Scientists have discovered why repeated cases of dengue fever are more severe than the initial infection

There is a significant increase in dengue cases around the world, with multiple outbreaks, raising new questions about who is at increased risk of severe forms of this mosquito-borne disease.

Infection rates have 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 areas of the South Pacific where densely populated islands are located. According to the World Health Organization, dengue is the most common and fastest growing vector-borne disease.

The Americas alone recorded more than 5.2 million cases and more than 1,000 deaths in the first three months of 2024, the Pan American Health Organization reported in April, marking a significant increase from the same period in 2023.

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

More than two decades of dengue monitoring in Thailand now provides many answers at a time when the world needs guidance most.

The study's findings showed how different subgroups - what virologists call subtypes - of the dengue virus influence the future risk of severe infection. It has been known for many years that those who become infected in subsequent outbreaks after a typically mild initial infection are at significant risk of severe illness in subsequent infections. A new study has finally analyzed more than 15,000 cases to find out why this is so.

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

The team also emphasized 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 every year, the situation is even more complex,” Wang continued. “People with high titers of antibodies against the dengue virus are protected from infection and the development of severe disease.

“However, people with subneutralizing antibody titers showed the greatest 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 an infection but are reinfected in a subsequent outbreak may experience more severe symptoms the second time they become infected. However, most studies of recurrent dengue infections have treated each serotype as indistinguishable from the others, Wang and colleagues said, noting that to better understand the potential risks, it is necessary to evaluate the genetic differences of each serotype.

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

To determine how each virus serotype affects the risk of severe disease, Wang and his colleagues analyzed genetic data from the virus. 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.

Based on hospital records of pediatric patients, the researchers found an association between hospitalizations and the order in which patients became infected with different serotypes of the dengue virus. 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 with very different serotypes, as in the case of DENV-1 and DENV-4, had a lower risk of severe disease if reinfected.

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

A new study adds clarity to a disease risk that may seem counterintuitive to the general public. For example, most people who are first infected with the dengue virus develop very mild symptoms or no symptoms at all. But for those who do get sick, the main symptoms include high fever, headache, body aches, nausea and rash, which get worse with severe forms of the infection.

For more than a century, a severe attack of dengue has been known as “breaking bones” fever due to the intensity of the pain and accompanying muscle spasms.

The virus is transmitted in the tropics and subtropics by Aedes aegypti and Aedes albopictus mosquitoes, which are endemic in the dengue belt. But while the 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 with climate change.

Wang, meanwhile, says the joint study lays 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 begin to be used.”

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