In late March, Josh Morrison was sitting in his apartment in Brooklyn, New York, feeling miserable. Work had slowed down at the nonprofit he runs, which advocates for living organ donors, and he was worried about his parents and whether they were following the guidelines to stay safe during the coronavirus pandemic. He’d been planning to visit them in early April for their 40th anniversary in Florida, but had to cancel. “That was hard, and that was really sad,” he says. “I really want to be able to see my parents as soon as I can, and be back to a situation where you can do that.”
This story originally appeared on WIRED UK.
Morrison, who is 34, felt powerless. He wanted to be able to do something constructive. It was in this context that he came across a paper in The Journal of Infectious Diseases which put forward the case for human challenge studies of Covid-19 vaccine candidates. Challenge studies purposely infect healthy volunteers with a pathogen in order to study a disease or test a treatment or vaccine. This paper suggested that using human challenge studies could speed up the development of a Covid-19 vaccine by months, potentially saving thousands of lives. “The idea of speeding that all up and getting this stuff done with is pretty appealing,” Morrison says. “And also, I thought that I personally could participate in one of these.”
After contacting some friends, Morrison set up 1 Day Sooner, a group that advocates on behalf of volunteers for Covid-19 human challenge studies. No such studies are yet being conducted, but at the time of writing, more than 24,000 people from 102 countries have signed up on the 1 Day Sooner website to express an interest in taking part in one. Globally, there have now been more than five million reported cases of Covid-19, and 300,000 deaths. Should we let people volunteer to be purposely exposed to a virus we know can sometimes be fatal?
Challenge studies have been used in research on vaccines and treatments for diseases such as malaria, typhoid and influenza. But the idea of purposely exposing people to a disease—especially one that, like Covid-19, we do not yet have a specific treatment for—is ethically fraught. “It kind of goes against your natural inclination to intentionally infect someone with something,” says Charlier Weller, head of vaccines at the Wellcome Trust.
In May, the World Health Organization (WHO) put together a list of criteria that would need to be met to make Covid-19 human challenge studies ethically acceptable, the first of which is scientific justification: what benefit could such a study offer?
The main argument for a human challenge study for a Covid-19 vaccine is speed. Normally, to test a vaccine, researchers would go through three phases of human trials. A phase one trial tests the vaccine in a small group of healthy volunteers to make sure it is safe. A phase two trial looks for signs that the vaccine is effective, for example by seeing if it produces the expected immune response. Finally, a phase three trial tests if it actually stops people from contracting the disease in the real world.
The phase three trial takes the most time. It involves a larger group of volunteers, with some receiving the vaccine and the other receiving a placebo as a control. These volunteers then go about their normal lives, and researchers see how many people in each group wind up getting naturally infected.
But letting nature take its course can be time-consuming. “[A phase three trial] can often take years, depending on the incidence of disease, and often involves thousands of people,” Weller says. In a challenge study, volunteers are given either the vaccine or placebo and are intentionally infected with the virus at a known moment in time, so there’s less waiting around to see the effects, and many fewer participants are needed. The volunteers would be kept in a specialized facility throughout the trial, to avoid transmitting the virus to third parties and make sure they have access to good medical care.
Most researchers, however, don’t believe a human challenge study could directly replace a phase three trial. Because a human challenge study is smaller, it may not gather enough data on the safety and efficacy of a vaccine to satisfy regulators. The trial may not exactly mimic natural infection, and it will only give information on the response of young, healthy volunteers, who may not be representative of the broader population. “I do think that they need to be run alongside phase three, it’s not either-or,” Weller says.
But a human challenge study could nevertheless speed up the vaccine testing process by giving an earlier indicator of whether a vaccine is effective or not. This could inform decisions on which trials to move forward with or which vaccines to start manufacturing at scale, weeding out non-effective candidates more quickly. Human challenge studies could also make it easier to test more vaccine candidates—there are more than 100 currently in development for Covid-19—so that researchers can choose the most promising ones, possibly resulting in an eventual vaccine that is more effective.
Besides speeding a vaccine up, human challenge studies could also gather other valuable research data, for example helping to elucidate how people are infected and how they gain immunity to the virus.
And they can be particularly useful where a regular phase three trial is difficult or impossible to conduct, for example if there is not enough natural infection going around to get good results. This may be the case with Covid-19: as many places currently have lockdown measures in place to prevent people from being exposed to the virus, it could be difficult to see how well a vaccine works, as both the vaccinated and control groups in a phase three trial could simply not come into contact with the virus. Ironically, if a country is doing well at containing the coronavirus, they may find it harder to test a vaccine.
