Break-bone fever. Break heart fever. Seven-day fever. They are all names for the painful — often debilitating and sometimes deadly — mosquito-borne disease called dengue fever.
Dengue can cause high fever, nausea, rash, body aches, and stiff movements, and can leave patients suffering from depression and fatigue in its wake.
Dengue has been around since at least the 17th century, but cases of the infection skyrocketed in the last two decades — from only a little over 505,000 cases in 2000, to 5.2 million cases in 2019. Today, half the world’s population — who live in areas where Dengue-carrying mosquitoes are prevalent — is at risk of the illness. While dengue is already endemic in 100 countries, new regions are reporting cases of the virus every year, thanks to travel, trade, urbanization, and climate change expanding the range of the mosquitoes that transmit dengue.
In March, Sudan, a country currently embroiled in a civil war, experienced its widest outbreak of the disease and detected dengue fever for the first time on record in its capital city of Khartoum. At the same time, Argentina reported “elevated” dengue fever activity across the country.
While dengue fever isn’t as deadly as other mosquito-borne viruses — such as Japanese Encephalitis, a dengue-related virus found in southern and eastern Asia — large outbreaks can quickly overwhelm health care systems, worsening the toll of other illnesses and medical problems. “It’s one of those rare diseases that impact families, impacts communities, and impacts the country-level health systems,” said Derek Wallace, a physician who is the dengue vaccine program lead for the pharmaceutical company Takeda.
But even as the threat of dengue grows, new developments over the past decade — including a recently approved vaccine and an initiative to infect mosquitos with a virus-resistant bacteria — could mean that dengue eradication is on the horizon.
“I think one of the terrible things about dengue, if you live in an endemic transmission area, is you can’t really protect against it,” said Scott O’Neill, founder and CEO of the World Mosquito Program, a nonprofit aiming to eliminate mosquito-borne illnesses. “When you live in a situation where you can’t control your exposure, that can be quite a frightening thing, and many people live with a lot of fear around diseases like dengue and Zika, and what it could do to their children or to their family.”
What is dengue?
Dengue fever and many other vector-borne viruses — including chikungunya, Zika fever, and yellow fever — are usually transmitted via the bite of the tropical Aedes mosquito. This mosquito prefers to live near and feed on humans, and can easily pass these viruses from an infected individual to others in the population. In the case of dengue fever, mosquitos are the vector — the living organisms that can spread infectious pathogens between humans — but other common disease-spreading vectors are ticks, flies, and fleas.
And since dengue fever symptoms normally do not appear until four to 10 days after infection, people often go about their normal life, going outside, and exposing themselves to mosquitos. When a mosquito bites an infected individual, it will then carry that virus and pass it on to other people via its bite.
“Sometimes people actually have asymptomatic disease. They don’t even know that they had dengue,” said Ashley St. John, an associate professor at Duke-NUS Medical School who researches vector-borne pathogens like dengue. “That’s a major way it spreads is through people who don’t realize that they’re infected still going about their daily routine, and being in an environment where mosquitoes can continue to transmit the virus.”
Unlike other vectors, the Aedes mosquito thrives in urban environments since it can breed in very small quantities of water, such as the water pooled in a leaf, said St. John. As more people live in urban areas, the risk the Aedes mosquitos pose — given their ability to thrive in populous communities— grows.
“Another aspect that goes hand-in-hand with it is really human mobility,” said St. John. “Overall, we’re traveling a lot more than we used to. Travelers are a major group who are at risk for exposure to dengue when they arrive in some of these dengue-endemic regions.” When a traveler is exposed to dengue in an endemic region, they risk bringing the disease back to their community.
Dengue fever causes a range of mild to severe symptoms, but one of the most concerning is plasma leakage, or when fluid leaves the blood vessels and enters the lungs or abdomen. This deadly condition occurs in only a small portion of the annual half a million dengue-related hospitalizations, but treatment for the problem — IV fluids — is not foolproof, said Wallace. If too much IV fluid is given to a patient, it can drown the lungs and send them into respiratory distress. This life-or-death balancing act often plays out over an approximately seven-hour period following an infected individual’s fever breaking.
The primary reason scientists and researchers struggled to make progress on dengue prevention and treatment methods is because there are four different serotypes — or variations — of the virus that cause dengue fever. That essentially means that dengue fever behaves like four different viruses.
When someone is infected with one of the four dengue serotypes, they develop antibodies that help them beat the infection and protect them against future infections of the same serotype. But, unlike many illnesses, dengue’s serotypes are so different that the antibodies that protect against one serotype of the virus may not protect against the other three, said St. John.
Sounds a little bit like another virus circulating around: Covid. Between omicron, delta, and beta, Covid had many different variants, and genetic diversity, said David Martinez, a co-author of a 2020 study on the diversity within dengue serotype genomes and an assistant professor of immunobiology at the Yale School of Medicine. “Vast genetic diversity is certainly out there for many different viral families. So this is not unique to dengue,” he said. “But within the flaviviruses [vector-borne RNA viruses] that can infect humans and are actually a major problem in human populations, then dengue does seem to be a bit more unique in that regard.”
The challenge with a dengue vaccine
There is still no treatment to counter the dengue virus itself, and there is no universally available prevention method.
