Human challenge trial: The ethics of infecting volunteers with Covid-19

If daring volunteers get their way, they will soon become infected with Covid-19 — on purpose.

They’re young. They’re healthy. And they want scientists to give them a candidate vaccine and then deliberately expose them to the coronavirus, so we can all find out faster whether the vaccine is effective.

This is called a human challenge trial, and it’s controversial for obvious reasons: The volunteers might get sick or even die. But proponents argue that it would speed up vaccine development, and even if it gets us to a successful vaccine just a bit faster, that could still mean many thousands of lives saved.

You may have heard the recent good news on the vaccine front: Pfizer says its vaccine is 90 percent effective and Moderna says its vaccine is nearly 95 percent effective. Those vaccines were developed via conventional clinical trials, not human challenge trials.

Here’s the difference: A conventional trial vaccinates people and then waits months to see if they get infected anyway while they go about their normal lives. A challenge trial eliminates the whole wait-and-see period by vaccinating people, exposing them to the virus on the spot, and seeing how well the vaccine protects them. Results come in extremely fast, and they’re reliably instructive because scientists can control all the conditions. They know exactly who was exposed, how big a dose of virus they were exposed to, and how their immune system responded day by day.

A human challenge trial is set to begin in London in January, assuming it gets final ethics and regulatory approval. Scientists have run such trials in the past for influenza, malaria, typhoid, dengue, and cholera, but this will be the first for Covid-19. A company called Open Orphan and its subsidiary hVIVO will run the study. Only healthy volunteers aged 18 to 30 will be allowed to participate. The challenge trial is not meant to replace conventional clinical trials — the different types of trials will proceed along parallel tracks.

Many young people are clamoring to participate in a challenge trial. The advocacy group 1DaySooner has gathered the names of nearly 39,000 people in 166 countries who say they’d be interested in volunteering.

In July, the group sent an open letter to Francis Collins, the head of the National Institutes of Health (NIH), calling for human challenge trials in the US. The letter was signed by more than 30 Nobel laureates and many prominent philosophers and psychologists, including Peter Singer, Steven Pinker, and Rebecca Goldstein. They wrote: “If challenge trials can safely and effectively speed the vaccine development process, there is a formidable presumption in favor of their use, which would require a very compelling ethical justification to overcome.”

So far, the US has not given the green light to such a trial, although the National Institute of Allergy and Infectious Diseases is paying for the preparation of the viral strains that would be needed if a trial gets the go-ahead. In Belgium, the government has dedicated $23.6 million to facilities to host such trials, which may include Covid-19.

The UK trial will begin with an initial phase that isn’t about testing vaccines at all; it’s about answering a preliminary question that lays the groundwork for testing vaccines later. The question is: How much of the virus does someone need to be exposed to in order to launch an infection?

Starting in January, scientists will expose a small group of unvaccinated volunteers (somewhere between 50 and 90 people) to a very low dose of the virus, gradually increasing it until they find “the Goldilocks dose” — enough to infect most participants, but not enough to make them very ill. All participants will be dosed with the virus, as there is no control group, and all will be paid for their time. They’ll be sequestered in a quarantine facility for over two weeks so as to avoid infecting anyone else, and so that doctors can monitor them 24/7 and give them immediate medical care — including the antiviral drug remdesivir — as soon as they show signs of sickness.

Only after this initial phase concludes in the spring would the company (if it gets approval) actually inject volunteers with candidate vaccines to study their effectiveness. At that point, there would be a control group. “Half the volunteers will get a vaccine, half will get a placebo vaccine, and all of them will be exposed to the virus,” explained Andrew Catchpole, the chief scientific officer at Open Orphan, who’s conducting the study.

But there is no reliable cure for Covid-19. So under these conditions, some say it’s unethical to infect healthy people with a virus that can cause death or long-term disability. Let’s break down the issues at stake to understand if and how a human challenge trial for a Covid-19 vaccine can be done ethically.

Can volunteers truly give informed consent in this case?

One of philosophy’s most famous thought experiments is known as the Trolley Problem. It poses this dilemma: Should you make the active choice to divert a runaway trolley so that it kills one person if, by doing so, you can save five people along a different track from getting killed?

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Consequentialists or utilitarians typically say yes, because you’re maximizing overall good and consequences are what matter. Deontologists (also known as Kantians) typically say no, because you have a duty to not kill anyone as a means to an end and your duties are what matter.

A challenge trial is a little bit like a Trolley Problem. We’re talking about potentially sacrificing a few healthy volunteers in order to save many thousands of other people’s lives. Again, the utilitarian would say we should go ahead with the trial because of its vast potential for good. But the deontologist may argue that we have a duty not to infect a healthy person with a life-threatening disease for which we have no cure.

There’s a crucial difference, however: The people getting run over in the Trolley Problem aren’t consenting to their fate. The volunteers in a challenge trial are.

Or are they?

