Japanese encephalitis virus (JEV) vaccination both prevents JEV and lowers dengue severity.
Singapore, 4 September 2025—Scientists from Duke-NUS Medical School, in collaboration with researchers in Nepal, have found that waning immunity to Japanese encephalitis virus (JEV) may increase the risk of more severe dengue disease in humans. Published in the journal Science Translational Medicine, the study highlights how fading vaccine protection from one virus can unintentionally affect the body’s response to another.
Japanese encephalitis is a serious disease that kills about 25 percent of those who develop severe symptoms and can leave many survivors with long-term disabilities. Dengue is also a major public health concern as the fastest-growing mosquito-borne viral disease worldwide, capable of causing severe illness and even death, with cases rising rapidly across Nepal in recent years. Fortunately, Japanese encephalitis can be prevented through vaccination, and countries like Nepal have made significant progress with mass immunisation campaigns. However, dengue prevention still primarily depends on mosquito control and personal protection measures. Although JEV vaccination generates high antibody levels, immunity can decrease over time, especially without booster doses.
The researchers examined over 500 patients across five years in Nepal, one of the few countries where both JEV and dengue are both actively spreading. The team discovered that people who had been vaccinated against JEV in the past, but whose antibody levels had declined, were more likely to experience more severe symptoms when they later contracted dengue. Those with strong JEV immunity were not affected in this way.
Dr Sidharth Malhotra, of the Programme in Emerging Infectious Diseases at Duke–NUS Medical School, and the study’s lead author, explained:
“We chose Nepal as a study site because it’s one of the few countries where dengue is spreading quickly in a population that already has widespread immunity to another flavivirus, Japanese encephalitis. This gave us a unique chance to see how prior immunity shapes dengue illness, and we found that people whose Japanese encephalitis immunity had waned were more likely to become severely ill from dengue.”
One important reason for this outcome appears to be a process known as antibody-mediated enhancement whereby partly effective antibodies backfire and make dengue worse. This happens when antibodies from a previous infection or vaccination are not strong enough to fully neutralise a different virus but still bind to it. These partially effective antibodies can help the dengue virus enter certain immune cells more easily, which may allow the virus to grow more rapidly and trigger a stronger immune response. That stronger immune reaction can cause greater inflammation, contributing to more severe symptoms.
While this mechanism has been well studied in people with multiple dengue infections, the new study shows that it may also occur when immunity from a different but related virus like JEV declines. These findings offer new insights into how cross-reactive immunity between related viruses can shape health outcomes.
The team of researchers assessed how severe the dengue illness became by measuring levels of chymase, a marker in the blood that increases during inflammation and is linked to more serious disease. They found that chymase levels were much higher in patients who had only moderate levels of JEV antibodies. These individuals were also more likely to show signs that dengue was becoming more dangerous, such as bleeding, stomach pain, and fluid leaking into surrounding tissues, which are all signs that suggest dengue is progressing towards its more dangerous forms.
Associate Professor Ashley St John, of Duke-NUS Medical School’s Programme in Emerging Infectious Diseases, who led the study, commented:
“This discovery matters for countries like Nepal and across Asia where both viruses circulate. It also highlights the need to keep JEV protection strong, through well-timed booster shots, not only to prevent Japanese Encephalitis itself but also to reduce the risk of severe dengue.”
Associate Prof Ashley thinks this knowledge could benefit millions of people living in regions where JEV vaccination is required or travellers who need to take the JEV vaccine. “Maintaining strong JEV vaccine coverage and possibly introducing booster shots when needed could be a practical way to not only prevent JEV but also reduce the severity of dengue, helping protect populations in Asia where both viruses are present.”
The new findings are particularly relevant as climate change and urbanisation increase the spread of mosquito-borne diseases. Nepal has seen a rapid rise in dengue cases over the past decade, including in areas where the virus was not previously common. Changing weather patterns and expanding mosquito habitats are helping diseases like dengue reach new regions.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, added:
“Japanese encephalitis is a devastating disease that causes a much heavier health burden than dengue fever, which is usually less deadly but still dangerous. What makes Japanese Encephalitis different is that it can be almost completely prevented with vaccination, while dengue still has no widely available vaccine. This means that strengthening JEV vaccination programmes by ensuring people develop and maintain strong, lasting protection has a double benefit.”
As part of their ongoing work, the team plans to monitor how dengue evolves in the region, particularly as more virus strains circulate and the population’s immune landscape becomes more complex. They are also working with partners to model the most effective vaccination strategies to protect communities against dengue and related viral infections.
This study was supported by the SingHealth Duke-NUS Global Health Institute and the Singapore Ministry of Education.