Influenza Hemagglutinin Stem Domain Polypeptides for Broad Strain Protection
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current influenza vaccines are ineffective in providing broad protection against various influenza virus strains due to antigenic drift and shift, leading to limited immunity and the need for annual updates, and they fail to protect against pandemic strains and antiviral resistance.
Innovation Solution
Development of influenza hemagglutinin stem domain polypeptides that lack the globular head domain, presenting conserved epitopes of the stem domain to induce a broad neutralizing antibody response, stabilized by specific mutations and linker sequences, to generate immunity against multiple influenza A and B virus strains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current influenza vaccines target the hemagglutinin head domain, then they induce strong neutralizing antibody responses, but the protection is limited to specific strains due to antigenic drift and shift
Solution Approach 1:
The patent extracts the stem domain from the complete hemagglutinin molecule by removing the variable head domain. This isolation of the conserved stem region eliminates the problem of antigenic variation while preserving the ability to induce neutralizing antibodies, thereby achieving broad cross-strain protection without being limited by drift and shift mutations in the head domain
Solution Approach 2:
The hemagglutinin molecule is segmented into head and stem domains, with the invention focusing specifically on the stem domain (amino acids 276-523 of HA1 and 1-172 of HA2). This segmentation allows the vaccine to target only the conserved region that is essential for viral function and less susceptible to mutation, providing reliable broad-spectrum protection
2Adaptability or versatility
If the hemagglutinin stem domain polypeptide is designed to present conserved epitopes, then broad neutralizing antibody response is induced, but the polypeptide may be unstable and fail to adopt correct conformation
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (e.g., F406S, V409T, L416S, M420I, V421I) into the stem domain polypeptide sequence. These mutations stabilize the polypeptide's three-dimensional conformation and prevent aggregation, ensuring that the conserved epitopes are properly presented to the immune system while maintaining broad neutralizing activity
Solution Approach 2:
The invention creates a composite structure by combining the stabilized stem domain polypeptide with adjuvants and formulation components. This composite approach enhances both the stability of the polypeptide and its immunogenicity, ensuring correct conformation is maintained during storage and delivery while effectively inducing broad neutralizing antibody responses
3Reliability
If seasonal vaccines are updated annually to match circulating strains, then strain-specific immunity is maintained, but protection against pandemic strains and antiviral resistance remains insufficient
Solution Approach 1:
The patent achieves universality by designing a vaccine based on the conserved hemagglutinin stem domain that can protect against multiple influenza A subtypes (H1N1, H3N2, H5N1, H7N9) and influenza B viruses simultaneously. This single vaccine platform provides multi-functional protection against both seasonal and pandemic strains, as well as offering cross-protection against antiviral resistance, eliminating the need for annual updates
Data Source
Figure 1
Figure 2A~2B
Figure 3A~3B
AI summary
The present invention provides influenza hemagglutinin stem domain polypeptides comprising (a) an influenza hemagglutinin HA1 domain that comprises an HA1 N-terminal stem segment, covalently linked by a linking sequence of 0-50 amino acid residues to an HA1 C-terminal stem segment, and (b) an influenza hemagglutinin HA2 domain, wherein on or more amino acids in the HA2 domain have been mutated. Also provided are nucleic acids encoding the polypeptides, compositions comprising the polypeptides and/or nucleic acid molecules, as well as methods of their use, in particular in the detection, prevention and/or treatment of influenza.