“I’m not convinced that we can actually obtain informed consent from people given that we’re still seeing the emerging effects of long Covid,” said Angela Rasmussen, a virologist at Columbia University. She was referring to the fact that, for at least 10 percent of people who contract Covid-19, some of the disease’s poorly understood effects — ranging from brain fog to lung scarring to heart conditions — can last for months. Scientists don’t yet have a clear understanding of the risk factors for long-term Covid-19, nor can they predict its duration.

Some argue this isn’t a problem: The researchers running a human challenge trial can just inform the volunteers that a lot of uncertainty remains about Covid-19, and that they might be signing up for long-term disability. The volunteers can consent to the uncertainty.

Rasmussen is not convinced. “People are going to dismiss that,” she told me. “I don’t think it’s possible to convey the seriousness by just saying it’s uncertain.” Her conviction stems from personal experience: In 2014, she was on an NIH panel on chronic fatigue syndrome. She’d read the facts about the condition, but said she didn’t fully internalize on a gut level the quality of the suffering it brought to people’s lives — until she actually met people who had the condition.

“Being physically unable to get out of bed and having doctors not believe you and having to completely change your life — it’s not the kind of thing you necessarily can understand by reading an informed consent document,” Rasmussen said.

Similarly, volunteers in a human challenge trial, who will be young people without experience of persistent illness, might not understand on an emotional level what it means to put themselves at risk of long-term effects from Covid-19. Data from previous studies suggest there is a gap between understanding health risk on an intellectual level and appreciating it emotionally.

Nevertheless, the philosopher and MacArthur “genius grant” winner Rebecca Goldstein said signing onto 1DaySooner’s letter in support of challenge trials was “almost a no-brainer” for her.

“I have more faith both in people’s ability to understand the consequences of things, and in some people’s incredible sense of responsibility to others,” she told me. “Maybe it’s hard to imagine that there really are altruistic people, and we think, ‘Oh, they just don’t understand that harm could come to them.’ But I do believe there are such people.”

Her conviction also stems from personal experience — namely, her Jewish family’s experience during World War II. “I only exist because some of my Hungarian forebears were hidden by people who risked! They knew exactly what was going to happen to them if they got caught. And they did it anyway. To me, this is the same kind of thing.”

Goldstein also argued that Rasmussen’s type of reasoning would have consequences we just couldn’t live with as a society. “We allow people to volunteer for the army, to become policemen, to become firefighters,” she said. “How is that any different? They’re young and they feel invulnerable. Nevertheless, we need them.”

Would paying volunteers be exploitative?

There’s another complicating factor here: money. If volunteers are offered payment for participating, there might be a problematic incentive for low-income people to take part in a trial that could harm their health, which is arguably exploitative.

Volunteers in the UK trial will be paid, though exactly how much remains unclear; an ethical review board will decide how they should be compensated. Typically, though, Open Orphan pays people around $5,000 to participate in a challenge trial, which entails over two weeks in quarantine, plus coming in for follow-up visits for up to a year.

“At a time when there’s skyrocketing unemployment, it’s going to be attractive to some people to make a few thousand dollars by agreeing to be in a study like that,” Rasmussen said.

Goldstein shares this concern. “I’m a little nervous about that, to tell you the truth,” she said. “It seems to me that muddies the incentive.”

But Seema Shah, a bioethicist at Lurie Children’s Hospital of Chicago and Northwestern University, said we should think about the flip side. “If people aren’t compensated for their time, then they are being exploited. They’re being asked to subsidize the research. That doesn’t seem fair.”

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She suggested the solution would be to reimburse participants for travel to and from the trial site and compensate them for their time. Specifically, they should be paid wages equivalent to what they’d earn for doing any other sort of unskilled labor. In addition, they should receive free medical care, including for any long-term effects that may result from participating in the study.

This is in line with the wage-payment model outlined years ago by nurse-bioethicist Christine Grady. More recently, bioethicists have authored a report explaining how reimbursement and compensation could be ethically paid out in the case of Covid-19 challenge studies in particular.

That report notes that “undue inducement does not seem to be a significant problem based on available evidence.” Broadly speaking, that is the impression that emerges from interviews with would-be volunteers. Many of them seem to be motivated not by financial need, but by altruism.

The words of Danica Marcos, a 22-year-old prospective volunteer, are emblematic of their rationale. “So many people are struggling right now, and I want this pandemic to be over,” she told the Associated Press. “Every day that goes on, more cases are going on, more people are dying. And if this vaccine trial could mean that this period of trauma for the whole world will be over sooner, I want to help. I want to be a part of that.”

For his part, Catchpole said he’s been “quite staggered” by the numbers of young people wanting to volunteer. “We had over 40,000 applications within a week. They pretty much crashed our website and our phones. And we’re seeing a high percentage very openly stating those altruistic reasons to do their bit.”

How much would a human challenge trial help us scientifically?

Initially, proponents advocated for challenge trials on the grounds that they’d help us discover a Covid-19 vaccine faster. But it now looks like a challenge trial won’t start its initial phase until January, and won’t begin actually testing vaccines until the spring. That doesn’t really save us time.

