As dengue spreads, researchers discover a clue to fighting the virus

Children who experience multiple cases of dengue virus develop an army of dengue-fighting T cells, according to a new study led by scientists at La Jolla Institute for Immunology (LJI).

The findings, published recently in JCI Insight, suggest that these T cells are key to dengue virus immunity. In fact, most children who experienced two or more dengue infections showed very minor symptoms—or no symptoms at all—when they caught the virus again.

"We saw a significant T cell response in children who had been infected more than once before," says study leader and LJI Assistant Professor Daniela Weiskopf, Ph.D.

Dengue virus infects up to 400 million people each year, and there are few vaccines and no approved therapies available for any of the four species (serotypes) of the virus. The researchers hope their findings can inform the development of a dengue virus vaccine that prompts a similarly strong T cell response.

This research comes as dengue-carrying mosquitoes expand their territory into new regions, including Southern California. Health officials in California reported the state's first-ever case of locally acquired dengue virus in 2023. Since then, Los Angeles County has reported 12 additional cases of locally acquired dengue virus, and San Diego County has confirmed two locally acquired cases.

"Dengue virus is expanding into areas where the majority of people have never seen the virus," says Weiskopf, who is a member of LJI's Center for Vaccine Innovation. "That will change the game."

T cells help fight dengue

Weiskopf and her colleagues set out to understand how T cells might sway the severity of dengue virus infection. Are T cells helping or hurting young patients?

After all, the immune system has to strike a careful balance when fighting viruses. A weak T cell response makes it tough to fight infection. On the other hand, an overzealous T cell response can cause harmful inflammation and potentially fatal complications.

The researchers studied a group of 71 children in Managua, Nicaragua, a region where dengue virus is endemic. Since 2004, study co-author Eva Harris, Ph.D., Director of the Center for Global Public Health at UC Berkeley, has worked with Nicaraguan scientists to study dengue infections in this patient group.

These children, ages 2 to 17, come in for regular blood draws to test for antibodies against dengue virus. By detecting a rise in these antibodies, compared to the previous year, researchers can tell if a child has dealt with a past dengue virus infection. Importantly, researchers can also use the blood test to catch inapparent cases of dengue infection—where a child has been exposed to the virus but is showing no clinical symptoms.

The researchers found that the number of dengue-fighting T cells in these children builds up with each infection, and these T cells appeared to be helping the pediatric patients.

Children with a history of two or more dengue infections were much less likely to show clinical symptoms if they caught the virus again. Meanwhile, children only infected once were more likely to show clinical symptoms of disease during a later infection.

Next steps toward a life-saving vaccine

The new study may offer context for why a recent dengue virus vaccine, called Dengvaxia, appeared safe and effective in just a subset of patients at risk for dengue infection. The vaccine was only FDA-approved for children who were ages 9 to 16 and lived in a dengue-endemic area, assuming that they had experienced dengue infection by that age. Subsequent licensure in other countries required an antigen test to prove previous exposure.

The vaccine didn't work if a person hadn't been exposed to dengue virus before. Could it be that their T cells weren't ready to jump into action?

As the new study suggests, it may take multiple dengue virus exposures to gain immunity. Weiskopf says scientists will continue to investigate how to harness T cells to fight dengue virus.

"There's a lot more work to be done," says Weiskopf.

Additional authors of the study, "Frequency of Dengue Virus-Specific T Cells is related to Infection Outcome in Endemic Settings," include Rosa Isela Gálvez, Amparo Martínez-Pérez, E. Alexandar Escarrega, Tulika Singh, José Víctor Zambrana, and Ángel Balmaseda.