Study Shows How Dengue Infection Resets the Immune System

A team from Duke-NUS Medical School working with international collaborators has found that natural dengue infection can alter the body’s immune system in a lasting way, unlike vaccination. Published in Med, their study explains how dengue leaves a genetic imprint on immune cells, reshaping their baseline state and influencing how people respond to subsequent infections or vaccines. These findings help clarify why older infections make vaccination more effective in some cases and why second infections carry greater risks. 

Dengue is transmitted by mosquitoes and affects millions of people each year, with illness ranging from mild fever to severe disease involving bleeding and organ damage. Because there are four types of dengue viruses, a person can theoretically be infected up to four times. Current vaccines work best in individuals with prior dengue infection, where the immune system’s pre-existing memory cells are boosted to provide protection against all four strains. For those without earlier exposure, however, vaccine effectiveness remains limited, even with two doses. 

To investigate the difference between infection-induced immunity and vaccine-induced immunity, the researchers conducted a clinical trial with 26 volunteers in the United States between 2018 and 2020. Participants received two doses of a dengue vaccine given 90 days apart. Their blood samples were then analyzed and compared with blood samples from volunteers who had previously been infected with dengue and with those who had not. The results showed that people with prior dengue infections already had distinctive gene activity patterns before vaccination. Importantly, these imprints were located not in antibody-producing memory cells but in the immune cells that dengue viruses themselves infect.

According to first author Eugenia Ong, “Our findings show that natural dengue infection can leave a lasting genetic imprint on the immune system. Instead of returning to normal, the immune system resets into a new baseline—one that may explain why second infections are often more severe.”

Because of this new baseline, the scientists found that in those who had been infected with dengue previously, the first dose of the vaccine triggered a stronger immune response than in those without a previous dengue infection. As vaccination, unlike natural infection, does not leave an imprint, the immune response in those without prior dengue virus infection remain lower than in those with prior dengue, even with two doses of the vaccine.   

Senior author Ooi Eng Eong compared this to sports training: “Think of it as training for a sport—the immune system only gets a real workout from the full game—the equivalent of a natural infection. A light warm-up from vaccination isn’t enough to reprogram it.”

The study also showed that dengue infection dampens certain antiviral gene responses, which may allow vaccines to generate strong antibody responses but also help explain why second infections are more dangerous.