Every year, up to 400 million cases of dengue fever—a viral infection transmitted by mosquitoes—are recorded worldwide. While most people experience the disease without symptoms, the risk of severe complications rises significantly with subsequent infections. This is because the virus can "reprogram" the innate immune system, a process that does not occur with vaccination.

Global Threat and Statistics

The World Health Organization has included the dengue virus on its list of pathogens capable of causing epidemics or pandemics. From January to April 2024 alone, at least seven million people contracted dengue fever, and from January to July 2025, more than four million cases were registered across 97 countries. In endemic regions, where healthcare standards are often low, a significant number of cases may go unreported. Since there is no specific treatment targeting the virus itself, doctors rely on supportive therapy.

Characteristics of the Disease

During a first dengue infection, most patients may have no symptoms or may experience high fever, headache, rash, and joint pain. However, with reinfection, there is a risk of developing a severe form of the disease, which can involve organ damage and internal bleeding. This is due to the presence of four different serotypes of the virus: a person can contract dengue up to four times, and it is repeat infections that most often lead to complications.

Vaccination: Effectiveness and Limitations

WHO-approved vaccines, such as CYD-TDV and TAK-003, have shown high effectiveness in people who have already had dengue—the vaccination protects them against all virus types. For those who have never been infected, the immune response after even two doses of the vaccine is weaker than in those previously infected after just one dose.

Studying the Immune Response

To understand the reasons for this difference, an international team of scientists from Duke University (USA) and the National University of Singapore compared the response to the TAK-003 vaccine among volunteers from three independent cohorts. In the USA, 26 healthy participants received two doses of the vaccine 90 days apart, while in Singapore, blood samples were collected and analyzed from 50 unvaccinated volunteers (without recent dengue infection). Among them were both seropositive (previously infected) and seronegative (never exposed to the virus) individuals.

The results, published in the journal Med, showed that in people who had previously had dengue, the activity of innate immune cells (especially monocytes and dendritic cells, which are typically infected by the virus) was altered even before vaccination. They also had reduced activity of genes that inhibit viral replication (RSAD2/viperin, IFIT1, and IFIT3). Paradoxically, this "weakened defense" actually promoted a more active production of antibodies.

In those who had never had dengue, antibodies were produced after vaccination, but even after the second dose, the level of neutralizing antibodies remained lower than in those previously infected and vaccinated with just one dose of TAK-003. The difference was especially notable in the duration of the response: in seronegative participants, gene activity peaks quickly subsided, while in seropositive individuals, changes persisted for months.

Perspectives and Conclusions

Since the TAK-003 vaccine does not cause long-term "reprogramming" of innate immunity, researchers suggest that such restructuring requires contact with the "wild" virus and a certain level of viral load. In other words, the vaccine only slightly "warms up" the immune system. Scientists note that the data obtained will help make better use of existing vaccines, but the emergence of an ideal dengue drug is unlikely in the next 10 years.