Prevention of the deadly disease remains elusive

Host Amber Smith: Upstate Medical University in Syracuse, New York, invites you to be The Informed Patient, with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

Researchers from Upstate's global health and translational sciences department have long been involved with investigations of dengue, and they're hosting infectious disease experts from around the world in Syracuse for a conference that imagines a world where dengue is under control.

To understand more about this disease, I'm talking with Dr. Stephen Thomas, director of the department.

Welcome back to "The Informed Patient," Dr. Thomas.

Stephen Thomas, MD: Thanks for having me, Amber.

Host Amber Smith: Researchers at Upstate were collaborating with the U.S. Army to develop an experimental dengue human infection model that was meant to help drug makers create a safe and effective vaccine against the dengue virus.

Is that model completed?

Stephen Thomas, MD: Human infection models: I'll probably take a moment to describe what those are. This is when we take weakened forms of bacteria or viruses or parasites, and we intentionally infect healthy volunteers. And the goal of trying to do that is to mimic a mild form of the disease that we're studying. And there are multiple models out there -- for influenza, for malaria, the one we work on, which is dengue. There are some cholera, for example. There's lots of different models, and they have been very instrumental in advancing our understanding of these hard-to-study diseases. And before you can even progress to doing these types of experiments, you have to fulfill a number of very strict criteria that basically lead you to the conclusion that there really is no other way you can do the type of research that needs to be done and that the risk is minimal and manageable and that there will be benefit on a very large scale.

So, with that as the background, yes, experimental human infections with dengue, they've been doing those experiments since the early 1900s. One of the researchers that did some of the seminal experiments was Albert Sabin, when he was in the Army. So, of polio vaccine fame, he did a number of experiments on dengue. And as we hit about 75 years of trying to, but unsuccessfully, develop a dengue vaccine, this was something that folks in the military said, "Well, geez, we really need to kind of brush this model off and try again." So, we've been working with the Army for about 10 years now, in terms of an Upstate/Army collaboration. And University of Maryland joined our consortium, and it's been a very productive collaboration. And we've done a number of studies, and there are a number of vaccine and drug developers who are collaborating with us now because the model works. It's safe, and it's reproducible, and it works. It works quite well.

Host Amber Smith: And so there are some Central New Yorkers who can be proud that they were part of this. They helped you. They were your volunteers, right?

Stephen Thomas, MD: That is absolutely correct. Yes, we enroll younger, so, from 18 to mid-40s, mid-50s people, they have to be extremely healthy, have very few, if any, medical problems. They have to take very few, if any, medications. And these are small studies, so these might be five to 10 people, and the intensive portion is about a month long, and we're seeing them every day or every other day for that entire month. We become quite close to the volunteers (laughs), as you can imagine.

If you count all the recent studies that we've done, and the studies that were done with the military since about 2000, I mean, geez, we've had about a dozen studies so far. And the models have worked quite well, and we're excited about it.

Host Amber Smith: What is unique about the dengue virus that makes creating a vaccine such a challenge?

Stephen Thomas, MD: That's a great question. Dengue is the disease, and when people develop dengue, they have fever. They have headache. They have muscle aches. They have fatigue. They can have pain kind of with moving their eyes. They have bone pain. They can get a rash. That clinical situation is caused by infection with one of four different dengue viruses. And they're named -- (laughs) not creative -- they're named dengue 1, 2, 3 and 4, and they're transmitted by mosquitoes. And the dengue viruses are in the same family as some other viruses, which people may be familiar with, such as Zika, yellow fever, Japanese encephalitis, West Nile virus, and then, a new virus, relatively new virus, that we have in the Hudson Valley, in this part of the world, called Powassan, which is transmitted by a tick, but the others are transmitted by mosquitoes. And they're typically found in tropical and subtropical climates, so places where it's hot enough, and there's enough moisture, that mosquito populations can thrive and live. And so what happens is you get someone who's sick with dengue, and they've got the virus replicating in their blood, and then the mosquito feeds on them. They get infected, and then they go feed on somebody else, and then they infect that person, and that cycle keeps going.

But what we've been seeing, because of changes in temperature and changes in moisture in different parts of the planet, we're starting to see dengue being transmitted in more temperate climates. So, we've seen dengue transmitted in Texas and in Hawaii. We had a large outbreak in Key West, in Florida. We've had cases in Miami, Dade County. They've had cases in Europe as well. So, people are concerned that as the temperatures on the planet change that these mosquitoes are going to find more and more places where they can live year-round, and with travel being the way that it is that there's going to be a lot more opportunity for viruses to be introduced into places where they have the mosquito, and they have people who are susceptible. So, four different viruses means you've got to develop a vaccine against each virus, and then you have to combine them all successfully. And that's been very, very challenging.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith.

