Defining T cell epitopes in Dengue virus infection

DESCRIPTION (provided by applicant): There is a well-recognized need to develop vaccines that stimulates humoral immunity as well as a potent T cell immunity in order to achieve protection from infection with pathogens. Although numerous investigations arefocused on developing vaccines that induce protective humoral responses, only a few studies are aimed towards developing specific T cell immunity for various infections, including dengue virus. The critical components for a successful vaccine, that provides protective T cell immunity, are the identity of specific T cell epitopes and an optimized vaccine delivery system that is capable of delivering the antigens and the adjuvants simultaneously. In the phase I of the project, we have successfully identifiedand characterized HLA-A2 (allele representing ~40% of the world population) specific conserved epitopes and have demonstrated the feasibility of epitope based vaccine for dengue infection. In the phase II of this project, we propose to extend the discovery process to identify epitopes specific for HLA- A24, the major HLA allele in Asian population and characterize both the HLA-A2 and A24 epitopes using PBL from dengue virus infected patient cohorts. In addition, we propose to characterize a vaccine formulation of these cross serotype conserved antigenic epitopes in a novel gold glyconanoparticle delivery system that incorporates Toll Like Receptor (TLR) agonist, a promiscuous synthetic T helper peptide from tetanus toxoid and the bacterial mimetic GlcNAc asadjuvants and assess in vitro and in vivo for CTL activation and toxicity to generate preclinical data. At the end of the phase II, we would have necessary preclinical data to file an IND for a pilot phase 0/I clinical evaluation of the muli-epitope-basedvaccine product that induces specific T cell responses against DV infection in HLA-A2 and A24 positive human subjects. PUBLIC HEALTH RELEVANCE: There is a well-recognized need to develop vaccines that stimulates humoral immunity as well as a potent T cell immunity in order to achieve protection from infection with pathogens. Although numerous investigations are focused on developing vaccines that induce protective humoral responses, only a few studies are aimed towards developing specific T cell immunity for various infections, including dengue virus, which causes Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF), a significant global public health problems. The overall goal of this Phase II proposal is to characterize a vaccine formulation of apanel of cross serotype conserved antigenic epitopes in a novel gold glyconanoparticle delivery system for the development of a universal vaccine against dengue infection.