Chimeric HA RNA Vaccine Composition for Broad Influenza Protection
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Solution Overview
Problem
Current influenza vaccines struggle to provide broad protection against various strains and subtypes due to antigenic drift and the inability to predict future pandemic strains, leading to inefficiencies in strain selection and reduced vaccine efficacy.
Innovation Solution
Development of chimeric influenza virus hemagglutinin polypeptides with a stable HA stalk and heterologous globular head, designed to elicit potent and broadly neutralizing antibodies against the conserved HA stem domain, using constructs like live viruses, VLPs, or subunit vaccines.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If strain-specific influenza vaccines are used, then vaccine efficacy against selected strains is improved, but the ability to protect against other strains and subtypes deteriorates
Solution Approach 1:
The hemagglutinin protein is segmented into two functional domains: the conserved stalk domain (for broad cross-protection) and the variable head domain (for strain-specific recognition). This segmentation allows the vaccine to simultaneously target both conserved and variable regions, resolving the contradiction between strain-specific efficacy and broad adaptability
Solution Approach 2:
The chimeric HA construct applies local quality by making the stalk domain highly conserved across different influenza strains while maintaining a diverse head domain that matches circulating strains. This local conservation strategy enables the immune system to generate antibodies that recognize the conserved stalk region across multiple strains, achieving both specificity and breadth
2Reliability
If strain selection is updated frequently to match circulating strains, then vaccine efficacy is improved, but the complexity of vaccine development and distribution deteriorates
Solution Approach 1:
The chimeric HA stalk domain serves multiple functions: it provides a conserved structural framework, elicits cross-protective immunity against multiple strains, and reduces the need for frequent vaccine reformulation. This multi-functionality simplifies the vaccine development process while maintaining efficacy against evolving influenza strains
3Reliability
If antibodies target the globular head domain, then strain-specific neutralization is improved, but cross-protection against other strains deteriorates
Solution Approach 1:
The conserved stalk domain acts as an intermediary that bridges strain-specific head domain recognition with broad cross-protection. By directing the immune response toward this conserved intermediary region, the vaccine achieves both potent neutralization and cross-subtype protection, resolving the contradiction between specificity and breadth
Data Source
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AI summary
Provided herein is an immunogenic composition comprising an RNA encoding a chimeric influenza virus hemagglutinin (HA) polypeptide in an admixture with a pharmaceutically acceptable carrier such as a biodegradable polymer, liposome, or micelle, wherein the chimeric influenza virus HA polypeptide comprises a HA stem domain and a HA globular head domain, wherein the HA globular head domain is from a different influenza A virus strain or subtype than the influenza A virus strain or subtype of the HA stem domain, as well as the use of the composition for immunizing a subject against influenza virus disease, or preventing influenza virus disease in a subject.