There are currently more than 3,900 people willing to be infected with the new coronavirus—if it could mean developing a vaccine more quickly.
The volunteers have signed up through the grassroots organization 1 Day Sooner to show their support for human challenge trials, a kind of study where subjects are intentionally exposed to a pathogen to see if a treatment works. This differs from a typical vaccine clinical trial, where people given a new vaccine wait to be infected naturally—part of the reason why vaccine trials can take years.
While 1 Day Sooner is not affiliated with any group officially making or studying coronavirus vaccines, more researchers and lawmakers are speaking out about the potential benefits of doing such trials. In March, Rutgers University bioethicist Nir Eyal argued in the Journal of Infectious Diseases that human challenge experiments would speed up the vaccine development process, and last week in Vaccine, Stanley Plotkin, a vaccine expert at the University of Pennsylvania and Arthur Caplan, a bioethicist at New York University, outlined how coronavirus challenge trials could be carried out. Also last week, a bipartisan group of 35 U.S. Representatives sent a letter to the Food and Drug Administration (FDA) and Department of Health and Human Services (HHS) calling for them to support human challenge trials.
There are more than 70 vaccine candidates right now, but the most optimistic estimates for when a coronavirus vaccine might be available to the public are between March and August 2021. We’ve done human challenge studies before for less deadly diseases, like influenza. But the risks of challenge trials are real. In 2001, a 24-year-old woman died in a challenge experiment for an asthma treatment. Researchers who conduct human challenges have said a COVID-19 trial would be riskier since there’s so much we still don’t know about it.
“Where you’re going to give somebody a virus on purpose, you really want to understand the disease so that you know that what you’re doing is a reasonable risk,” Matthew Memoli, an immunologist at the U.S. National Institute of Allergy and Infectious Diseases who conducts human challenge studies of influenza, told Science Magazine.
The pandemic has already altered or sped up many of the fundamental processes that guide scientific research, from the reliance on preprint studies that are not peer reviewed to the testing of interventions without clinical trial evidence. Some scientists have worried that taking these short cuts could lead to greater health risks and confusing data.
VICE spoke to Caplan, the bioethicist and co-author of the Vaccine paper, about why he thinks human challenge trials are still worth the risk.
This interview has been edited for length and clarity.
VICE: There’s been a lot of discussion about the best ways to proceed with research and trials given that we need solutions as soon as possible, but we also don’t want to put people in danger or do shoddy science. You and Stanley Plotkin wrote in Vaccine that "extraordinary diseases require extraordinary solutions." Can you define what you mean by "extraordinary?" What other situations from the past would you also classify as extraordinary?
We’ve got one of the most highly infectious viruses we’ve ever seen, combined with very serious fatality, and serious [health consequences] even if you survive it. This is a public health challenge that the World Health Organization classified as a "Public Health Emergency of International Concern." When those get declared, that’s the kind of trigger for me to call something an extraordinary circumstance.
We have some precedents. Ebola was threatening to become this. Swine flu, smallpox, yellow fever, polio. These were infectious diseases that created tremendous health burdens for which we don’t have treatments and for which there’s nothing that can be done other than behavior modification— isolation, quarantine, those sorts of things.
What you’re calling for in response to this is a human volunteer challenge study. Can you describe what makes this different from a typical vaccine clinical trial?
Normally in vaccine development, you start out in the lab and you find something that seems to attack the virus in a Petri dish—either kill it or stop it from growing, proliferating and invading cells. Then you move on to try it in animals to see if what looks like it might be useful in a dish has any sort of biological impact.
Then, you try it in human volunteers in safety studies. Those are normally just healthy volunteers and you're looking to see if there's any adverse events at very low doses—you're not looking for any benefit or protection [from the virus]. Then you start to escalate up [to] a little bigger dose.
The death toll indicates there's absolutely a strong ethical case to ask people if they're willing to do this.
Now you might start to look to see if the vaccination does anything that seems to trigger any kind of immunity. If all that works, and you're still pretty sure nothing bad has happened, you go to a big trial for vaccines. You're looking over time in the vaccinated people, compared to a group of people who didn't get vaccinated, if they seem to get the disease less often and, if they get it, does it seem to be less severe?
