Dengue is one of the most important arboviral infections worldwide, infecting up to 390 million people and causing 25,000 deaths annually. Although a licensed dengue vaccine is available, it is not efficacious against dengue serotypes that infect people living in South East Asia, where dengue is an endemic disease. Hence, there is an urgent need to develop an efficient dengue vaccine for this region. Data from different clinical trials indicate that a successful dengue vaccine must elicit both neutralizing antibodies and cell mediated immunity. This can be achieved by designing a multi-epitope peptide vaccine comprising B, CD8+ and CD4+ T cell epitopes. As recognition of T cell epitopes are restricted by human leukocyte antigens (HLA), T cell epitopes which are able to recognize several major HLAs will be preferentially included in the vaccine design. While peptide vaccines are safe, biocompatible and cost-effective, it is poorly immunogenic. Strategies to improve its immunogenicity by the use of long peptides, adjuvants and nanoparticle delivery mechanisms are discussed.
Vaccination remains the major approach to the prevention of dengue. Since the only licensed live attenuated vaccine (LAV) lacked efficacy against all four serotypes, other vaccine platforms, such as synthetic peptide vaccines, should be explored. In this study, four multi-epitope peptides (P1–P4) were designed by linking a universal T-helper epitope (PADRE or TpD) to the highly conserved CD8 T cell epitope and B cell epitope (B1 or B2) against all four DENV serotypes. The multi-epitope peptides were conjugated to polystyrene nanoparticles (PSNPs) and four nanovaccines (NP1–NP4) were constructed. Mice immunized with NP1–NP4 elicited significantly higher titers of IgG and neutralizing antibodies when compared to immunization with naked P1–P4. The immune responses in mice immunized with peptide vaccines were compared with nanovaccines using ELISA, ELISPOT, and a neutralization test based on FRNT50. Among the four conjugated peptide nanovaccines, NP3 comprising the TpD T-helper epitope linked to the highly conserved B1 epitope derived from the E protein was able to elicit significant levels of IFN-γ and neutralizing antibodies to all four dengue serotypes. NP3 is a promising tetravalent synthetic peptide vaccine, but the selection of a more effective CD8+ T cell epitope and adjuvants to further improve the immunogenicity is warranted.
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