By January, we may already have an Emergency Use Authorization for a vaccine that’s gone through clinical trials, like the Pfizer or Moderna vaccine. The reason these trials have been able to get results quickly is that many countries have totally failed to get Covid-19 under control. As the virus has ripped through populations, it’s infected enough people in Pfizer and Moderna’s samples that the scientists were able to get the data they needed.

So the case for a challenge trial has changed. Even though it might not get us to the first vaccine faster, advocates say, it could accelerate the development of better second-generation vaccines. After all, the first vaccine is rarely the best, and it’s likely a few different vaccines will come on the market in the next few years.

“To me the question is, is the risk of doing a trial like this sufficiently low and justified by the value?” said Shah, the bioethicist. “And I think we’re sort of at a point where we’re pushing the bounds of what’s been accepted in other kinds of research.”

On the one hand, the value of getting us to a second-generation vaccine faster is significant. “Generally, in order to bring down the cost of any drug or intervention, you need at least four other versions of it available on the market. If you think about trying to get the vaccine to countries that will have great need but won’t be able to pay huge amounts of money, you can imagine there’s really a need to develop cheaper vaccines for them,” she said.

What’s more, a challenge trial could offer scientists valuable information about the pathogenesis of the disease, say, or about the immune responses that vaccinated people mount when exposed to the virus.

Rasmussen, the virologist, acknowledges that could be useful intel, but says it’s not urgently needed; a challenge trial can wait until we have a vaccine that we know is effective from a regular clinical trial, and better rescue therapies.

In the meantime, Rasmussen argued, the lack of diversity in a challenge trial will limit its scientific utility. “A challenge trial is going to have to be done in young healthy people, and that’s fine, but that isn’t really going to tell us how the vaccine works in people who need it the most” — elderly people, immunocompromised people, and people with underlying medical conditions.

That said, it’s not like such a trial would tell us nothing that’s of use to these vulnerable populations. If we have a vaccine that works in young healthy people, it may not work as well in the elderly, because their immune systems don’t work as well — but chances are it’ll still be effective to some degree.

What’s more, Catchpole said, “It’s as important to kill a vaccine that’s not got any chance as it is to promote one that does. If we can use the challenge model in the younger population to see which vaccine doesn’t have efficacy, we can get a very quick read and prioritize the next candidate vaccine.”

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So where does that leave us? Shah said that at this point, it’s not clear to her that the value of Covid-19 challenge trials quite justifies the risks. “I’m glad I’m not the one who has to make the call, honestly, because I think it’s still a very close question whether they’re justified. There’s room for reasonable people to disagree.”

Many people are suspicious of extreme altruists. Why?

Running through this whole debate is a fundamental question about human nature: Is true altruism possible?

Some people are highly skeptical that it is, and the open letter released by 1DaySooner this summer contains a fascinating paragraph betraying an awareness of that: “Decades of psychological research on highly altruistic behaviors has demonstrated that a large, and likely growing, fraction of the general population is willing to undergo meaningful risks to benefit others due to genuinely altruistic motivation rather than insensitivity to risk, psychopathology, or other ethically concerning motives.”

We can infer the implicit concern that people may be suspicious of someone who volunteers to get Covid-19 — that they may assume any such volunteer must be irrational or incapable of understanding the risks.

This concern about altruism isn’t new. A long line of philosophers and economists have expressed or observed suspicion toward altruists who are willing to incur a major cost to themselves in order to help perfect strangers.

We can see this, for example, in the 1982 paper “Moral Saints” by Susan Wolf. The philosopher observes that we don’t tend to like extreme altruists (she uses the phrases “a moral fanatic” and “a disgusting goody good”) and says, “there seems to be a limit to how much morality we can stand.”

In more recent years, the Stanford psychologist Benoit Monin has demonstrated an effect called “do-gooder derogation.” He’s shown that we feel less warm toward people who are extremely altruistic. That may be because they make us feel moral conflict about our own behaviors.

And neuroscientist Molly Crockett at Yale has conducted studies to determine whether people prefer consequentialists or deontologists. To get at that, she showed subjects the classic Trolley Problem and the different ways of responding to it. She found that when people are looking for a friend or spouse, they strongly prefer deontologists, viewing them as more moral and trustworthy. People are suspicious of consequentialists. It’s possible that that same suspicion is now being extended to extreme altruists signing up to be exposed to the coronavirus.

But scientific research has shown that some people truly are extreme altruists, who perform impressively noble acts out of a genuine desire to help others. Neuroscientists like Abigail Marsh have shown that extreme altruists may actually have neurological differences that make them predisposed to such extraordinary behavior; they’ve got larger amygdalae, for one thing.

Steven Pinker and Peter Singer have argued that this is a more widespread phenomenon than we might think, one not limited to people who are biologically predisposed to extreme altruism. They contend that people everywhere seem to be becoming more altruistic overall. As societies become wealthier and the world globalizes, we’re expanding our circle of moral concern to include distant strangers. Hence the line in the open letter asserting that “a large, and likely growing, fraction of the general population is willing to undergo meaningful risks to benefit others.”

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