Speaking of Science Podcast

>> Diego (narration): Welcome to another episode of Speaking of Science, the podcast that explains the research and tells the stories of science-in-the-making in the Intramural Research Program of the National Institutes of Health, or as some of you may know it, the NIH IRP. I’m your host Diego Arenas.

Well, the summer has officially come to a close. And unfortunately, that means waving good-bye to long sunny days of barbeques and pool parties. 

[POOL SPALSH]

On the bright side though, as the heat and humidity take their leave, so do pesky mosquitos.

[MOSQUITOES BUZZING]

That’s especially good news in a year that has seen a wider spread of dengue, a viral disease that’s transmitted through mosquito bites.

[SWAT]

>> News clip: This year, dengue is breaking records in the Americas. Seven point eight million suspected cases reported so far, up more than 230% from last year, with severe outbreaks in Brazil, Argentina, and Puerto Rico. 

The disease is most prevalent in tropical and subtropical regions, where poverty, low levels of healthcare access, and limited resources for medical research are also widespread. As a result, dengue is considered a neglected tropical disease, with the likes of other mosquito-borne diseases like Zika, that only really pique public interest in the U.S. when they cross our borders. But that could very well be changing as climate change is expanding the areas where the mosquito that spreads dengue can thrive. 

So as dengue surges and begins to creep north, experts urge that we have to prepare. That includes controlling mosquito populations, as well as figuring out new methods for treating dengue and protecting against infection.

But there’s something peculiar… 

[MYSTERIOUS MUSIC FADES IN]

…about the way dengue infects the body that has stumped scientists for decades. 

Unlike most other infectious diseases, dengue deceives our bodies’ immune system such that a second infection can potentially be more harmful than the first. It’s a conundrum that has stunted the development of effective medicines and vaccines. That is, until now. 

[MYSTERIOUS MUSIC ENDS]

Stay tuned to hear how NIH scientists are digging into dengue and coming out the other side with new ways to defy it.

[TRANSITION MUSIC]

>> Dr. Katzelnick: I'm Leah Katzelnick. I am a tenure-track investigator and I've been studying dengue for 12, 13 years now. I find it a really fascinating pathogen. And so built up a group here focused on trying to understand immunity to dengue and how we can develop better vaccines in the future.

>> Dr. Odio: And I'm Camila Odio. I'm a medical doctor, physician investigator. I'm leading our vaccine study as the medical principal investigator and then setting up some other studies to better understand and hopefully treat dengue severity.

>> Diego (narration): Dr. Katzelnick and Dr. Odio work at the National Institute of Allergy and Infectious Diseases, or NIAID in NIH-speak. Together they’re conducting studies looking at nuts and bolts of dengue and how it disrupts our defenses. But before we get down to brass tacks, I asked them break down the basics.

>> Dr. Katzelnick: So, dengue is a virus and we call it dengue, but it's actually four distinct viruses that all cause the same disease and they're transmitted by a specific kind of mosquito called an Aedes mosquito.

[MOSQUITO BUZZ]

Each of the four viruses circulates pretty much all over the world. And so, dengue is a global disease, really it’s one of the most common vector-borne viral diseases, maybe the most common. It affects people in the Americas, there's dengue in the US, Central America, South America, throughout parts of Africa and Asia and the Pacific—largely in tropical areas, also subtropical areas, really wherever this mosquito is able to live. Dengue also is transmitted by mosquito that loves urban areas. So it thrives in cities, it thrives in breeding in trash and standing plastic. So as cities get bigger and you see increasing urbanization, dengue also is getting worse.

>> Diego (interview): And what are the telltale signs of dengue?

>> Dr. Odio: The most common symptom is fever, and that's kind of the first telltale sign. After that, you can have muscle and joint aches, and that's where dengue gets its infamous nickname of breakbone fever because it can be so painful in the joints. Headaches, nausea, vomiting, and then a rash can also be present. And that can be kind of a red rash all over the body. Sometimes it can be very itchy.

>> Dr. Katzelnick: Yeah, there's fever, there's a lot of symptoms that are very common, and then there's some that are quite unusual or specific to dengue, I think it's fair to say that. 

The main place that I have gotten to do research and work very closely with dengue experts is in Nicaragua. So I was originally in Nicaragua, totally unrelated to dengue, but then got dengue.

>> Diego (interview): You, yourself, had dengue?

>> Dr. Katzelnick: Yeah, I got dengue in an epidemic in 2009.

>> Diego (interview): Oh wow.

>> Dr. Katzelnick: Yeah, I had a very classic case. So I had even a rash on my hands, I had, it's called retroorbital pain. So kind of pain behind your eyes. It was very unpleasant, but I did not have a super severe case. I was hospitalized, but not in shock.

