The review details the historical and current status of dengue vaccine development, underscoring key themes of future research

Dengue fever caused by a flavivirus named DENV is a major global health challenge, risking almost half of the world’s population. Since the early 20^th century, the scientific community has faced multiple challenges to develop effective dengue vaccines. This spanned a variety of techniques – from the use of ox bile to weaken DENV to the 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 its endemic regions, led to the development of more sophisticated dengue vaccines.

In a recent review published in Pediatric Investigation on 15 April 2025, lead authors Professor Kevin C. Kain from the University of Toronto, Canada, and Dr. Ran Wang, Associate Professor at the Capital Medical University, China, discuss the current status and implications of dengue vaccines like CYD-TDV, TAK-003, and Butantan-DV while exploring the challenges in Dengue vaccine development like ADE, and proposes future directions in this field.

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

The review draws from insights and implications from three Dengue vaccines—CYD-TDV (Dengvaxia) was the first licensed dengue vaccine and showed efficacy in phase III clinical trials. However, it was found to have reduced protection against DENV-1, DENV-2, and DENV-3. Moreover, this vaccine was only recommended for individuals with confirmed prior DENV infection, limiting its practical application. Further, vaccination regime of three doses over 12 months, was particularly difficult to achieve in resource-limited settings. Due to these reasons, CYD-TDV was withdrawn from widespread use, although the WHO still recommends it for individuals aged 9-45 years with prior DENV infection.

The second vaccine—TAK-003 – was evaluated over a four-and-a-half-year-long Phase III trial across eight countries where Dengue is endemic. With an overall efficacy of 61.2% (against current dengue infection) and 84.1% (against hospitalized cases), it offered strong protection against DENV-1 and DENV-2 serotypes. But, due to the insufficient number of cases of the other two serotypes, TAK-003’s efficacy against these could not be evaluated. This vaccine has a two-dose regimen, presenting logistical challenges as in the case of CYD-TDV.

Contrary to the above cases, the Butantan-DV vaccine with its single-dose regimen proved to have an edge over the others in simplifying vaccination where healthcare facilities were limited. Dr. Wang explains further about this vaccine, “A 2-year analysis reported an overall efficacy of 73.6% in sero-naïve individuals and 89.2% in those 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 demonstrated an 89% decrease in severe dengue and dengue with warning signs. However, the efficacy of this vaccine against DENV-3 and DENV-4 is yet to be established. Although the current dengue vaccines exhibit effective reduction of severe and fatal dengue in clinical trials, their impact on individuals aged above 60 years is still unclear.

The possibility of severe dengue after vaccination has been a significant challenge, particularly thought to be driven by ADE. When non-neutralizing, cross-reactive antibodies recognize conserved epitopes on the DENV envelope protein, it triggers immune responses that weaken antiviral activity, leading to severe disease. “Understanding the role of conserved epitopes and FcγR signaling in ADE is crucial for dengue vaccine development, and ADE issues in real world may only be revealed through efficacy studies in phase IV clinical trials of vaccines”, comments Professor Kain.

Looking ahead, global collaboration among researchers, health agencies, and vaccine developers will be essential to advance dengue vaccine research. Future efforts should explore diverse platforms like mRNA vaccines and focus on avoiding ADE. Priorities include: 1) Phase IV trials to refine strategies, 2) vaccines adaptable across populations and serotypes, and 3) region-specific formulations targeting local DENV variants.

With global collaboration, advanced vaccine platforms, and a better understanding of ADE, we may finally be on the path toward eliminating dengue.
Reference
Titles of original paper: Advancing dengue vaccine development: Challenges, innovations, and the path toward global protection
Journal: Pediatric Investigation
DOI: 10.1002/ped4.70005