Instead, the World Health Organization (WHO) recommends that infected individuals rest, hydrate, and take over-the-counter pain relievers — treatments that can address symptoms. To prevent infection, WHO suggests avoiding mosquito bites by wearing full-coverage clothing, sleeping with insect-repellent-treated nets, and installing window screens.
But no one can stay indoors or under a mosquito net forever — which is why researchers have for decades been working on an effective dengue vaccine.
In 2015, Mexico approved the first dengue vaccine, Sanofi Pasteur’s Dengvaxia. At first, health experts welcomed the shot, given it was the only available medical prevention measure, but, two years later, after at least 11 countries approved it, concerns began to arise around its safety for those who had never been infected with dengue before.
In most types of viral infections, antibodies protect someone from developing severe disease. But dengue can act differently, essentially “hitching a ride” on antibodies and using them to enter and infect healthy cells, said Martinez. That’s why a strong immune response — where antibodies are produced — is not always beneficial, and instead can increase the risk of severe disease.
An analysis by Sanofi, WHO, and partnered researchers of long-term data showed that individuals who were never infected — seronegative people — were more likely to develop a severe reaction to a first-time infection if they received the Dengvaxia vaccine. The shot contains a live, weakened virus that teaches a recipient’s body to produce antibodies, which is also similar to how the chickenpox and measles vaccines work. (Dengvaxia uses a genetically engineered yellow fever virus to create this response.) But some researchers believe that because antibodies can help dengue infect cells instead of fight the virus, first-time dengue infections after the vaccines become more similar to reinfections, which are more likely to be severe.
In response, Sanofi updated its guidance for the shot in 2017, recommending the vaccine only be given to those with a confirmed prior dengue infection, or seropositive people. But the damage was already done — in the Philippines, where the vaccine was rolled out as part of a national campaign, parental confidence in vaccines plummeted, from 82 percent in 2015 to 21 percent in 2018.
Aside from the Dengvaxia vaccine (which is still approved in over a dozen countries, including the US, for those with a laboratory-confirmed prior dengue infection), there are approximately five other dengue vaccines in development as of 2018. The Japanese pharma company Takeda’s vaccine, TAK-003, is showing promising results. It’s a live-attenuated vaccine like Dengvaxia’s shot, but rather than using the yellow fever virus as its backbone, it uses the dengue serotype 2 virus. Takeda’s series of shots have been approved in Indonesia, Argentina, and Brazil for both seropositive and seronegative people, and the US Food and Drug Administration has granted the shot priority review.
One reason for the vaccine’s seeming success is that the Takeda team distinguished between seropositive and seronegative individuals in its trials (to ensure the vaccine was effective and safe for both populations), said Wallace, who is leading Takeda’s dengue vaccine development. “From a vaccine perspective, what we don’t want to do is be priming somebody for a worse infection later,” said Wallace. “We don’t want the vaccine to be acting like a primary infection, meaning the first real natural exposure to dengue is worse than it would otherwise have been.”
To ensure this safety, the trial took baseline blood samples from 20,000 children across eight countries, Wallace said. Additionally, the team collected data over four and a half years on the efficacy of the vaccine. This data showed that the vaccine prevented 84 percent of hospitalized dengue cases and 61 percent of symptomatic dengue cases.
Outside-the-box prevention methods
In the last two decades researchers have made tremendous progress in dengue-vaccine development, but the nature of the virus means it’s likely a single immunization alone will not stop the disease.
A vaccine that uses only one serotype to protect against dengue fever may not create a balanced immune response, said St. John. Over time, immunity to the four different serotypes diminishes at different rates, making an individual more susceptible to certain serotypes of dengue but not others.
“When we’re thinking about whether a vaccine is good, we think not only on the immediate protection that comes out on the first clinical trials, but also the longevity of this protection and how those immune responses are shaped over time as you get further and further away from that exposure,” said St. John.
One non-vaccine approach that has seen success is the World Mosquito Program’s initiative to breed virus-resistant mosquitoes. The bacterium Wolbachia prevents the Aedes mosquito from passing on dengue, yellow fever, chikungunya, and Zika virus. The World Mosquito Program breeds mosquitos that carry this naturally occurring bacteria and then release them into the natural environment.
“It’s exactly the same rationale for how vaccination works for humans. So you don’t need to vaccinate 100 percent of the people in the population to give protection to the whole population,” said O’Neill. “It’s effectively the same for our intervention … the bacteria that causes this effect has its own mechanism to transmit itself into the mosquito population.”
This initiative launched in Australia in 2011, and since then the country has reported no dengue transmission and the Wolbachia-positive mosquito population has become self-sustaining, said O’Neill. Additionally, this public health approach is cost-effective and socially acceptable. The initiative addresses multiple viruses at once, is self-sustaining, and does not create the same fear among those living in endemic areas as practices such as genetic engineering do, he added.
As the world turns its attention away from Covid, it’s important that scientists and policymakers continue to make progress — through vaccines and other more experimental methods — on long-existing diseases that continue to incapacitate and kill many people, especially the poor. And when it comes to dengue fever, vaccine manufacturers and public health leaders need to learn from past mistakes to ensure faith in these interventions does not wane.
“We should be using evidence to guide policy in the area of dengue control,” said O’Neill. “Any new intervention has to be able to show with the highest epidemiological evidence that their treatment or their innovation actually reduces disease before it can be heavily recommended.”