>> Diego (interview): Okay.

>> Dr. Katzelnick: But one of the things, you know, talking with a friend when we were living in Nicaragua, her son got dengue. And one of the scariest things about it is, it has a huge burden on, especially children in areas where dengue is most common. So, you know, she was in a room with her son and three other kids just because it was such a huge epidemic, they had to have multiple kids in the same room. So it was multiple kids, multiple parents, and all of them are sort of waiting for something bad to happen. That's the scary thing about dengue. It's very hard to predict when you're going to progress. Your kid can be fine and then five to 10 hours later, they're in the ICU. So there's sort of anxiety of not knowing what's going to happen to you.

>> Diego (interview): Wow. And it can happen that quick.

>> Dr. Katzelnick: It happens very quickly, but without great predictors of progression. So severe disease really is quite severe. It can cause hemorrhagic fever and can be fatal. 

>> Diego (interview): Sorry, what makes a fever hemorrhagic? 

>> Dr. Odio: So hemorrhagic fever means that they're bleeding, and so you can have bleeding like from your nose or in your stool or bleeding where people are trying to give you injections, things like that. There's also dengue shock syndrome. Shock is actually the most common form of severe dengue, which means your blood pressure gets really low and you're not getting enough blood to your organs. And so that's the most common reason people die.

>> Diego (interview): Ok, so that’s what can happen when you get infected with dengue. But what can people do to manage the infection? 

>> Dr. Odio: Yeah. So the most important thing is if you think you have dengue is seeing a healthcare provider because they're going to examine you closely, check your blood pressure, check your labs to just see if you have any signs of progression to severe disease. And you really need to be checked, as Leah was saying, daily, sometimes twice a day because of that risk of getting worse so quickly. 

Oral fluid hydration has been shown to really improve outcomes and decrease people's risk of shock.

>> Diego: Does that just mean drink a lot of water?

>> Dr. Odio: Yeah. Ideally, water or hydration fluid with electrolytes. So, you know, like water with saltine crackers and a little bit of sugar to help your body absorb the water, because if you just drink water, your body will get rid of it. 

>> Diego (narration): It’s worth noting here that clinical management of severe dengue is delicate and not universal. IV fluids can be administered in a hospital setting, but require careful surveillance, because with severe dengue, blood vessels can become damaged and leaky, so that too much liquid too fast can seep out and lead to shock, internal bleeding, and other medical complications. 

>> Diego (interview): Alright. So that’s treatment, now what about prevention? What can people do to avoid getting dengue? 

>> Dr. Odio: Yes. Great question. So number one is not traveling to places with dengue, but of course, many of us love to travel or have family or live, half of the world's population lives in places with dengue. So this is not always an option for many people or preference for many people. The other things we can do are mosquito avoidance. So these mosquitoes love humans. So you need to have a really good mosquito repellent with DEET, for example, at least 20% DEET. The mosquito repellent bottles will say often like, repels the mosquitoes that carry Zika, dengue, West Nile, so you can look for those bottles. And then, you know, long sleeves, long pants, having screens in your home, trying to get rid of standing water around your home, that sort of stuff. And then the last thing is vaccines. One is approved in the US, but it can only be used in people who have had dengue before. And people who have never had dengue before, it can actually increase the risk of severe disease. 

>> Diego (interview): Oh no, that’s literally the opposite of what you’d want.

>> Yeah. The vaccine ends up inducing an immune response that could actually help the virus to get into and infect more cells.

>> Diego (interview): Doesn’t that kind of fly in the face of how we’ve come to think of vaccines and building in immunity towards different pathogens? I mean, isn’t it all kind of predicated on this notion that exposing the immune system to some version of the threat we want it to neutralize, will then prepare it to fight the thing that causes full-scale disease in the future.

>> Dr. Katzelnick: Yeah, normally, your body induces a good response against the thing it was infected with just because that's the thing you got to see, right? And so, every virus has sort of a different set of proteins on its surface. And your body gets to become really, really good at knowing that set of proteins. And normally, that's good, right? Because it means you have something that your body remembers. So, if it gets infected with a different but related pathogen, it has something to start with. It's not starting from zero. And the issue with dengue is it takes advantage of that immunity to actually infect better the second time around.

>> Diego (interview): How does it do that? 

>> Dr. Katzelnick: So the mechanism is that the antibodies that are induced from the first infection or this vaccine bind to the virus, but don't prevent it from infecting cells. They actually help the virus to get into a larger number of cells and different kinds of cells, then the virus is able to infect directly. Kind of like a Trojan horse. 

