Influenza HA Stem Polypeptides for Broad Protection
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Solution Overview
Problem
Current influenza vaccines are ineffective in providing broad protection against various influenza virus strains due to high variability in the HA protein, leading to limited immunity and the risk of pandemics from virulent strains.
Innovation Solution
Development of novel influenza HA stem polypeptides that lack the globular head domain, incorporating specific modifications for stability and trimerization, which induce an immune response by presenting conserved epitopes of the HA stem domain, thereby eliciting broadly neutralizing antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current influenza vaccines target the HA head domain, then they induce immune response against circulating strains, but they fail to provide broad protection due to high variability in the head domain
Solution Approach 1:
The patent extracts the stem domain from the complete HA protein by removing the variable head domain. This isolation of the conserved stem region allows the vaccine to target epitopes that are invariant across different influenza strains, thereby providing broad protection while maintaining reliability against both seasonal and pandemic strains
Solution Approach 2:
The patent applies local quality by focusing the immune response on a specific region (the stem domain) with uniform properties across all influenza strains. By concentrating vaccine design on this conserved local region rather than the variable head domain, the vaccine achieves both broad adaptability and reliable effectiveness
2Adaptability or versatility
If HA stem polypeptides are designed to present conserved epitopes, then broadly neutralizing antibodies are elicited, but the polypeptides require modifications for stability and trimerization
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (e.g., I38M, L41P, V42P) that modify the physical-chemical parameters of the stem polypeptide. These changes enhance trimerization efficiency and structural stability without altering the conserved epitope sequences, thereby maintaining broad neutralization capability while improving polypeptide performance
Solution Approach 2:
The patent creates a composite structure by combining the HA stem domain with stabilizing modifications and trimerization motifs. This composite design integrates the immunogenic conserved epitopes with structural elements that ensure proper folding and stability, achieving both broad antibody response and structural integrity
3Adaptability or versatility
If the HA head domain is removed to expose conserved stem epitopes, then cross-reactive immunity is achieved, but the polypeptide stability and expression levels decrease
Solution Approach 1:
The patent introduces stabilizing amino acid substitutions that modify the thermal and structural parameters of the truncated stem polypeptide. These parameter changes compensate for the instability caused by head domain removal, maintaining cross-reactive immunity while ensuring sufficient polypeptide stability for vaccine application
Data Source
AI summary
Provided herein are influenza hemagglutinin stem polypeptides, nucleic acids encoding said polypeptides, vectors comprising said nucleic acid and pharmaceutical compositions comprising the same, as well as methods of their use, in particular in the prevention and/or treatment of influenza virus infections.