Scientists reveal why repeated cases of dengue fever are more severe than the primary infection

There has been a significant increase in dengue cases worldwide, with multiple outbreaks, raising new questions about who is at higher risk for severe forms of the mosquito-borne disease.

The incidence of infection has increased by an order of magnitude in the so-called “dengue belt,” which includes Central and South America, sub-Saharan Africa, Southeast Asia, and large swaths of the South Pacific, home to densely populated islands. Dengue is the world’s most widespread and fastest-growing vector-borne disease, according to the World Health Organization.

In the Americas alone, more than 5.2 million cases and more than 1,000 deaths were reported in the first three months of 2024, the Pan American Health Organization reported in April, noting a significant increase compared with the same period in 2023.

A similar situation is observed in other dengue- affected areas, where failures in vector control, coupled with global climate change, have led to an explosion of bloodthirsty mosquitoes, with swarms moving into areas previously considered dengue-free. Only female mosquitoes feed on blood, as they constantly need the nutrients from it to feed their eggs.

Now, more than two decades of dengue monitoring in Thailand provides answers to many questions at a time when the world most needs leadership.

The study's findings show how different subgroups — what virologists call subtypes — of the dengue virus affect future risk of severe infection. It has been known for years that those who become infected in subsequent outbreaks after a typically mild first infection are at significant risk of severe disease with subsequent infections. The new study finally analyzed more than 15,000 cases to find out why.

In a paper published in Science Translational Medicine, an international team of scientists explained how four dengue virus subtypes — DENV-1, 2, 3, and 4 — affect the risk of repeated severe infections. These findings provide a new basis for disease monitoring and lay the foundation for vaccination strategies as new dengue vaccines become available.

The team also highlighted that dengue, an insidious tropical disease, can be understood in the context of other common viral diseases circulating around the world.

“The ability of viruses such as SARS-CoV-2 and influenza to continually change their genetic structure in response to selective pressure from population immunity complicates control efforts,” said Dr. Lin Wang, lead author of the dengue study.

"In the case of dengue virus, an arbovirus that infects more than 100 million people each year, the situation is even more complex," Wang continued. "People with high titers of antibodies against dengue virus are protected from infection and from developing severe disease.

"However, people with sub-neutralizing antibody titers showed the highest risk of severe disease through several hypothesized mechanisms, including antibody-dependent enhancement," said Wang, a researcher in the Department of Genetics at the University of Cambridge in England.

Dengue infection can be insidious. Some patients who have had the infection but become reinfected in a subsequent outbreak may experience more severe symptoms the second time they get it. But most studies of reinfections of dengue have treated each serotype as indistinguishable from the others, Wang and colleagues say, noting that the genetic differences of each serotype need to be assessed to better understand the potential risks.

To paint a clearer picture, the researchers studied each serotype in more than 15,000 patients to understand why first dengue infections are typically milder than subsequent ones. Wang worked in collaboration with two centers in Bangkok, Thailand, several research institutes in the U.S., and one in France.

To determine how each serotype of the virus affects the risk of severe disease, Wang and his colleagues analyzed the virus’s genetic data. The team also looked at hospitalizations of dengue patients to determine which subtype of the virus caused their infection. The researchers collected data from 21 years of dengue surveillance, from 1994 to 2014, at a children’s hospital in Bangkok, covering 15,281 cases. This allowed them to identify repeat cases and each viral serotype across all infections.

Using hospital records of pediatric patients, the researchers found a link between hospitalization and the order in which patients were infected with different dengue virus serotypes. They were also able to determine which combinations of viral subtypes indicated mild or severe forms of dengue. For example, people who were infected with serotypes that were very similar to each other, such as DENV-3 and DENV-4, or very different serotypes, as in the case of DENV-1 and DENV-4, had a lower risk of severe disease if they were reinfected.

However, patients infected with serotypes that were only moderately different had a higher risk of severe symptoms with subsequent infections. The highest risk group in this category included patients who were first infected with DENV-2 and then subsequently infected with DENV-1.

The new study adds clarity to the risks of the disease, which may seem counterintuitive to the general public. For example, most people newly infected with dengue develop very mild symptoms or no symptoms at all. But for those who do become ill, the main symptoms include fever, headache, body aches, nausea, and rash, which worsen with severe infection.

For more than a century, a severe attack of dengue has been known as "breaking bone" fever because of the intensity of the pain and accompanying muscle spasms.

The virus is carried in the tropics and subtropics by the Aedes aegypti and Aedes albopictus mosquitoes, which are endemic in the dengue belt. But while that belt, which stretches between latitudes 35 degrees north and 35 degrees south, has traditionally been home to dengue-carrying mosquitoes, scientists say their range is expanding northward as climate change continues.

Wang, meanwhile, says the joint study has laid the foundation for a better understanding of immune system function in subsequent severe dengue infections.

“These results suggest that immune imprinting helps determine dengue disease risk and provides a way to monitor the changing risk profile of populations and to quantify the risk profiles of vaccine candidates,” Wang concluded. “This will become increasingly important as dengue vaccines are deployed.”

The results of the work are described in detail in an article published in the journal Science Translational Medicine.