For some, the urgency of the current pandemic, and the desire to speed up the search for a vaccine, means human challenge studies make a lot of sense. But at what cost? We know that Covid-19 can cause severe symptoms and even death, and we do not have an effective treatment (beyond some evidence for the antiviral drug remdesivir).
Advocates of Covid-19 human challenge trials say that the risk to young, healthy people is minimal, and is justified when compared to the potential benefits of a faster vaccine. “There are multiple reasons why, in this case, we should proceed with human challenge trials,” says Nir Eyal, director of the Center of Population-Level Bioethics at Rutgers University, New Jersey and the lead author of the paper that inspired Morrison to start 1 Day Sooner.
Younger people are much less likely to die from Covid-19 than older people, although it is hard to put an exact number on the risk; some reports suggest that the rate of death for people under 30 is around 0.03 percent. Eyal compares this to donating a kidney, and argues that the risk posed to volunteers in a human challenge study for Covid-19 is therefore below the threshold of what would be considered unethical. “Clearly, this research could be considered permissible, especially in light of its tremendous public health importance,” he says.
But others disagree. “I would say that existing standards would say that you can’t do Covid-19 challenge studies,” says Charles Weijer, a professor of bioethics and research ethics at Western University, Canada and a member of the WHO’s working group for guidance on human challenge studies in Covid-19.
In 2016, Weijer co-authored a paper that stated human challenge studies in infectious diseases “should be limited to self-limiting or easily treatable infections.” (A self-limiting infection is one that gets better by itself.) As well as the risk of death, participants of human challenge studies could be at risk of experiencing other harmful effects of Covid-19, with reported symptoms including everything from headaches and breathlessness to blood clots, lung and kidney damage. We don’t know why even some young, healthy people get worse symptoms than others and, given we only discovered the Sars-Cov-2 virus less than six months ago, we don’t know much about the long-term effects.
We are also continuing to discover new symptoms: Weijer highlights recent reports of younger people suffering strokes related to Covid-19 and children exhibiting inflammatory symptoms similar to Kawasaki disease as reasons to remain cautious. “My profound worry with Covid-19 challenge studies, even with protections in place, is that people will die in these studies, and people will suffer disabling complications,” he says. “That deeply troubles me as an ethicist.”
To Morrison, the math is still simple. “Even in a world where tragically at least one person in the challenge trial died, you’re still talking about a benefit to society that’s maybe 1,000 times higher or more than the risk to the participants,” he says.
But Weijer is not convinced. “I think someone once remarked that, in a pandemic, we’re all utilitarians,” he says. This approach, however, doesn’t square up to scientists’ duties to research participants: “We can’t just do anything to research participants in the name of science, no matter how great the number of lives saved.” He is concerned that the pressure of the pandemic may push scientists to loosen ethical standards or make decisions they otherwise might not.
And it’s not just the risk to individual participants. In its ethics criteria, the WHO writes that challenge studies must be designed and conducted particularly carefully to avoid damaging public trust in scientific research (and particularly vaccine research) at a time this is most critical.
Seema Shah, associate director of research ethics at Lurie Children’s Hospital of Chicago and also a member of the WHO working group, says that the urgency of the pandemic should be factored into decision-making, but not to the extent that short-term thinking takes over. Making decisions about studies that could be considered ethically problematic could undermine trust in research beyond coronavirus. “When we’re looking at this at some future date, when the pandemic is behind us, there will be longer term consequences that we’ll have to grapple with then,” she says.
Part of the problem, she says, is that there is no perfect ethical equation that can be applied to every situation, as every disease and pandemic is different. “We should have better frameworks, but they’re never going to be perfect algorithms or equations, because each time a new disease emerges it will have these unique features,” she says. In a piece for Science, Shah and colleagues lay out their own ethical framework for a Covid-19 human challenge study, although they differ on whether such a study would currently be justified.
In 2017, Shah chaired a panel that considered the ethics of a proposed human challenge study for Zika in 2017 and concluded it would not be ethical at that point, even though Zika is less dangerous than Covid-19. She says, however, that one of the panel’s main reservations with the Zika study was the potential risk to third parties who hadn’t agreed to the study, such as future sexual partners of participants. If Covid-19 study participants were kept in a controlled facility for the trial, third-party transmission wouldn’t be such a concern. “But I wouldn’t say that either of them is an easy call,” she says. “I think there was good reason to consider doing a Zika virus challenge study at that time as well.”
