Immunological Challenges and Emerging Strategies in Dengue Virus Vaccine Development

Dengue is one of the most rapidly spreading arboviral diseases worldwide, and the development of effective vaccines has long been constrained by antibody-dependent enhancement (ADE) and the difficulty of inducing protective immunity against multiple viral serotypes. Although several live-attenuated dengue vaccines have received regulatory approval in different jurisdictions, including Dengvaxia (CYD-TDV), Qdenga (TAK-003), and, more recently, Butantan-DV in Brazil, important challenges remain regarding vaccine safety in relation to pre-vaccination dengue serostatus, balanced cross-serotype protection, and the durability of vaccine-induced immunity. This review focuses on the immunopathogenic mechanisms of dengue virus infection, with particular emphasis on how ADE and immune bias impose critical constraints on vaccine design. We systematically summarize the technological platforms, immunological rationale, and major limitations of licensed and investigational dengue vaccines. Building on this analysis, the potential advantages and remaining challenges of emerging vaccine technologies, particularly mRNA vaccines, in precise antigen design, multivalent immune regulation, and safety optimization are further discussed. This review aims to provide a theoretical basis and strategic reference for the development of next-generation dengue vaccines with improved safety and efficacy.