Development of New Live-Attenuated Vaccine Candidates Lacking Antibody-Dependent Enhancement (ADE) Against Dengue.

Dengue virus (DENV) threatens public health, especially in regions with tropical and subtropical climates. In 2024, the World Health Organisation reported 3.4 million confirmed dengue cases, with 16,000 severe cases and 3000 dengue-associated fatalities. The first licensed dengue vaccine, CYD-TDV (Dengvaxia,Sanofi-Pasteur, Paris, France), is recommended by the WHO only for individuals aged 9-45 years with a prior history of dengue infection. However, being vaccinated with Dengvaxia increases the risk of developing severe dengue infections in seronegative individuals. Recently, a second licensed dengue vaccine, Qdenga,Takeda, Singen, Germany), was approved and recommended by the WHO to be administered only in highly dengue-endemic countries, as it was not shown to elicit a robust immune response against DENV-3 and DENV-4 serotypes in dengue seronegative individuals. Due to an imbalance in immune response against all four DENV serotypes, there is a higher risk of developing the antibody-dependent enhancement (ADE) effect, which could lead to severe dengue. This review has identified mutations throughout the DENV genome that were demonstrated to attenuate the virulence of DENV in either in vitro or in vivo studies. Several amino acid residues within the DENV prM and E proteins were identified to play important roles in ADE and modifying these ADE-linked residues is important in the rational design of novel live-attenuated dengue vaccine candidates. This review provides current insights to guide the development of a novel live-attenuated tetravalent dengue vaccine candidate that is effective against all DENV serotypes and safe from ADE. The efficacy and safety of the live-attenuated vaccine candidate should be further validated in in vivo studies.