Dengue Virus Epitopes for Multi-HLA T Cell Activation
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Solution Overview
Problem
Current dengue virus treatments and vaccines have limited success in inducing robust and cross-reactive CD8+ T cell responses, and existing peptide identification methods struggle to account for variability in HLA molecules worldwide, particularly in regions where HLA-A24 is common, necessitating peptides that bind to multiple HLA alleles.
Innovation Solution
The development of HLA-A2 and A24 binding dengue virus epitopes that activate T cells in both HLA-A2 and A24 restricted manners, identified using an immunoproteomic approach, allowing for the recognition of peptide-pulsed and dengue virus-infected cells in a pro-inflammatory and cytotoxic manner, and potentially serving as universal vaccine candidates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide-based vaccines are designed to bind to specific HLA alleles (e.g., HLA-A2 or HLA-A24), then they can induce robust T cell responses in individuals with that specific HLA type, but they fail to provide cross-protective immunity in populations with different HLA allele distributions
Solution Approach 1:
The vaccine composition employs multiple peptide epitopes that bind to different HLA class I molecules (HLA-A2, HLA-A24, and other supertype molecules). This multi-functional approach ensures that at least some epitopes will bind to and activate T cells in individuals regardless of their specific HLA allele distribution, thereby achieving universal protection across diverse populations
Solution Approach 2:
The invention changes the parameter of peptide binding specificity by selecting epitopes that recognize multiple HLA supertypes rather than single alleles. By modifying the peptide sequence characteristics to accommodate variations in HLA binding grooves, the vaccine maintains T cell activation capability across different HLA backgrounds
2Reliability
If vaccine formulations use live-attenuated viruses to induce robust B and T cell responses, then protection is achieved through activation of B and T cells, but safety concerns and limited success in inducing cross-reactive T cell responses persist
Solution Approach 1:
The invention extracts and isolates specific protective epitopes from the entire viral protein structure. By identifying and using only the critical T cell epitopic regions (such as those from capsid, NS3, NS5 proteins) rather than whole viruses, the vaccine achieves targeted T cell activation without the safety risks and immune deviation associated with live-attenuated approaches
Solution Approach 2:
The patent uses peptide epitopes as intermediaries to bridge the gap between viral antigens and T cell recognition. These synthetic peptides serve as safe mediators that present viral-derived epitopes to T cells without requiring actual viral infection, thereby eliminating the harmful factors of live virus while maintaining immunogenicity
Data Source
AI summary
Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF) are significant global public health problems and understanding the overall immune response to infection will contribute to appropriate management of the disease and its potentially severe complications. Live attenuated and subunit vaccine candidates, which are under clinical evaluation, induce primarily an antibody response to the virus and minimal cross-reactive T cell responses. Currently, there are no available tools to assess protective T cell responses during infection or post vaccination. Herein, we report novel, naturally processed and presented MHC class I restricted epitopes, a subset of which binds to and activates T cells in both an HLA-A2 and HLA-A24 restricted manner. We show that epitope specific T cells can be activated in vivo in transgenic mice and in vitro in seropositive and seronegative individuals and that these T cells are functional, recognizing peptide pulsed and dengue virus infected cells in a pro-inflammatory and cytotoxic manner. These epitopes have potential as new informational and diagnostic tools to characterize T cell immunity in Dengue virus (DV) infection, and may serve as a universal vaccine candidate complementary to current vaccines in trial.