Like other research, challenge studies would have to be approved by the relevant institutional, regional or national bodies; different countries have different systems of review. Given their controversial nature, the WHO group says there should be a specialised independent review of proposed challenge trials at the national or international level.
Weijer concedes that there may be a few cases in which a challenge study for Covid-19 could be conceivable. One factor that may help tip the ethical scale is how much people are at risk of contracting the virus outside of the study; if there is a high chance someone will get Covid-19 anyway owing to a high level of circulating virus, this reduces the additional risk presented by taking part.
He cautions, however, against selecting volunteers who have a higher background risk owing to some form of social injustice. In the UK, people from BAME backgrounds are disproportionately likely to be hospitalized with or die from Covid-19, and poor communities and those without access to good healthcare are also at higher risk. But singling out these groups for volunteers would be exploitative in that it would mean taking advantage of people who are already unfairly disadvantaged.
Although human challenge studies could in theory speed up vaccine development, this isn’t a given. Exactly how much we would benefit from such trials is difficult to predict, yet this is one of the key factors in weighing up their value. “It’s the first question: could this actually make a difference?” Shah says. “If it can’t, if it’s not sufficiently likely to make a difference, then it’s not worth the investment, and it’s not worth exposing volunteers to risk.”
Part of the problem is that it would take time to set up a human challenge trial, especially given how little we know about the Sars-Cov-2 virus. Researchers need to decide which “challenge agent”—which version or weakened version of the virus—to give participants, manufacture it and get it approved for use. They also need to work out how much of the challenge agentvirus to give participants. This needs to be balanced such that participants exhibit signs of illness but without putting them at more risk than necessary. “You want to have an indication of disease without the volunteers being too poorly,” Weller explains.
This process is likely to take months. Specialized facilities capable of running the studies will also have to be identified and prepared, and suitable volunteers recruited. All of this could mean that, by the time a human challenge study is ready to go, it may have lost some of its advantage; researchers at the University of Oxford are already recruiting volunteers for phase two and three trials, while US company Moderna is hoping to run phase three trials in summer.
Those who think that human challenge studies may be worth considering for Covid-19 say that this is only another reason to start preparing for them now. “Because those things take time, we should start them yesterday,” says Eyal. “Even people who think challenge trials are a bad idea should be in favor of starting them, just so we have the option.”
In the time it takes to set a human challenge study up, things could have changed that make it more or less desirable. We may have a better treatment for Covid-19, which would lower the risk to volunteers, or we may be in a position where it is impossible to do regular phase three trials, for example if there is not enough circulating virus or people are self-isolating, which may make a human challenge study more urgent. On the other hand, we may have discovered new harmful effects of Covid-19 that make it more risky for volunteers, or we may have advanced far enough in the development of a vaccine already that the study no longer seems necessary. The trajectory of the pandemic itself may also have changed. “It’s kind of a catch-22,” Weller says. “You want to wait to find out, but at the same time, if you wait, then are you delaying everything?”
“I think that it’s too soon to green-light challenge studies at the moment, but that they have enough potential that we should lay the groundwork for conducting them and make a decision about whether or not to conduct them later in time,” Shah says. But she warns against bias affecting future decisions: “We’ll have to be careful, because if you start investing in something it’s often hard to stop it if it doesn’t actually have continued value.”
She argues that if we do end up conducting human challenge studies, researchers are ethically obliged to make the most of the data collected in order to maximize their value to society. Results should be shared, even if they are negative, and efforts should be coordinated — if different studies don’t use a standardized dose, for example, then it may not be possible to compare results. Regulators also need to be happy to use the data. Even at the end of the process, if a vaccine that is developed using human challenge studies is not made available in an equitable fashion, this reduces the potential social value.
Morrison acknowledges that it is not a settled question that human challenge studies will work. “But what we do think is that there’s enough range of cases where they could be useful that it’s absolutely urgent to be doing everything we can to prepare these as soon as possible, in case they’re helpful,” he says. He would like to see a human challenge study shave at least a month off the time it takes to develop a vaccine, but even if it only saved a day, he thinks the lives saved would make it worthwhile (hence the name of the organization 1 Day Sooner). “If people understand the risks, they want to take them, and those risks are likely to get a vaccine one day sooner, that we think would be justified,” he says.
For him, offering to participate in a human challenge study brought a sense of agency. “To be able to volunteer to be a constructive part of the solution—that felt very empowering,” he says. “I would much rather be contributing and trying to fight suffering and be in the fight than to just be passively experiencing this really sad, tragic time.”
This story originally appeared on WIRED UK.
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