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One day last spring, my colleague Dylan Matthews drove out to the University of Maryland and made his way to a biosafety level two lab there. Which sounds very fancy and whatever. It's not like that at all. Therno has mat suits or anything. It's just like...
some plastic folding tables and some metal folding chairs. Basically like an ordinary doctor's waiting room. So Dylan's sitting there with a bunch of other volunteers waiting. And eventually, a nurse comes in with these cardboard tubes that are about the size of a peanut butter jar. And each one of those has a bunch of mosquitoes in it. Mosquitoes carrying malaria.
Now, malaria is an awful disease. Without treatment, it can kill you. In tropical places with limited health care, it kills a lot of people. The global total is around half a million people every year. So just overall, this is not a disease that you want to be exposed to. And yet, Dylan was here at this lab in Maryland to get exposed to it on purpose.
The procedure is they go up to you, you put your arm out, and they put the cylinder against your arm, and you sort of wait for the mosquitoes to bite you. Dylan was so determined to be exposed to malaria that he ended up having to go through two separate rounds of this biting. The first time around, the mosquitoes hadn't taken enough blood, and another volunteer ended up giving him some tips. He was like, dude, take your socks off.
I was like, "What are you talking about?" He's like, "I don't know why it works, but you take your socks off. They have all your, like, disgusting foot sweat on it. You rub that against your arm. Mosquitoes love it. They love it, bird." Now, at this point, you might be wondering, why? Like, beyond even the sock sweat of it all, why did Dylan decide to voluntarily expose himself to this deadly disease?
Well, this is Unexplainable. I'm Bird Pinkerton, and today on the show, we will tell you why Dylan did this to himself. In some ways, it's actually kind of simple. Dylan once gave his kidney to a stranger, so he's just unusually down to put his body on the line to help other people. But he'll tell us why this specifically is the approach that he took, why he thinks that getting exposed to a disease like malaria can be a good way to help people. ♪
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The first thing to know is that Dylan's exposure to malaria was part of a study, this trial to test out a new technique for fighting off malaria that's kind of like a vaccine. I would sometimes tell people I was testing a vaccine just for simplicity, but it's not actually a vaccine. Oh, yeah. A vaccine basically teaches your immune system to defend itself, to produce antibodies it needs to fight off a disease.
But this thing that Dylan was testing was just the antibodies. Like, instead of showing your body how to make the tools that fight off the disease, it was kind of just pumping you full of those tools. Vaccines teach your immune system to fish, and this just gives your body some fish. And there are effective cures for malaria out there.
But in places where healthcare infrastructure isn't robust, it can be hard to diagnose people or get them that care if they need it. So the ideal is just to prevent people from getting malaria in the first place. And while there are also already some malaria vaccines out there,
They don't work as well as we would like them to. Maybe 70% effectiveness. And if you're in a place like the Sahel, the sort of region just below the Sahara, where on average kids are getting malaria three times a year, 70% is good, but you're still going to get malaria a bunch of times. So the hope is that this new approach, this give a man a fish, and by fish, I mean antibodies, this
this kind of strategy, the hope is that it will do better. It will be more effective at staving off malaria. And there are a couple of different ways that you can test out an intervention to see how effective it is. You could test drugs like this, and people do, by going to a region where malaria is endemic, like West Africa. You could offer people the drug, and then they are probably going to get exposed to malaria in their daily life.
And you could see how well the drug works at preventing infection. This is what's called a field trial. And it's really important to do these. They give you a sense of how your intervention works in the real world. The problem is that this kind of test requires a lot of resources, like resources.
In this West African example from Dylan, right, you would need a big group of people from that region because you'd need to have enough people in your study to be sure that a significant number of them would be exposed to the disease at some point as they went about their daily lives.
But then you'd also need to keep track of all those people, potentially over a long period of time. And that can be hard. Because you're doing it in a community and often in a very poor community that sometimes doesn't have the best communications infrastructure. It can be hard to follow up with people. It just takes longer. It takes more time. It takes more money. Which means that studies like these can be pretty expensive. Yeah.