I'm talking with Dr. Stephen Thomas. He's the medical director of the Upstate global health and translational sciences department, and we're talking about dengue virus.

So, are doctors in the U.S. seeing more cases of dengue that were contracted in the continental U.S.?

Stephen Thomas, MD: It's not a frequent occurrence when it has happened. So, I mentioned, in Key West, there was a large outbreak a number of years ago. There have been large outbreaks in Hawaii. And then there have been sort of sporadic cases that have occurred on the Texas/Mexican border. So it doesn't happen often that we have large outbreaks, but the potential is certainly there.

But what they do see is they see a lot of travelers who come back. So, Puerto Rico has a lot of dengue. The Caribbean can have a great deal of dengue. People who go to Southeast Asia; there's a ton of dengue in Southeast Asia. Central and South America, so Brazil, for example; there's a big outbreak in Peru right now.

The problem is, most people, when you get that first infection, most children who get a first infection, don't even know they've been infected. Adults, they have a higher frequency of developing the type of illness that I mentioned before. But what happens is when you get a second infection with a different type of virus than you had the first time, so let's say your first infection is with dengue 1, and then a couple of years later, you get a dengue 2 infection, then there is this increased risk of getting severe disease and potentially dying. And, in places where they don't know how to take care of people with severe dengue, the mortality rate can be up to 20%, which is extremely high.

And unfortunately, in many of these places, the burden of that severe disease is on kids, so anywhere between 5,000 and 40,000 people a year die of dengue, and unfortunately, most of them are children.

They do think, though, that about 400 million people are infected every year, and about 100 million people get sick. And so what you have is places that don't have a lot of health care resources, the resources are getting consumed by people experiencing dengue, which is why we're trying to make vaccines, to sort of lower that burden and at the same time, protect travelers, protect expatriates and protect military personnel deployed to these areas.

Host Amber Smith: So, if most people who are infected don't get sick, or very sick, with this, is it our immune system that is able to typically fight it off? At least the first time?

Stephen Thomas, MD: Yes, the first time. So, you get exposed, and then your body has sort of a nonspecific reaction to that particular virus, which is an antivirus-type reaction, like we've experienced with lots of other viruses that we become in contact with. And we believe that for multiple decades, you will be protected against getting severely ill if you get infected again with that same type of virus.

The problem is that in about 5% of people who get a second infection with a different type, the immune system is not our friend. And what happens is that immunity that exists from that first infection actually helps this second virus to infect more cells to replicate more aggressively and to then have all sorts of problems where we get leaky blood vessels, we can get fluid in our lungs, fluid in our belly, we can have problems with our coagulation system, and we can have bleeding into our gut, and people develop very low blood pressure and shock, and their organs start to shut down, and it can happen very, very quickly.

And it's another reason why it's been difficult to make a vaccine, because you don't want to create an immune response with a vaccine that could potentially place somebody at increased risk for severe disease when they get that first natural infection, so it's been another reason why it's been so difficult to make a vaccine against this disease.

Host Amber Smith: Well, are there any medications that are used to treat dengue if someone gets infected?

Stephen Thomas, MD: In places that are very, very experienced with treating dengue infections, and severe dengue infections, the case fatality rate can be extremely low, so it can be less than half a percent. So you have dengue, even severe dengue, and you get to one of these hospitals, like the hospitals in Bangkok, Thailand, which is where we do a lot of our research, then they treat you with IV fluid replacement to keep your blood pressure up. They treat you with acetaminophen, which is the ingredient in Tylenol, or paracetamol overseas, to help with your aches and pains and fever. On rare occasions, they may need to transfuse blood, but most of the time, just Tylenol and fluids, and people will do quite well.

But we do not have anything that is specific for the virus. And people have tried, and companies have tried, and academic groups have tried, but it's been sort of one failure after another, unfortunately.

And then there are some groups, including Upstate, that are looking at whether or not it produced antibodies, so kind of like an immune system in a jar, much like we did for COVID, these monoclonal antibodies.

There are groups that are looking at that, and that holds some promise. Groups have looked at whether or not they could impact the immune response that seems to damage people's organs, like using steroids, for example, right, to try to suppress inflammation, but that hasn't shown to be highly effective, either, so right now there is no specific drug that is available to treat dengue.

Host Amber Smith: Is there progress on a vaccine?

