I started studying dengue virus infections 25 years ago as a young U.S. Army medical corps officer in Thailand and Southeast Asia. Dengue had been a constant health threat in the region since the mid-1950s. Since then, the mosquitoes that transmit the dengue viruses have been expanding their habitats and establishing new geographic footholds, and the U.S. is now firmly among them.
Today, dengue epidemics are raging in several countries across Africa, the Americas and Southeast Asia. Experts estimate nearly 100 million people across the tropics and subtropics suffer from dengue every year. There have been over 360,000 dengue cases in Brazil this year alone. Dengue is also becoming a problem in more temperate climates like the U.S. and Europe. In 2023, there were more than 175 locally acquired cases in Florida.
What Is Dengue?
Dengue is an illness caused by infection with one of four dengue virus strains (dengue-1, -2, -3 or -4). The viruses are transmitted to humans when infected female mosquitoes feed on the blood of non-immune people.
Like many viral infections, a significant percentage of people who are infected do not even know it, or they have symptoms so mild their lives are minimally disrupted. But for some, the symptoms can be incredibly debilitating. It is not infrequent I receive distress calls from friends or friends of friends who are spending their tropical vacations hospitalized with dengue. According to the U.S. Center for Disease Control and Prevention, between 2010 and 2023, over 10,000 travelers returned to the U.S. or its territories with dengue.
High fever, headache, eye pain, muscle pain, bone pain, fatigue and rash make the dengue patient miserable for more than a week. Most people recover completely, but in many cases, there can be weeks to months of considerable physical and emotional fatigue. One of the first descriptions of these persistent symptoms was provided by Dr. Benjamin Rush, the only physician to sign the U.S. Declaration of Independence. He published his clinical observations of a large dengue outbreak in Philadelphia in 1780 and described the prolonged, “dejection of the spirits,” associated with dengue.
People living in areas where more than one dengue virus circulates are at risk of being infected with any of the four strains. When a person sustains a second infection with a second strain there is an increased risk of developing severe disease. Up to 5% of people sustaining second infections will experience leaky blood vessels, fluid accumulation in the lungs and abdomen, the potential for significant bleeding or development of shock and potentially death.
Most deaths, up to 40,000 each year, occur in children and people with significant pre-existing medical problems. It’s not clear why this severe second infection phenomenon occurs, but we do know it is less about the virus itself and more about the human immune response to the second infection. Interestingly, once a person has experienced infections with two different strains there is very little risk from a third or fourth infection.
There is no specific anti-dengue virus treatment. Physicians treat the patient’s symptoms (fever and pain relief) and use intravenous fluids to replace what leaks out of the blood vessels. In places experienced in treating dengue, fatality rates are often less than 1%, but one in five patients can die in more austere environments.
A Long Road Toward A Vaccine
Scientists have been trying to develop a safe and effective dengue vaccine for nearly 100 years. The U.S. military has experienced mission-debilitating dengue outbreaks since the Spanish-American War. World War II, and the Pacific theater saw tens of thousands of service members become ill with dengue.
Before Dr. Albert Sabin earned fame through his development of an oral polio vaccine, he was a young Army officer working on dengue vaccines. It would be 62 years between Sabin’s first dengue research publications and the time when vaccine developer Sanofi Pasteur would license the world’s first dengue vaccine.
Because there are four different dengue virus strains which often co-circulate in the same geographic region, dengue vaccines are expected to immunize recipients against all of them. The observation that a second infection can be much worse than a first infection also requires that a vaccine provide immunity to all viruses. Sanofi’s vaccine demonstrated itself to be well tolerated and to significantly reduce the risk of becoming ill with dengue. These initial results were based on a single year of volunteer follow-up and were the basis for acquiring numerous licenses and a massive vaccine rollout in the Philippines.
What happened next shocked the science and vaccine worlds. In the third year of the Sanofi trial researchers observed that vaccinated children who had never been infected with dengue before vaccination had a much higher risk of developing severe or hospitalized dengue compared to children who were not vaccinated. The exact reason why this occurred remains unknown, but it is likely the vaccine preferentially immunized recipients to only one strain, setting them up for the second infection phenomenon associated with severe cases.
In response to these findings, the World Health Organization changed its earlier vaccine recommendation to include only vaccinating people who were previously infected. Vaccine licensing authorities around the globe followed suit. By this time, however, the Philippines had already vaccinated over 800,000 children. Controversy and scandal ensued, child deaths were blamed on the vaccine and it was ultimately pulled from the Philippine market.
There is no conclusive proof the Sanofi vaccine was the cause of the deaths that occurred shortly after the vaccine rollout, and there is little information on whether there was a subsequent safety signal in the hundreds of thousands of children who were vaccinated. Regardless, the vaccine has suffered from market neglect ever since.
In 2022, Japanese pharmaceutical company Takeda brought the second dengue vaccine to market. It does not share Sanofi’s challenges, but it has issues of its own. The vaccine appears well tolerated even in people who have not been previously infected, but it does not work against the dengue-3 virus, and effectiveness against dengue-4 remains a question. Regardless, the company plans to deliver over 15 million doses to Brazil over the next two years in support of mass vaccinations occurring in response to the current outbreak. Takeda withdrew its license application from the U.S. Food and Drug Administration review process, meaning the vaccine will not be available in the U.S. any time soon.
The U.S. National Institutes of Health developed another dengue vaccine candidate and licensed its vaccine materials to Instituto Butatan in Brazil and Merck (MSD). The Butantan vaccine formulation is being tested in a five-year study in over 16,000 people in Brazil. Recently published data from the trial demonstrates the vaccine appears well tolerated in all recipients, and the vaccine significantly lowers the risk of disease caused by dengue-1 and -2. There were not enough dengue-3 or -4 cases to draw any conclusions, and the study continues. MSD is finalizing plans for testing its vaccine formulation.
Reducing the global dengue burden will require a multidisciplinary approach including development of vaccines, specific treatments, rapid diagnostic tests and innovative approaches to controlling mosquitoes. It will also require a hefty dose of expectation management and acceptance that even imperfect dengue vaccines can deliver a public health benefit (I wrote about this in a recent review). Environmental changes are expanding the list of countries at risk for dengue, and Europe and the U.S. will not be spared. If nothing changes, it may be time for your doctor to dust off those old medicine textbooks and brush up on dengue and other mosquito-borne tropical diseases.
Disclaimer: Dr. Thomas is a dengue researcher and receives research support in the forms of contracts and grants from the Department of Defense, NIH and numerous commercial partners. He also consults for several pharmaceutical companies developing countermeasures against dengue.
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