Dylan says it can be hard to get exact numbers for the cost of field trials, but he was able to find some specifics. There's currently a big tuberculosis vaccine trial happening right now, and it costs about $550 million. Oh, my God. This is a field trial of one vaccine. Half a billion dollars for one vaccine? Over half a billion dollars.
That's a huge price tag. It's not necessarily the exact price for every field trial, but still, it's a lot of money to think about. Especially because, remember, a trial can fail. The researchers testing this new give a person some antibodies approach could go through this whole process, spend all this money, and then realize that they didn't have the exact right recipe for their antibodies, for example.
So these researchers decided to do a different kind of trial first, a smaller, less expensive kind of trial that would show them essentially if it was worth doing a bigger, more expensive field trial down the line. Something called a challenge trial. These are used for all kinds of diseases, from malaria to Zika, cholera, even the common cold. And literally, they're called challenge trials because they challenge a drug directly.
What that means is, in a challenge trial, researchers give people a drug, like this drug that will hopefully prevent malaria, and then instead of waiting around to see if they happen to get exposed to malaria out in the world, they just expose those people to the disease directly. In this case, by applying mosquitoes in a tube to Dylan's sock-sweat-covered arm. And a major advantage of challenge studies is...
You can do them anywhere. So in this case, a team based in Maryland can do this with volunteers from the United States rather than going to a country where malaria is common. And also you can use a much smaller pool of people.
If you can guarantee that everyone in your study is going to be exposed to malaria because you're the one doing the exposing, you can study fewer people. You also have control over when they're exposed so you don't have to monitor them for as long or work as hard to keep track of them. And the amount that you pay participants, in Dylan's case about $5,000, that money is not going to break the bank.
So you can get a sense of whether these things work much more cheaply than trying to do a full-scale field trial. So remember, that one TB study is going to cost around half a billion dollars. By contrast, a challenge trial can cost as little as one or two million dollars. Which means that if a challenge trial fails, it's a setback, but it's not a half a billion dollar setback. This all felt pretty worthwhile to Dylan.
Which is why he volunteered his body for a challenge trial for this like beta test to see if these antibodies were effective. But I was curious what the results were. Like, did this mix of antibodies work and keep malaria at bay? So it did not work.
In my case, I was going in every day and testing and kept hearing that I was negative. And I was on a call with my editor at Fox. And I was saying like, yeah, it's going well. I don't seem to have malaria. And then I got a phone call and it was like one second. And so he heard me be like, uh-huh. Oh, it's positive. That's interesting. All right. Well, I'll see you soon.
And I hung up and I was like, Brian, I have to drive to Baltimore and I have to take some anti-malaria medicines is what I have to do. How was your Friday?
Again, in a healthcare context like this one, where Dylan was in an actual lab, he wasn't at huge risk. Right from the start, researchers told him that they would be able to cure volunteers if they had breakthrough infections. That was part of their study design. And so basically, all he had to do was take an anti-malarial drug and then go home and deal with what was either malaria or the side effects of the anti-malarial drug.
I came down with what felt like sort of a stomach flu. Like, I felt nauseous. I think I had a temperature. I was kind of tired and wanted to sleep. So it wasn't pleasant, certainly. But it also wasn't the end of the world. And similarly, it wasn't the end of the world that this approach to fighting off malaria didn't prove to be 100% effective.
Dylan says the full results of his challenge trial aren't out yet, but his sense is that he was not the only person who had a breakthrough infection. So the researchers maybe want to make a few tweaks to the recipe of their antibodies and see if they can do better, basically make them more sophisticated or more effective somehow. And I think that's one of the things that challenge trials can help with is that
If they'd done this study and absolutely none of us had gotten malaria, I think a reasonable reaction would be like, wow, this is...
this is a really effective thing, we should do a bigger, larger field trial of it. By contrast, if you do it and it's less effective than you hoped, then you have a reason to try some other things first. And that cheaper price tag means it's more financially realistic to try some other things. And I think for diseases like tuberculosis and malaria, like, bluntly, rich countries, or at least rich people in rich countries, just do not get these diseases.
