Advanced Formulation and Delivery Strategies for Next-Generation Dengue Vaccines: A Systematic Review

Background: Dengue virus (DENV) infection remains a major global health concern, with four antigenically distinct serotypes requiring balanced and durable immune protection. Despite advances in vaccine development, challenges including serotype imbalance, antibody-dependent enhancement (ADE), variable immunogenicity, limited immune durability, and formulation instability remain significant.

Objective: This systematic review evaluated recent pharmaceutical strategies for improving dengue vaccine development, focusing on advanced antigen engineering, delivery platforms, and formulation optimization technologies.

Methods: A PRISMA 2020-based systematic review was conducted. PubMed, Scopus, and Web of Science were searched using predefined terms related to dengue vaccines, antigen engineering and antigen design, virus-like particles (VLPs), nanoparticles, mRNA platforms, delivery systems, and formulation technologies. Eligible studies were screened and analyzed based on vaccine platforms, delivery approaches, immunogenicity, safety characteristics, and formulation stability.

Results: Among 1530 identified records, 46 studies were included in the qualitative synthesis. Evidence synthesis revealed three major strategies: antigen engineering, advanced delivery systems, and formulation optimization. VLPs, nanoparticle-based platforms, lipid nanoparticle (LNP)-mRNA systems, microneedle technologies, and thermostable formulations demonstrated potential to improve antigen presentation, delivery efficiency, immune responses, and vaccine stability.

Conclusion: Advanced pharmaceutical technologies provide promising opportunities to overcome current limitations in dengue vaccine development. Integration of innovative antigen design, efficient delivery systems, and optimized formulations may contribute to safer, more effective, and accessible dengue vaccines. Further clinical validation and scalable manufacturing studies are required.