[KNOCKING ON OLD GATE] 

>> Diego (narration): Like the myth that tells the story of how Greek soldiers infiltrated the city of Troy by hiding inside a large hallow wooden horse, a dengue virus can trick the body into letting subsequent infections take a stronger hold. 

That’s important to understand, because typically when the immune systems comes up against a virus it has never seen before, whether inadvertently through nature or more deliberately through vaccination, it produces antibodies that capture and neutralize the virus.

The antibodies stay in circulation, so that if the same virus tries to infect again, they can recognize the intruder, literally grabbing it and usher it inside the immune cells that do the actual destroying. 

That’s what happens in a second infection of the same virus. But remember…

>> Dr. Katzelnick: We call it dengue, but it’s actually four distinct viruses. 

>> Diego (narration): The four dengue viruses are similar enough that antibodies for one will recognize and attach to another, so that the killer cells think it’s business as usual and engulf the Trojan virus, ready to destroy it. But this new virus is different enough, that once it’s inside the killer cell, it evades destruction, and then goes on to do what viruses do best; it co-opts the cell, turning the body’s waste management facility to a factory for more virus production. 

>> Dr. Katzelnick: And that increases the amount of virus in your body more quickly. And that is related to getting more severe dengue disease.

>> Diego (narration): This is called antibody-dependent enhancement, because again, the antibodies against a first infection, make the second worse. And it’s why the vaccines that do exist, like those developed by the pharmaceutical company, Sanofi, are only given to people who have had dengue before. 

>> Dr. Whitehead: If I give that to a naïve person that's never had dengue, then I'm setting them up to be partially immune. And partial immunity can be dangerous.

>> Diego (narration): That’s Dr. Stephen Whitehead. He’s a microbiologist and senior investigator, also at NIAID. He’s been studying dengue for more than 20 years and has seen where other vaccines come up short. 

>> Dr. Whitehead: When they started looking at hospitalization with Sanofi, young children, aged two to five, had a sevenfold higher chance of being hospitalized for dengue if they were vaccinated. 

>> Diego (narration): So for the last decade, Dr. Whitehead has been puzzling together a new dengue vaccine at the NIH, with the central question: how do you protect people who’ve never had dengue from getting more severe disease if they get infected?

>> Dr. Whitehead: Well for dengue vaccine, you need to be vaccinated against all four serotypes. simultaneously, hopefully.

>> Diego (narration): A vaccine that immunizes against all four viruses at the same time is called a tetravalent vaccine. And it sounds simple enough, but you can’t just throw them all together and call it a day. First you have to make sure that each live virus is attenuated, or weakened enough so as to not cause full-blown infection, but not so much that it doesn’t induce an immune response. 

>> Dr. Whitehead: We wanted to develop separate vaccines for each of the four serotypes—we called these the monovalent vaccine entities. And we spent a lot of time finding a dengue four, a dengue one, a dengue two, and a dengue three vaccine that actually worked in nonhuman primates.

And instead of putting them all together at the beginning, we had nine different vaccine candidates that we wanted to test as monovalents to make sure that they were completely infectious because if you infect with a live virus, you only get an immune response if it replicates. If it doesn’t replicate, you’re not going to get immunity. 

 Now, we had some general principles that we tried across the board, across the different serotypes, several different ways to attenuate. And we found that none of those methods worked across all of the serotypes. They behave very differently. What works for one serotype or virus, doesn’t always work for the other serotypes. So, we had to use different methods or different attenuating mutations for each of the four serotypes. That took some time. 

Then, we tested those all individually in humans. That took us about a decade. We got a lot of folks saying, "Why didn't you just put it together and make the tetravalent vaccine?" But we really wanted to make sure that every component in the vaccine was immunogenic.

And so, we have nine different monovalents for the different serotypes. We selected the ones that worked the best, then we tested it as a tetravalent. Some different tweaks to the tetravalent formulation and the potency, but then we came up with this ultimate tetravalent combination that we think gives you solid immunity to all four serotypes. 

>> Diego (interview): What about dosing? Is it just one shot or a series?

>> Dr. Whitehead: Yeah, that became the next set of clinical trials. We had to test whether it was sufficient with one dose or whether we needed two doses. And our data and data from other companies who have licensed the vaccine technology from us. It's a one dose vaccine.

Your second dose, the vaccines don't replicate because they’re completely neutralized from the first dose which makes sense. And that is how a live attenuated vaccine should work. If you're not, if I could say, protected against replication of the second dose, how are you going to be protected against replication of a wild-type virus that infects you.

>>Diego (narration): But the buck doesn’t stop there. To develop a safe and effective vaccine, there are lot more questions that needed answers. 

