Chimeric Dengue E Glycoprotein Hinge Mutations
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Solution Overview
Problem
Current dengue virus vaccines often induce non-neutralizing antibodies, leading to increased risk of pathology upon subsequent exposure, and existing technologies have not effectively identified epitopes targeted by human neutralizing antibodies, which are crucial for developing effective immunogenic compositions.
Innovation Solution
A dengue virus epitope spanning adjacent E protein dimers, specifically the hinge region between domains I and II, and portions of domain III, is identified and utilized in chimeric dengue virus E glycoproteins and flavivirus particles to induce neutralizing antibodies, allowing for the development of immunogenic compositions that target this quaternary structure epitope.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current dengue virus vaccines are used, then an immune response is induced, but non-neutralizing antibodies are produced leading to increased risk of pathology
Solution Approach 1:
The vaccine design segments the E protein into specific epitopic regions (hinge region between domains I and II, and domain III) that are presented in a specific spatial arrangement on the virion surface. This segmentation allows the vaccine to target only the neutralizing epitopes while avoiding induction of non-neutralizing antibodies against other regions.
Solution Approach 2:
The invention focuses on presenting specific local regions of the E protein (the quaternary epitope spanning adjacent dimers) with their native conformation and spatial arrangement. This local quality approach ensures that the immune response is directed toward the neutralizing epitopes while maintaining the structural characteristics that elicit protective immunity.
2Ease of manufacture
If existing vaccine technologies are used, then immunogenic compositions are developed, but the epitopes targeted by human neutralizing antibodies remain unidentified
Solution Approach 1:
The invention creates a copy of the native quaternary epitope structure through recombinant E proteins that preserve the hinge region between domains I and II and domain III in their native spatial arrangement. This copying approach allows identification of the neutralizing epitopes without requiring complete viral particles, enabling easier manufacturing while maintaining epitope information.
3Reliability
If chimeric dengue virus E glycoproteins with mutant hinge regions are used, then neutralizing antibodies are induced, but the complexity of protein engineering increases
Solution Approach 1:
The invention introduces specific amino acid substitutions in the hinge region between domains I and II of the E protein to create chimeric glycoproteins that stabilize the epitopic structure. These parameter changes (amino acid substitutions) are targeted and limited to specific regions, allowing induction of neutralizing antibodies while controlling the complexity of protein engineering through focused mutagenesis rather than comprehensive redesign.
Data Source
AI summary
The present invention provides compositions and methods of use comprising a chimeric dengue virus E glycoprotein comprising a dengue virus E glycoprotein backbone, which comprises amino acid substitutions that introduce a dengue virus E glycoprotein domain I and domain II hinge region from a dengue virus serotype that is different from the dengue virus serotype of the dengue virus E glycoprotein backbone.