Dengue Virus T Cell Epitope Vaccine Design
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Developing an effective vaccine against dengue virus (DENV) is challenging due to the virus's four serotypes and the immune response's contribution to severe disease, particularly during secondary infections, where serotype cross-reactive antibodies can enhance infection and T cells may play a dual role in pathogenesis and protection, making it difficult to study their contribution.
Innovation Solution
Identification of CD4+ and CD8+ T cell epitopes from DENV structural and non-structural proteins, which can be used to elicit specific immune responses, and administration of peptides derived from these epitopes to induce protective T cell responses, as demonstrated in mouse models and human donors, providing protection against DENV infection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a vaccine is designed to protect against all four DENV serotypes, then broad protection is achieved, but the risk of antibody-dependent enhancement (ADE) increases during secondary infections
Solution Approach 1:
The vaccine is segmented into multiple components targeting different serotypes and immune responses. It includes T cell epitopes from all four serotypes to elicit cross-protective T cell responses, while antibody components are designed to target conserved epitopes that minimize ADE risk. This segmentation allows broad protection while reducing harmful cross-reactivity.
Solution Approach 2:
Different regions of the vaccine elicit different types of immune responses. T cell epitopes are selected to induce protective cellular immunity across all serotypes, while antibody-inducing regions are carefully chosen to avoid enhancing infection. The vaccine creates localized immune responses with different qualities (cellular vs. humoral) to balance protection and safety.
2Reliability
If T cell responses are enhanced to provide protection, then viral clearance is improved, but the dual role of T cells in pathogenesis and protection makes the outcome unpredictable
Solution Approach 1:
The vaccine pre-activates protective T cell responses before natural infection occurs. By exposing the immune system to engineered T cell epitopes in advance, the vaccine establishes a primed, protective T cell repertoire that will respond effectively upon encounter with actual virus, preventing the unpredictable dual role scenario by establishing protective responses first.
Solution Approach 2:
The vaccine uses engineered peptide epitopes as intermediaries to bridge the gap between vaccine administration and protective immunity. These selected T cell epitopes act as mediators that specifically activate protective T cell pathways while avoiding those that contribute to pathogenesis, simplifying the complex T cell response dynamics.
3Adaptability or versatility
If serotype cross-reactive antibodies are produced, then immunity to multiple serotypes is achieved, but enhancement of infection in FcγR+ cells occurs during secondary infection
Solution Approach 1:
The harmful capability of cross-reactive antibodies to enhance infection is extracted and removed from the vaccine design. Instead of relying on traditional whole-virus or subunit vaccines that generate broad cross-reactive antibodies (some of which enhance infection), the vaccine extracts only the beneficial T cell epitopes that provide cross-protection without the harmful antibody-mediated enhancement effect.
Solution Approach 2:
The vaccine converts the potential harm of cross-reactivity into benefit by focusing on T cell cross-reactivity rather than antibody cross-reactivity. T cell epitopes from all four serotypes are included to generate cross-protective cellular immunity, which provides broad protection without the harmful FcγR-mediated enhancement that plagues antibody-based cross-reactive responses.
Data Source
AI summary
Dengue virus (DV) peptides, including T cell epitopes, structural and non-structural (NS) polypeptide sequences, subsequences and modifications thereof, nucleotide sequences encoding such peptides, and compositions including such peptides and encoding nucleotide sequences, and cells expressing such peptides, are provided. Such DV peptides, nucleotide sequences and compositions, can be used to elicit, stimulate, induce, promote, increase, enhance or activate an anti-DV CD8+ T cell response or an anti-DV CD4+ T cell response. Such peptides, nucleotide sequences and compositions can also be used for and in methods of vaccination/immunization of a subject against Dengue virus (DV) (e.g., to provide protection against DV infection and/or pathology), and for treatment of a subject in need thereof, for example, treatment of the subject for a Dengue virus (DV) infection or pathology.