There's no political urgency to develop better vaccines for these within the countries that have the money to develop better vaccines for these things. And so money is scarce.
If every vaccine candidate costs half a billion dollars to test, we're just like never going to get effective vaccines against these things. And I think that's why challenge trials are so exciting to me is that we can find cures anyway. And all it takes is a few people in rich countries being willing to step up and put their bodies on the line. And at least in the case of malaria, take some not very large risks. So this, basically, is Dylan's case for challenge trials. I found it compelling, but...
But I also still had questions about these not very large risks. So that's after the break. It's been reported that one in four people experience sensory sensitivities, making everyday experiences like a trip to the dentist especially difficult. In fact, 26% of sensory sensitive individuals avoid dental visits entirely.
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That's a challenger. Yeah, I know that. So, Dylan, before the break, we were discussing your challenge trial. And it basically sounds like it was kind of a low-risk-for-you, high-potential-reward-for-humanity kind of situation, right? Yep. But is that always the case? Like, have volunteers ever died doing something like this? So...
The history of deliberate infection to study diseases goes back to when the smallpox vaccine was invented in the 1790s. So this is hundreds of years. And it will not surprise you to learn that not every study over that period was conducted with the utmost in ethical rigor. There was a famous case where an army doctor in Cuba in 1900, so this was two years after the US had invaded Cuba and was occupying it after the Spanish-American War,
There was a horrible yellow fever problem, and he wanted to prove that mosquitoes transmitted yellow fever. And so he got bitten by mosquitoes. And I know I'm not prepared you for this twist. He died of yellow fever. And sort of afterwards, his boss, who was a guy named Walter Reed... Like the hospital? Yes, that one. Decided to do his own human trials, and he wrote up an actual ethical code. And I don't think it's an ethical code that...
I would sign. Wait, what's in this ethical code? It says, "...the undersigned understands perfectly well that in the case of the development of yellow fever in him that he endangers his life to a certain extent, but it being entirely impossible for him to avoid the infection during his stay on this island, he prefers to take the chance of contracting it intentionally in the belief that he will receive the greatest care and the most skillful medical service."
It's like, you understand that this is a risk. However, you also say, I'm going to die anyway, because there's so much yellow fever here. And I have gotten this awesome deal from Dr. Walter Reed. And so I'm going to take that. Yeah.
But he did pay them and he did demonstrate that mosquitoes transmit disease. And the result of that was a eradication campaign that dramatically reduced the level of yellow fever there. So I think that's a situation I look back at. Was it perfectly awesome? No. Like the U.S. was occupying them. You could not have full informed consent in that circumstance. Full stop.
But it did work, and they did learn important information that led to saving many, many lives. In the modern context, there was a review that went over about 308 challenge studies that took place from 1980 to 2021. So this is sort of the modern period of challenge studies. We have left Walter Reed in the past. Left Walter Reed in the past.
So they found that there were 24 serious adverse events out of 15,000 patients. So less than 0.2% had a serious side effect of any kind. And it didn't seem like any of these were life-threatening. They were just some kind of medical side effect. And not a single out of the 15,000 people died. Okay. So...
That seems like a pretty good safety record to me. Like, it's not perfect. Is this just on malaria or this is all challenge trials? This is all challenge studies, regardless of pathogen. Malaria is, I think, the longest running one, but flu is the other major category that we've done a number of challenge studies on. Are there steps that have been taken, you know, to sort of make sure that this is fully ethical, I guess? Yes.
Yeah, I think all of these things run through IRB panels for ethical review. I think there's much longer and more detailed disclosures, like all the documents I got at the start of the study. Every day that I went in, even just to sort of get my temperature taken and my blood drawn, the first thing they would ask is, do you still consent to participate in the study? And they made it very clear that I could drop out at any moment if I wanted to. So, like, things are better now.
Are there any arguments against challenge trials that you do find compelling? So I think the best argument against challenge trials, which is not so much against them, but is sort of pointing out their limitations, is...