But you're depending on nature to infect those people. They just wander around and do whatever they're doing. If they happen to get infected, then you study to see whether that group is less sick or less dead than a comparable group. And that can take many, many years. That's why vaccine development is slow.
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The clinical trials that are taking place right now are happening in this framework?
Yes. The challenge study tries to shorten things in two ways. One, you may shorten the animal study period and jump into volunteers that are humans and literally challenge them for safety with doses that you think are very low, but you haven't really proven it in the animals. That speeds you up by months.
You're probably restricting who you try—people that are 20 to 35, because the death rate is much lower than older people. And obviously you wouldn't do it in kids because they can't consent to this kind of no-benefit safety exposure.
If things look okay, instead of waiting for people to get naturally infected, which may take years to see a significant number of cases, you deliberately give the disease to people who have been vaccinated to see whether they are protected.
How would you decide what kind of volunteers for a human challenge study would be ethical to accept?
First, you need to have competent researchers. Not somebody like Elon Musk or Peter Thiel setting up a vaccine study in a hotel room in Saint Kitts, which has happened. We don't want that. We need to have real, experienced vaccine experts doing this. You have to have people who can make very high-quality doses of the vaccine and the virus itself.
You need to have a place where you can let people reside so you can watch them and make sure that, at the first sign of trouble, they get either medical care or get isolated. You want to have some sort of dedicated medical research facility.
Then you want to make sure that the people in the study are actually fit physiologically. You have to examine them and make sure they don't have any underlying diseases that might make them more at risk [to the virus]. Then you want to make sure their consent is sound. You want to make sure that they get the information about the risks and that they could die.
You need to have the consent done a couple of times to verify it and have somebody look at it who is there as an advocate for the person [and] who doesn't care if they sign up or not. I sometimes call it a subject advocate. We use them in things like living kidney donation to make sure that the person really wants to do it.
In addition to written consent, I would make them answer a quiz that shows they really comprehend what's going on. You want to make sure if you're going to volunteer for a high-risk study that you really know what's happening, you understand it's not going to benefit you.
I don’t think we should run around deliberately injecting people.
In my view, you probably are not going to pay them except expenses because you don't want anybody signing up just for money. You would give them their meals and their housing, but you don't want to incentivize them to say, “Oh I’ll sign up for this because they’re giving me a million dollars.” You could offer them compensation for death, which isn't just to reward their bravery, but also to kind of bring home the fact that you could die.
It is possible that somebody could die doing this, and you argue in the paper that people will also die if the vaccine trials take too long. From an ethical standpoint, how do you go about making death count comparisons? Is it a difficult rationalization to make in your mind when either way you’re still talking about human lives?
In this case, it’s not a really difficult calculation. We’ve already seen over 50,000 deaths in the U.S. If we go at the pace that vaccination normally takes, it's probably four to five years to get everything done. We’re presuming the virus rebounds aren’t going to come back less nasty. The [death toll] indicates there's absolutely a strong ethical case to ask people if they're willing to do this. There is a group that formed to see whether people would be willing to do it. It’s called 1DaySooner and they already have over thousands people after just a week of looking.
1DaySooner is a grassroots effort that's not affiliated with any of the groups or companies developing the vaccines. What do you think about this initiative coming from the community, instead of experts, and have you vetted their consent process at all?
I've talked to them loosely. They haven't gotten to the point of developing a consent form, they’re just saying: Would you be willing to do this? This group has been involved with living organ donation, that’s the background of the founder, so they know a little bit about consent and doing risky things to benefit others. But I absolutely think [experts should be involved]. You’d have to really subject this to careful review. I’m not even saying that this is the pool of people you’d use, there may be a whole slew of other people who volunteer.
During the pandemic, a lot of the ways we do other kinds of science have been sped up, or changed. For example, we've been relying a lot on preprint papers, partly out of necessity. But it means we're not able to go through the normal peer-review process. We've gotten some really interesting work out of that, but there have been some problems too—like questions about the French hydroxychloroquine studies or the Santa Clara antibody study . Are human challenge studies in the same realm as this? Do you consider it a shortcut that could potentially lead to some issues?
