Chimeric HA Stem Polypeptide for Broad Influenza Protection
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Solution Overview
Problem
Current influenza vaccines require frequent updates due to antigenic drift and shift, leading to strain mismatch and limited protection against diverse influenza virus subtypes, with challenges in expressing the HA2 subunit in a native, pre-fusion conformation for effective neutralization.
Innovation Solution
A headless hemagglutinin (HA) stem domain polypeptide comprising HA1 and HA2 fragments connected by flexible linkers, with specific amino acid sequences and modifications to maintain a native, pre-fusion conformation, eliciting broad neutralizing antibodies across influenza subtypes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the HA2 subunit is expressed independently in a native, pre-fusion conformation, then neutralizing antibody efficacy is improved, but expression success rate deteriorates (spontaneously adopts low-pH conformation)
Solution Approach 1:
The patent introduces the HA1 stem fragment as an intermediary component that mediates the stabilization of HA2 in pre-fusion conformation. The HA1 stem acts as a molecular chaperone, preventing HA2 from spontaneously adopting the low-pH conformation during expression, thereby enabling successful production of functional immunogen while maintaining neutralizing antibody efficacy
Solution Approach 2:
The patent merges the HA1 stem fragment with the HA2 subunit to create a chimeric polypeptide construct. This combination allows the HA1 stem to provide structural support and conformational stability to HA2, enabling the expression of HA2 in its native pre-fusion state which is essential for eliciting neutralizing antibodies
2Reliability
If the globular head domain is targeted for vaccine development, then receptor binding inhibition is improved, but antibody breadth deteriorates (escape variants limit protection)
Solution Approach 1:
The patent extracts the HA1 stem fragment (amino acids 1-41) and HA2 stem fragment (amino acids 289-323) from the complete HA protein structure. By isolating and utilizing only the stem regions rather than the entire HA protein or globular head, the invention targets the conserved stem epitopes that are less prone to antigenic drift, thereby achieving broader antibody coverage across influenza subtypes
3Reliability
If current influenza vaccines are updated frequently to match circulating strains, then strain-specific protection is improved, but vaccine complexity and update requirements worsen
Solution Approach 1:
The patent creates a universal influenza vaccine construct by combining conserved stem regions from different influenza subtypes (H1N1, H3N2, H5N1) into a single chimeric polypeptide. This universal immunogen can elicit cross-subtype neutralizing antibodies, providing broad protection against multiple influenza strains without requiring frequent vaccine updates, thereby achieving multi-functionality
Data Source
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AI summary
The present disclosure relates to a polypeptide comprising hemagglutinin stem domain fragments that can elicit broadly cross-reactive anti-influenza antibodies and confer protection against influenza virus. The disclosure also provides a method of preparing the polypeptide with biochemical and biophysical properties that enhance its immunogenic properties. Also provided are recombinant DNA constructs, vectors, and host cells comprising the nucleic acid encoding the polypeptide, as well as uses of the polypeptide, particularly in the prevention, and detection of influenza.