The getting infected in a lab in a rich country is not the same thing as getting infected the way that people get infected with malaria in West Africa, the way people get dysentery from unclean drinking water in poor countries. You're sort of mimicking the way that this disease transmission happens in real life, but you're never going to mimic it perfectly.
And what's more, you're doing this with mostly young, healthy volunteers. And so this was a big issue during COVID where the people who were dying from COVID tended to be old, have underlying health conditions. And they were never in a million years going to get like an immunosuppressed 75-year-old in a challenge trial for COVID. Like that is just way too high risk.
But at the same time, because of that, a challenge study wouldn't have been able to tell you necessarily how effective a vaccine was for that person. And that was the person who needed a vaccine the most. So I don't think that rules it out, but it does mean that it's a complement rather than a full replacement. So challenge studies are sort of quick and cheap first step before you do broader field testing. So they're not a replacement for a full field vaccine trial. Can we...
Can we use them for every disease? So I think generally places will only do challenge trials for diseases for which we have ready and available cures. The thing people are worried about ethically with challenge trials is what if we expose people to an illness and then we can't cure it from them if they get it and the vaccine we're testing doesn't work.
So, for example, we haven't had challenge trials for TB yet because while you can cure TB, sometimes it's drug-resistant. Curing it often takes like six months of antibiotics rather than like a week of anti-malaria drugs that I had to take. And having tuberculosis for six months could actually be like an issue. Right, right. It could have long-term health consequences. So that's considered too dangerous. And I think in particular...
new diseases, new pandemics, things like COVID that feel like they come out of nowhere are going to be hard to do challenge studies on just because we probably don't have a way to fully cure them yet. Did we do challenge trials on COVID despite that?
We did not in 2020 during vaccine development. There have since been some challenge studies on COVID investigating various aspects of it. But only now that we have vaccines, now that we have Paxlovid, other highly effective treatments for it, such that we can be reasonably sure that the people on the challenge trial will be okay at the end of it. Overall, why did you think it was important that you do this? So I think...
Sometimes when I was doing it, people would ask, like, isn't it scary to expose yourself to malaria? Like, isn't that just too much? Like, you'd have to be a pretty extreme person to do that. You'd have to be the kind of person who gives a kidney. I would just like to remind them that in countries like Nigeria, on average, you have kids being infected with malaria two or three times a year. And like, that's on average. Some kids get it six times a year. That...
It's like the flu or RSV or the cold. It is something they're being exposed to every single day. And I think the question I asked myself is like, what does it say about me if I'm not willing to face what they face every day just for one day on a one-off in a much comfier environment? And I think that centers it a bit for me of this isn't about me. This is about
specific people who are suffering. And they're suffering specifically because they are against their will being exposed to a very dangerous illness. And it's better that I consentingly be exposed to a dangerous illness in a context where it's made as safe as possible than that they keep being menaced by it day after day. I think that's a really great answer. It makes me feel like
It's a long drive to Baltimore, in my defense, and I can't drive. You can't, no. If you live in New York, absolutely not. All right, great. If you feel bad, yeah, like on the scheme of things, I'll bug you about kidney stuff before I bug you about this. Great.
Dylan Matthews is the head writer for Vox's Future Perfect. If you want to read more about challenge trials and malaria, he has a great piece about all of this on our site. Also, this particular trial was funded by a foundation, but Dylan has done some reporting on what the loss of federal funds could mean for anti-malaria efforts worldwide. We will link to both of those in the transcript.
This episode was produced by me, Bird Pinkerton. It was edited by Meredith Hodnot, who runs the show. Noam Hassenfeld is our host. He did the music for this episode. Christian Ayala did the mixing and the sound design. Anouk Dussault checked our fax. Anouk, thank you for everything. You have been amazing. And thanks also, as always, to Brian Resnick for co-founding the show.
Meanwhile, have you participated in a study of some kind or do you have other thoughts on this episode? Please tell us right into unexplainable at Vox.com. If you want to support the show and help us keep making it, I cannot tell you how much we'd appreciate it if you join our membership program today. That is at Vox.com slash members.com.
And we will be back next week.
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