Immunoinformatic approach to design T cell epitope-based chimeric vaccine targeting multiple serotypes of dengue virus

Abstract

The global dengue outbreak is a significant public health concern, with the World Health Organization recording over 3 million cases and a 0.04% case fatality rate until July 2023. The infection rate is anticipated to rise in vulnerable regions worldwide. While live-attenuated vaccines are the current standard, their effectiveness in certain populations is debated. Furthermore, the presence of four closely related dengue virus serotypes can lead to antibody-dependent enhancement, compromising vaccine efficacy. In response, we propose the development of a therapeutic subunit-vaccine based on epitopes from all four serotypes to induce robust cross-protective cellular immunity. Our approach involves designing a multi-epitope chimeric immunogen using the envelope protein of the dengue virus. MHC-I and MHC-II binding T-cell epitopes were selected based on their antigen processing criteria. The most potent and immunodominant epitopes for each serotype, considering immunogenicity, population coverage, and prediction scores, were combined using AAY linker peptides to create a stable multi-epitope polypeptide. Predicted to be both antigenic and non-allergenic, the protein design exhibits a stable and soluble tertiary structure with a half-life of 4.4 h in mammalian systems. In addition, we employed an agonist to toll-like receptor-4 at the N-terminal of the vaccine design to induce downstream immunostimulatory response, validated through docking and molecular dynamics simulations. This multi-epitope construct shows promise in eliciting an effective cellular immune response against all dengue virus serotypes.

Keywords: Dengue; T cell epitopes; chimeric peptide; cytotoxic T cells; immunoinformatics; vaccine.