Dengue infection can permanently reprogram the body’s immune system, leaving behind a genetic imprint that influences future responses to the virus, according to new research published in Med by Duke-NUS Medical School and international collaborators.
Unlike vaccination, which stimulates immunity without altering the genetic baseline, natural infection triggers long-term shifts in gene activity—particularly in immune cells directly targeted by the virus. This “trained immunity” explains why second dengue infections are often more severe, while also clarifying why vaccines are less effective in those without prior exposure.
The study, which involved vaccine trials in the United States and blood sample analyses from Singapore, found that people with previous dengue infections mounted stronger immune responses to their first vaccine dose compared to dengue-naïve individuals. Researchers discovered that the genetic imprint dampens certain antiviral pathways, allowing a more robust antibody response upon subsequent exposure.
Senior author Professor Ooi Eng Eong likened this to sports training: “The immune system only gets a full workout from natural infection, while vaccination is more of a light warm-up.”
These findings highlight both the risks of secondary dengue infection and the need for new vaccine strategies that account for long-term immune reprogramming. With dengue affecting nearly 100 million people worldwide each year, the study underscores the importance of harnessing even imperfect vaccines while pursuing next-generation solutions.