Challenge studies have been done in the past—it's not like no one ever did them. Even Walter Reed’s yellow fever experiments involved infecting Reed and his coworkers with mosquito bites from mosquitoes known to have yellow fever. There have been challenge studies for pollution, industrial products, household products.
What you’re describing we wouldn’t normally put up with except under extreme conditions. Challenge studies we have put up with even without extreme conditions.
In Science, Alex London and Jonathan Kimmelman wrote a paper titled "Against Pandemic Research Exceptionalism," where they argued that a crisis is not an excuse for changing our scientific standards.
And I agree, and point out that these challenge studies are not a change in science. We’re not calling for no consent or no review. We’re not calling to abandon the ethics that have governed research. I don’t think we should run around deliberately injecting people. You wouldn't want to do these studies in poor nations where they might be exploited. But it’s wrong to think that we’ve never done the challenge study work that we have.
I’m seeing a kind of distinction you’re arguing for, which is that there’s science that's accelerated or rushed, but then what you're talking about is a study that’s more risky but not necessarily with lower scientific standards.
Exactly. I think people worry, “Well are they going to go do this to prisoners or poor people?” No. We’re not arguing for any suspension of the ethical rules on how to do experiments. We may be arguing that the risk/benefit facing the world justifies offering the opportunity, but no one would be forced coerced, tricked, exploited.
So because a human challenge trial carries higher risk, the study design and ethical considerations would be more rigorous?
To the highest standard. There’s no way you're going to launch a [human challenge trial] without the absolute best experts agreeing with the design. We can't afford to have muddied results about the only thing that's going to ultimately save us from this plague.
And, as strange as it may seem, the toughest ethics questions aren't just asking someone to knowledgeably, competently consent in an informed way. I think we can get that, I'm sure we can get that. Look at the kinds of work people are already doing: First responders going in with inadequate equipment and taking the same risk we're talking about. Those people are out there, we’re calling them heroes.
What I am worried about is that we better figure out that the science is sound enough that we can get the benefits in a quick enough way through manufacturing that we think are worth doing. It may be that you get a wonderful vaccine and it takes five years to make a million. That's not good. You don't ask people to take that [infection] risk if you're never able to make the thing in bulk.
The stakes are too high to chase a number of different vaccines and try to test them all. We've got to get it right as to which one's the best. Knowing, by the way, we almost never get anything close to 100 percent efficacy. We’ll have a decision to make: If you do the challenge study and let's say 60 percent of people respond. Is that good enough? I'd love to have that problem. But it is a problem.
We can't afford to have muddied results about the only thing that's going to ultimately save us from this plague.
Then we’ll have to watch a subsample of people just to make sure there's no side effects from the vaccine later on. And that we could make this in big enough quantities that would make a difference.
What do you make, ethically, of some of the more radical claims that taking risks is worth it, like the reopening Southern states or the Las Vegas mayor offering her entire city's population as a control group to see what happens when people don't have social distancing.
If somebody was to offer their city, offer their grandparents, to be experimented on, I think that they should go first. I mean, it’s silly. You don’t volunteer others. You don’t say, “Hey, the people who own the casinos in my town are willing to kill the workforce.” Come on.
That seems like a good ethical baseline: You don’t volunteer others.
You can’t decide to just let this thing sweep through and knock out the weak. And it’s easier to [suggest] if you’re going to be isolated inside a hotel with pretty good room service or living in a mansion on the outskirts.
There is another situation here which is that, while we're bemoaning stretching the research in trying to get a fast answer to various antiviral drugs that are rattling around, we at the same time allow the president to stand up for two hours every day and direct absolute nonsense at the population with no one standing there to correct his risk and benefit calculations. Instead we try to interpret if Tony Fauci is grimacing or Dr. Birx is frowning. In a society that is willing to tolerate letting people poison themselves because they're afraid to take on the president, arguing about a challenge study seems a bit of a luxury.
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