious foes, as well as some new ones. The strategy is popular with organizations such as the British biomedical charity the Wellcome Trust and the Bill & Melinda Gates Foundation, as they spend their billions trying to tackle neglected ailments of the developing world. Malaria, dengue fever, cholera, influenza, typhoid, and tuberculosis — which among them kill some three million people each year — are all being investigated by scientists who make healthy people purposely sick.

"It's not without risk, but we work to make it as safe as we possibly can," says Robert Read, an infectious disease expert at the University of Southampton who is leading the whooping cough trial. The conventional way to develop vaccines is expensive and inefficient, he says. "It wastes the lives of thousands of animals that are not physiologically relevant — and then, when we do pre-clinical work in people, we find it doesn't work."

In this re-creation of a challenge trial to investigate treatments for malaria, volunteers place their arms over cups containing infected mosquitoes. In this phase of the trial, conducted at the Walter Reed Army Institute of Research, each volunteer had to be bitten by five mosquitoes. | (WALTER REED ARMY INSTITUTE OF RESEARCH/Courtesy Knowable Magazine)

Still, ethicists say it's time for a more detailed assessment of the rights and wrongs of human challenge trials. That's because, although the vast majority have taken place in rich nations, scientists increasingly seek volunteers in places where the diseases being studied are endemic. The shift is important if treatments and vaccines are to work, proponents of these studies say, because people who live under constant threat of a disease often develop a different immunological response.

Known risks, uncertain benefits

Deliberate infections can help researchers develop new vaccines, as well as test the effectiveness of some that have been in use for decades and try to improve them. Take Read's Southampton project. Like most countries (both developed and developing), the U.K. routinely vaccinates against whooping cough in childhood, but protection by the vaccine is patchy, and serious epidemics crop up every few years. The Southampton study aims to understand why that is, by analyzing physiological responses, especially of people who silently harbor and pass on the bug without getting ill themselves.

Read's team has squirted a solution containing up to 100,000 of the Bordetella pertussis bacteria that cause whooping cough into the noses of 52 people. Thirty-two were colonized by the microbe, and all were confined and closely watched in hospital for two weeks, at which point the infection was ended with antibiotics. The scientists now want to launch a second study that would allow volunteers to live at home and spend time in the community, enabling the number of enrollees to be much larger. The researchers have been working with public health experts to make sure it would be safe, for example by showing that infected volunteers do not shed infectious bacteria from their noses.

Such work poses a unique ethical conundrum. The volunteers — and sometimes those around them — are required to take on a known risk without the promise of any direct benefit to themselves in return. That's very different, say, from people who already have cancer or are infected with HIV signing up for an experimental medicine. It's why human challenge trials tend to focus on conditions with acute (that is, immediate) symptoms that can be treated and cleared up with no lasting damage. Ethical review committees charged with assessing and approving these projects have given most the green light.

Most, but not all. In February 2017, bioethicists put the kibosh on a human challenge trial that a group of scientists had proposed for Zika — a virus that flared across Latin America in 2016 and is linked to severe birth defects. The trial was going to give volunteers a potential vaccine and then see how well it worked against injections of small doses of the virus.

The ethicists, led by Seema Shah, then at the University of Washington School of Medicine in Seattle, raised two sticking points. The first is what's known as the bystander risk. Because Zika can be sexually transmitted, participants could pass it on to partners who did not know about the trial and had not given consent. The second is that in rare cases, Zika infections can lead to chronic paralysis and even death, and the panel judged that a risk too far.

Participants in human challenge trials may expose their communities to infection and the risks that come with it. In 2017, a bioethics committee voted against human challenge trials for the Zika virus after concluding that the potential risks to third parties were too high. The chart compares these risks with risks from human challenge trials for malaria and dengue fever, and from standard early safety studies done for drug or vaccine development. | (NIAID/NIH; Ethical considerations for Zika Virus Human Challenge Trials 2017/Courtesy Knowable Magazine)

Shah didn't see enough justification when the virus was widely circulating: Why not inoculate and try to protect people in natural populations? Since then, though, natural cases of the disease have dramatically declined, so there could now be no realistic alternative. And recent discoveries about the virus have also tipped the ethical scales in favor of such a human challenge trial — for example, new research shows that infected men are contagious to sexual partners for just 30 days, which is less time than previously thought. "It would be more ethically acceptable to do it today," says Shah, who is now at Lurie Children's Hospital and Northwestern Medical School.

The Zika case highlights a conundrum in vaccine testing, says Michael Diamond, a virologist and immunologist at Washington University School of Medicine in St Louis, Missouri. "A waning epidemic is bad news for a vaccinologist," he says, because to show that vaccines work, "after they have been vaccinated you need people to get infected." The severe drop in Zika cases — while good news for everybody else — means it's become much harder to do that, and much more expensive. A major benefit of human challenge trials is that, because they deliberately cause infection, vaccines can be verified using far fewer people — in the Zika case, perhaps just 200, says Diamond, who co-wrote an update on Zika vaccine development in the 2019 Annual Review of Medicine.

Read the rest of the story at Knowable Magazine. Knowable Magazine is an independent journalistic endeavor from Annual Reviews.