Flavivirus E-Protein Immunogens Without Domain II to Limit ADE
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Solution Overview
Problem
Current flavivirus vaccines, such as those for Zika and Dengue, elicit poorly neutralizing antibody responses that can lead to antibody-dependent enhancement (ADE), increasing the risk of severe disease, and there is a lack of effective vaccines for children under 9 years old or over 16.
Innovation Solution
Development of immunogens comprising Domains I and III of the flavivirus envelope protein, linked by flexible linkers, without Domain II, which fold into a soluble and well-expressed recombinant protein to induce potent cross-neutralizing antibodies across multiple flaviviruses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full envelope (E) protein is used in flavivirus vaccines, then immunogenicity is achieved, but antibody-dependent enhancement (ADE) responses occur leading to severe disease
Solution Approach 1:
The patent extracts and removes Domain II from the full envelope protein, retaining only Domains I and III. This extraction eliminates the fusion loop epitope in Domain II that triggers ADE responses, while preserving the neutralizing epitopes in Domains I and III that provide protective immunity.
Solution Approach 2:
The envelope protein is segmented into distinct domains, with only the protective Domains I and III being utilized in the vaccine immunogen. This segmentation allows selective presentation of protective epitopes while excluding harmful epitopes that cause ADE.
2Reliability
If Domain II is removed from the E protein to prevent ADE, then cross-neutralizing activity is improved, but protein solubility and expression may be affected
Solution Approach 1:
A flexible linker peptide is introduced as an intermediary element to connect Domains I and III after the removal of Domain II. This linker serves as a structural mediator that maintains proper folding, solubility, and expression of the truncated E protein while preserving the neutralizing epitopes.
Solution Approach 2:
The patent modifies the structural parameters of the E protein by removing Domain II and introducing a flexible linker, changing the protein's conformational landscape to achieve both solubility and potent neutralizing activity without ADE responses.
Data Source
AI summary
This application relates generally to flavivirus immunogens and to methods and compositions related thereto. More particularly, the disclosure relates to compositions and methods for the preparation, production, and administration of flavivirus immunogens comprising modified E proteins, including, for example, compositions for use as vaccines against flavivirus and for capturing antibodies against flavivirus.