SINGAPORE, 8 September 2025 — Dengue infection can “re-programme” the body’s immune system much like a computer operating system being rewritten, leaving a long-lasting genetic imprint that influences how people respond to future infections. Strikingly, this imprint is not seen with vaccination.

Published in Med, the new study by Duke-NUS Medical School and an international research team uncovers how dengue reshapes immunity and why vaccines behave differently from natural infection. The findings fill a key knowledge gap, providing insights that could inform the design of safer, more effective vaccines and guide global health policy.

Dengue’s Global Impact

Dengue is a mosquito-borne virus that infects millions each year across tropical and subtropical regions. Symptoms range from mild fever to life-threatening illness involving bleeding and organ failure. With four dengue virus types circulating, individuals can be infected up to four times in their lifetime.

Current vaccines offer only partial protection. They work best in people who have already been infected, as the immune system’s memory cells can be “boosted” by vaccination. For people without prior infection, vaccine-induced responses are weaker, even after two doses.

A Closer Look at Immune Responses

To better understand why, researchers conducted a clinical trial in the US between 2018 and 2020, involving 26 volunteers who received two doses of a dengue vaccine 90 days apart. Their blood samples were analysed and compared with those from Singapore-based volunteers with no recent dengue infection.

The results revealed that people who had previously been infected showed distinct gene activity patterns even before vaccination. Surprisingly, these changes were not in the usual antibody-producing memory cells, but in immune cells targeted by dengue itself.

Dr Eugenia Ong, Principal Research Scientist at Duke-NUS and first author, said:

“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.”

Trained Immunity: A Lasting Imprint

This phenomenon, known as trained immunity, has been observed in other infections such as malaria and after vaccines like BCG. The Duke-NUS study is the first to demonstrate this effect in dengue.

In individuals with prior infection, the first vaccine dose triggered a stronger immune response compared to those without. However, because vaccination does not reprogramme immunity in the same way natural infection does, responses in dengue-naïve individuals remained weaker, even after two doses.

Professor Ooi Eng Eong, senior author from Duke-NUS, explained:

“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 reprogramme it. This reveals a threshold of immune response needed to leave an imprint on the immune system.”

The Double-Edged Sword of Immune Reprogramming

Researchers also found that in previously infected individuals, genes normally responsible for triggering an immediate antiviral response were less active. While this dampened response allowed the vaccine virus to generate strong antibody levels, it may also explain why secondary infections with a different dengue strain often carry higher risks of severe disease.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, highlighted the broader importance of these findings:

“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. These insights are vital not only for developing better vaccines but also for guiding global and national health policies. At Duke-NUS, our goal is to ensure that discoveries like these translate into real protection for the communities most at risk.”

Looking Ahead

The researchers hope their work will inspire further studies into how immune reprogramming affects other infections and vaccines. They also stress that while a “perfect” dengue vaccine may be a decade away, current vaccines—though imperfect—remain important tools in reducing the estimated 100 million dengue cases worldwide each year.

Summary of Findings

• Dengue infection leaves a long-term genetic imprint on the immune system, unlike vaccination.
• This “trained immunity” boosts vaccine responses in previously infected individuals but not in those without prior infection.
• Immune reprogramming dampens antiviral gene activity, helping vaccines generate strong antibodies but also explaining the severity of second infections.
• The findings highlight the urgent need to refine dengue vaccine strategies and global health policies.
• Current vaccines remain safe and valuable in reducing global dengue burden, even if not fully effective.

Original Publication
Authors: Eugenia Z. Ong, Jia Xin Yee, Clara W. Koh, Justin S. Ooi, Christine Y.L. Tham, Kuan Rong Chan, Bettie W. Kareko, Zoe L. Lyski, Vianney Tricou, Hansi Dean, Ralph Braun, Shirin Kalimuddin, Jenny G. Low, William B. Messer, Mayuri Sharma and Eng Eong Ooi.
Journal: Med
DOI: 10.1016/j.medj.2025.100841
Method of Research: Randomized controlled/clinical trial
Subject of Research: Cells
Article Title: Dengue virus infection reprograms baseline innate immune gene expression
Article Publication Date: 8-Sep-2025

Original Source: https://www.duke-nus.edu.sg/newshub/media-releases

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