Navigate the challenges and advances in dengue vaccine development

Navigate the challenges and advances in dengue vaccine development

Dengue fever, caused by a flavivirus called Denv, is a major global health challenge, putting nearly half of the world's population at risk. Since the early 20th century, the scientific community has faced several challenges to develop effective dengue vaccines. This included a variety of techniques – from using ox bile to weaken DENV to chemical processing of DENV -infected mosquitoes! However, the limitations of these techniques and the urgent need to save millions of people from the infection in their endemic regions led to the development of more sophisticated dengue vaccines.

In a recently published review inPediatric examinationOn April 15, 2025, the lead authors, Professor Kevin C. Kain from the University of Toronto, Canada, and Dr. Ran Wang, Associate Professor at Capital Medical University, China, discussed the current status and impact of dengue vaccines such as Cyd-TDV, TAK-003 and Butantan-DV.

DENV has four serotypes (DENV-1 to DENV-4) and triggers both protective and pathogenic immune responses. Serotype-specific immune responses are typical when first infected, while secondary infection due to ADE can lead to more severe dengue. “ADE is initiated when immune complexes of DENV and IgG antibodies bind to Fcγ receptors (FCγR) on myeloid cells. This suppresses antiviral defenses and improves viral replication. “explains Professor Cain. This is an important aspect to consider when designing vaccines for dengue.

The review highlights findings and implications from three dengue vaccines - CYD-TDV (Dengvaxia) - was the first licensed dengue vaccine and demonstrated efficacy in phase III clinical trials. However, it was found to have reduced protection against DENV-1, DENV-2 and DENV-3. In addition, this vaccine was only recommended for people with confirmed DENV infection, which limited its practical use. Furthermore, the three-dose, 12-month vaccination system has been particularly difficult to achieve in resource-limited settings. For these reasons, Cyd-TDV has been withdrawn from widespread use, although WHO still recommends it for people aged 9 to 45 years with prior DENV infection.

The second vaccine - TAK-003 - was evaluated over a four-and-a-half year Phase III trial in eight countries where dengue is endemic. With an overall efficacy of 61.2% (against current dengue infection) and 84.1% (against hospitalized cases), it provided strong protection against DENV-1 and DENV-2 serotypes. However, due to the insufficient number of cases of the other two serotypes, the effectiveness of TAK-003 against them could not be evaluated. This vaccine has a two-dose regimen, which presents logistical challenges as in the case of Cyd-TDV.

In contrast to the above cases, the Butantan DV vaccine with its single-dose regimen proved to have an advantage over the others in facilitating vaccination where health facilities were limited. Dr. Wang further explains about this vaccine, “A 2-year analysis reported an overall efficacy of 73.6% in sero-naïve individuals and 89.2% in patients with prior dengue exposure, with protection against DENV-1 (89.5%) and DENV-2 (69.6%)"Also, in a study that spanned more than 3 years, Butantan-DV showed an 89% reduction in severe dengue and dengue with warning signs. However, the effectiveness of this vaccine against DENV-3 and DENV-4 is not yet established. However, current dengue vaccines have yet to be effective in reducing severe and fatal dengue in clinical trials.

The possibility of severe dengue following vaccination was a significant challenge, particularly viewed by ADE. In non-neutralizing, cross-reactive antibodies, recognizing conserved epitopes of the DENV coat protein, it triggers immune responses that weaken antiviral activity, leading to severe disease. “Understanding the role of conserved epitopes and FCγ R signaling in ADE is critical to dengue vaccine development, and real-world ADE problems can only be revealed through efficacy studies in Phase IV clinical trials of vaccines. “Comments Professor Cain.

Looking forward, global collaboration between researchers, health authorities and vaccine developers will be essential to advance dengue vaccine research. Future efforts should explore different platforms such as mRNA vaccines and focus on preventing ADE. Priorities include: 1) Phase IV trials to refine strategies, 2) vaccines that are adaptable to populations and serotypes, and 3) region-specific formulations that target local DENV variants.

With global collaboration, advanced vaccine platforms, and a better understanding of ADE, we can finally be on the path to eliminating dengue.

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