SINGAPORE, 8 SEPTEMBER 2025—Just as a computer's operating system can be rewritten after a major update, dengue infection can 're-programme' the body's immune system, leaving a long-lasting genetic imprint that influences how people respond to future infections—an effect not seen with vaccination.
These novel insights from a recent study shed light on the mechanics of dengue disease progression and vaccine action, filling an important knowledge gap on how even imperfect vaccines can be used safely. It also paves the way for the future development of safer and more effective dengue vaccines. The research was published in the journal Med, by scientists at Duke-NUS Medical School in collaboration with an international team of researchers.
Dengue is a mosquito-borne virus that affects millions of people in tropical and subtropical regions each year. The illness can range from a mild fever with rash to a severe, life-threatening disease involving bleeding and organ failure. As there are four different types of dengue viruses, everyone is theoretically vulnerable to being infected up to four different times in a lifetime.
Currently, dengue vaccines have limitations—they are more effective in preventing the disease in people who have been infected with dengue previously. In such individuals, vaccination protects against illness from all four types of dengue viruses. The conventional thinking is that vaccination activates memory immune cells generated from prior dengue virus infection, to boost protection against the remaining types of dengue viruses. Without such pre-existing immune cells, the quality of the immune response to vaccination is thought to be poorer.
On these grounds, vaccines that have been approved by the World Health Organization require more than one dose. Theoretically, the first dose should generate immune cells resembling those formed following a previous dengue infection. The second vaccine dose would then activate these cells to enhance protection against dengue. However, the immune response to the second dose is still lower than in those with prior infection with just one dose.
To understand how the immune response to vaccination is different from that of natural dengue virus infection, the researchers conducted a clinical trial involving 26 volunteers in the US from 2018 to 2020. Participants received two doses of a dengue vaccine [1] , administered 90 days apart. The team then analysed and compared blood samples from those volunteers who had previously been infected with dengue with those who had not. To ensure wider representation, around 50 volunteers from Singapore with no recent dengue virus infection also contributed blood samples to be analysed from 2022 to 2023.
The team discovered that even before being vaccinated, those with prior dengue infection already showed distinct patterns of gene activity. Surprisingly, these gene activity patterns were not found in the memory cells that produce antibodies, but in specific types of immune cells that the dengue virus infects.
Dr Eugenia Ong , Principal Research Scientist from the Emerging Infectious Diseases Programme at Duke-NUS Medical School and first author of the study, explained:
"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.
This long-term imprinting, also known as trained immunity, has been observed in other infections, like malaria, and after certain vaccines, such as BCG. This study adds dengue to that list and shows that both the type and intensity of infection matter.
Professor Ooi Eng Eong from the Emerging Infectious Diseases Programme at Duke-NUS Medical School and senior author of the study, 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."
A particular set of imprint that the researchers found involved genes that normally trigger immediate antiviral response to infection. These genes were less active in those with prior dengue infection. The dampened response means that upon vaccination (which uses a weakened viral strain), the resulting infection generates high levels of antibodies against the dengue virus. However, the dampened antiviral response may also explain why a second dengue infection with another dengue virus strain, often carries a higher risk of progressing to severe illness.
Professor Patrick Tan , Senior Vice-Dean for Research at Duke-NUS Medical School, said:
"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."
The team hopes their work will encourage more research into the long-term effects of immune reprogramming and its impact on responses to other infections and vaccines. They also hope that this new evidence would shape advocacy and global health policies on dengue vaccines that have been approved or are close to being approved. The scientists feel it is unlikely that a perfect dengue vaccine would be developed in the next 10 years—current vaccines, although imperfect, can still be used safety to reduce the estimated 100 million cases of dengue globally each year.