Stephen Thomas, MD: As we discussed, I mean, people have been trying to make dengue vaccines for over 75 years, close to 90 years, and it's been very, very difficult, and there has been one vaccine, which was licensed a couple of years ago, to include licensed in the United States. The problem is that it does not protect, in a balanced way, against infection and disease caused by all four types, first of all.

Second of all, there is a concern about the safety of the vaccine in people who get vaccinated that have never been exposed to dengue before. So, if you've been exposed to dengue before, and you get this vaccine, it seems to boost your immune system very nicely and offers you lots of protection, and it's highly safe. If you've never been exposed to dengue before, and you get this vaccine, we have seen an increased risk in people who then subsequently get infected, and we think it's that phenomenon that I was talking about earlier, about these second infections kind of resulting in more severe disease.

So, the vaccine is licensed in lots of countries, but it is only to be used in people who have been previously infected, which makes it very complicated to use, and it has really reduced the uptake of that vaccine.

So now there's a second vaccine -- that first vaccine was made by Sanofi Pasteur -- the second vaccine, which has just started to get licensed in different countries, is made by a company called Takeda.

And that vaccine is similar to the Sanofi vaccine in the sense that there is an imbalance in how well it protects against the four different types, but it's an improvement upon the Sanofi vaccine because it appears to be safe in people, whether they've been previously infected or whether they have not been previously infected. And so, they've been licensed in the EU (European Union) and Brazil and Thailand and Indonesia. And I'm assuming that there's going to be more licenses to come in the near future, but not in the U.S. The U.S. has one vaccine. It's the Sanofi vaccine, and it's only for people 9 to 16 years of age and only people who have been previously infected, so I don't think it gets used that much.

Host Amber Smith: Now, for the summit that you're hosting at Upstate, you'll explore the historical challenges associated with dengue control. Can you explain what those are?

Stephen Thomas, MD: This is a summit that's being sponsored by the Institute for Global Health and Translational Sciences. It's been largely coordinated by Tina Lupone and Dr. Adam Waickman, who is of the basic scientists in microbiology and immunology and a dengue expert. And we have, you know, geez, about 100 people that are coming from all over the world, Brazil, Singapore, Puerto Rico, Thailand, and they're going to represent academia, industry, government, military, ministries of public health, and they're going to talk about how difficult it has been in these countries where the disease is endemic, so, meaning there's always virus, it's always being transmitted. And it's a constant battle for these folks, and they're going to talk about what the challenges have been in trying to reduce the burden of this disease on their populations without having highly effective vaccines available, without having treatments available and the types of things that they have been trying to do, whether it's spraying to try to reduce mosquito populations or education or a combination of all the above.

So that's going to be one part of the conversation, is sort of, "This is what's going on, on the ground, frontline, right now, in the world, in these places." And it's very interesting because we're going to have U.S. territory: Puerto Rico. We'll talk about their experience, and then we're going to have a highly resourced country like Singapore talk about their experience, and then we're going to have Brazil and Thailand, which are developed and developing economies, kind of talk about their experience. So the comparisons and contrast, I think, are going to be really quite interesting.

And then we're going to have people that talk about the tools that they are trying to develop, whether it's drugs or antibodies or monoclonal antibodies or vaccines, whether it's new ways to make diagnoses, whether it's new ways to address mosquito populations, we're going to talk about all the tools that folks are trying to develop and the tools that are currently available.

And then we'll end the two-day summit by kind of taking all of that in and saying, "OK, well, where do we go from here? What are the questions that are not being asked? How could we do better, and how do we prepare these countries for when vaccines and drugs and antibodies actually start to roll out in a highly scaled way."

So, I'm very excited. I'm excited to have all these people coming to our little old Central New York (laughs).

Host Amber Smith: Different countries will be able to learn from each other, maybe.

Stephen Thomas, MD: Absolutely. Absolutely. They all have unique elements of their experience. But in addition, they all share a lot of common themes, that being that dengue infects a lot of people, dengue causes a lot of pain and suffering in communities, and dengue consumes a ton of resources to try and manage in places that don't have lots of resources, in places that they would prefer to use the resources for nutrition or other vaccine-preventable diseases or education -- you name it -- things other than trying to keep people out of the hospital or keep people from dying from this disease.

Host Amber Smith: Well, Dr. Thomas, thank you so much for making time for this interview.

Stephen Thomas, MD: Well, thanks for having me.

Host Amber Smith: My guest has been Dr. Stephen Thomas, medical director of the Upstate global health and translational sciences department.

"The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe.

Find our archive of previous episodes at upstate.edu/informed.

This is your host, Amber Smith, thanking you for listening.