AsianScientist (Oct. 14, 2025) – Dengue is a highly prevalent viral disease transmitted by Aedes mosquitoes, infecting up to Symptoms range from fever and rash to life-threatening bleeding or organ failure. To make matters worse, four different versions—or serotypes—of the virus mean a person can be infected up to four times in a lifetime.
Vaccines exist, but they protect people who have already had dengue. Even then, scientists are puzzled over why two doses of vaccine do not match the immunity gained from one natural infection.
Researchers at Duke-NUS Medical School at the National University in Singapore, working with international collaborators, have uncovered a fundamental difference between the body’s natural reaction to dengue infection and the immunity triggered by vaccination. In a study published in Med, they show that dengue infection does not just trigger an immune response and fade away. Instead, it reprogrammes the immune system, leaving a lasting genetic imprint. This effect, they found, does not occur with vaccination.
To investigate, the scientists ran a clinical trial administering two TAK-003 dengue vaccine doses 90 days apart in 26 volunteers in the United States and analysed 50 additional blood samples from Singapore. Through advanced gene expression profiling, the team found that, even before vaccination, people who had recovered from dengue carried distinct patterns of gene activity. This “imprint” was not in the expected antibody-producing memory B cells, but in the very innate immune cells—monocytes and dendritic cells—that the dengue virus targets.
“This shows that natural dengue infection can leave a lasting genetic imprint on the immune system,” said first author Eugenia Ong, principal research scientist at Duke-NUS. “Instead of returning to normal, the immune system resets into a new baseline, one that may explain why second infections are often more severe.”
This long-term rewiring, known as “trained immunity”, has been observed in malaria and after certain vaccines like BCG, but never in dengue. It means that after infection, the immune system doesn’t simply reset to factory settings. Instead, it installs a new baseline that influences every response thereafter.
The difference also explains why vaccines behave differently depending on infection history. For dengue-naïve individuals, two doses act like light warm-ups. For those with prior infection, one vaccine dose triggers a far stronger response because the immune system has already been “trained”.
“Think of it as training for a sport,” explained Ooi Eng Eong, senior author and researcher at Duke-NUS’ Emerging Infectious Diseases Programme. “The immune system only gets a real workout from the full game, which is the equivalent of a natural infection. A light warm-up from vaccination is not enough to reprogram it.”
The finding clarifies why two vaccine doses don’t equal the protection conferred by one prior infection and sheds light on secondary dengue pathogenesis: a reset baseline that mutes antiviral defences can combine with antibody effects to worsen outcomes in some people.
“As dengue continues to affect millions across Asia, Latin America and other tropical regions, this study closes a critical gap in our understanding of how infection reshapes the immune system,” said Professor Patrick Tan, a senior author of the study and vice-dean for research at Duke-NUS. He noted the insight could inform vaccine design and policy.
The researchers hope their findings will inspire new approaches to dengue prevention. While a perfect vaccine may still be years away, the evidence shows that even imperfect ones can be deployed safely to curb the estimated 100 million annual cases worldwide.
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Source: Duke-NUS Medical School; Image: Freepik
This article can be found at: Dengue Virus Infection Reprograms Baseline Innate Immune Gene Expression
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