>> Dr. whitehead: Then, we had to, then we go down the road, does it work in adults? Does it work in children? How soon are you protected? Can I give this single dose of vaccine and then travel a month later? How quick…how long do you…is it a good neutralizing antibody…what about the T cell response…what the response to other proteins… 

[FADES OUT]

>> Diego (narration): It’s a lot to consider, but all that work is paying off.

>> Dr. Whitehead: We are getting complete immunity against all four serotypes after the single dose. So, we can, we think you can vaccinate naïve individuals, meaning it can be a pediatric vaccine. And that was always our design from the beginning—vaccinating naïve individuals, children, in these endemic areas, so they would have protection.

And that's still our goal. And I think that's still a possibility. I think all of our studies in endemic areas, whether it's the phase three study in Brazil, the phase two study that we did in Bangkok or the phase three study that's just starting in India, these all indicate that naïve individuals can be fully vaccinated.

>> Diego (narration): The fact that it’s a live attenuated vaccine not only provides long-lasting immunity, but production is cost effective, which makes distribution easier for the developing countries that Dr. Whitehead mentioned have already licensed the technology and are currently running their own clinical trials. 

That said, roll-out could still take some time. And while the world waits for the NIH vaccine to hit pharmacy shelves, people are still getting sick with dengue. And even when it does, there’s no guarantee that it will be 100% protective for everyone. So scientists, like Dr. Katzelnick and Dr. Odio are exploring other strategies that cobble together what’s already available. 

>> Dr. Katzelnick: Camila wrote a really nice review on the idea of mix and match. Kind of like COVID, they did mix and match of Moderna and Pfizer, you know, different kinds of vaccines partly out of necessity. But there's these different dengue vaccines, they have sort of different issues, right? Different biases. But there's reason to believe that actually if you gave them in sequence, they might induce a really good response, 

>> Diego (narration): Because as it turns out, and to make matters even more complicated, after two exposures to two separate dengue viruses, the immune system appears to have less trouble fighting off a third or fourth. 

>> Katzelnick: We're trying to really understand what is it about immunity after two infections that does protect you? And then draw on the fact that in the vaccine trials, the people who had natural immunity and then got a vaccine were protected, right? So something good happens, it's just not that well characterized.

The problem is that there is not actually very much known about this because it's been really hard to study. And that was a lot of the reason that, you know, we set up this particular study was to look at this immunity that is induced after you've had two exposures. 

>> Dr. Odio: So in order to do that, we're using one of the four vaccines that Steve Whitehead developed, the dengue-3 type specifically. And we are vaccinating people who have never had dengue before, people who've had one prior dengue infection with a non-dengue-3 type, meaning they've had dengue-1, 2, or 4 in the past. So these people are at risk for enhanced disease if they were to get dengue-3. And then people who've had multiple dengue infections in the past. So we're giving these three groups of people the vaccine and then we're comparing what symptoms do they get after vaccination, how much virus do they get in their blood and what is their immune response like. And so this is allowing us to really dig into how does prior exposure to dengue influence the severity of illness and the immune response? In a way, that's very hard to do in natural history studies because we know what people have going in, we know exactly where they're starting and we know exactly when they get exposed. And we're able to collect blood at very early time points, which you can't really do in natural infection because people often don't know they have dengue until the virus has been in their blood for like a week. So we're able to capture that really early time where the virus is hanging out to kind of answer questions about what is going on in the body that is determining how much virus you end up with when you feel sick.

>> Dr. Katzelnick: We're hoping a nice thing that will come from our trial is knowing which components of the immune system are really important for providing protection that you could then use to go look at existing vaccines. Once they get licensed, right, evaluating how well they're working in different kinds of people.

>> Dr. Odio: Better understanding those immune responses, I think, can also be really helpful to develop treatments for severe disease. And that's kind of my big interests. And one of the things I want to do down the line is think about drugs that we can use to help prevent or treat the severe infections and have those drugs potentially be directed at the immune response. So if we can understand it better, then we can target it better.

>> Diego (narration): Dengue research feels especially urgent as we think of the future. If the record number of dengue cases this year is a sign of things to come, a combination of efforts will undoubtedly be needed to manage the threat, especially as a warming planet amplifies dengue’s reach. 

>> Dr. Katzelnick: Climate change specifically is so linked to dengue and dengue is kind of a marker of climate change. And so you're seeing it get worse just in the news, right, there's these huge epidemics, but it's not projected to get better. It's just projected to get to become more of a problem in more areas. And that's not true for a lot of tropical diseases. Many of them are getting better, but dengue, because it's sort of really, really hard to target, even just for vector control effort. It's hard to reduce the mosquito enough to be able to prevent outbreaks. There's just going to be a huge need for vector control, better treatment and using vaccines to bring dengue under control.