Ferritin Nanoparticle HA Stem Trimer Vaccine Design

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Solution Overview

Problem

Current influenza vaccines face challenges such as strain-specific efficacy, limited production capacity, and the inability to induce robust, broadly neutralizing antibodies against the conserved HA stem region.

Innovation Solution

Development of novel nanoparticle-based vaccines that express modified influenza HA stem-region proteins in the pre-fusion conformation, fused to ferritin nanoparticles, to elicit broadly neutralizing antibodies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If conventional influenza vaccines target the globular head region of HA protein, then they can induce antibodies against immunodominant epitopes, but the antibodies are strain-specific and cannot neutralize antigenically distinct viruses

Engineering Contradiction:

Improvebroad neutralization capabilityVSAvoidstrain-specific efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent extracts the conserved stem region from the variable globular head of the HA protein, creating a truncated HA construct (HA1-HA2) that displays only the stem region. This extraction eliminates the strain-specific variable regions while preserving the conserved neutralizing epitopes, enabling broad cross-subtype neutralization

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies local quality by stabilizing specific regions of the HA stem with mutations (e.g., K394M, E446L, E448Q, R449W, D452L) to lock the protein in a pre-fusion conformation. This localized stabilization enhances the immunogenicity of the conserved stem region while maintaining the overall structure's ability to elicit broadly neutralizing antibodies

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If the HA stem region is targeted for vaccine development, then broadly neutralizing antibodies can be elicited, but the conserved stem region is not very immunogenic compared to the immunodominant head

Engineering Contradiction:

Improvebroad neutralization capabilityVSAvoidimmunogenicity

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent changes the conformational parameter of the HA stem by introducing stabilizing mutations that lock the protein in a pre-fusion state. This parameter change increases the immunogenicity of the stem region by presenting a more stable and accessible epitope configuration to the immune system, thereby enhancing antibody elicitation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite structure by fusing the stabilized HA stem region with the ferritin nanoparticle carrier. This composite material combines the immunogenic properties of the pre-fusion stem with the adjuvant and presentation advantages of the ferritin nanoparticle, significantly enhancing the overall immunogenicity and broad neutralization capability

Inventive Principle:

Principle #40Composite materials

3Adaptability or versatility

If traditional influenza vaccines are updated annually to reflect predicted HA and neuraminidase, then they can address seasonal variants, but they cannot protect against antigenic shift and pandemic viruses

Engineering Contradiction:

Improveprotection against diverse strainsVSAvoidvaccine update time

Core Design Contradiction:

Adaptability or versatilityVSLoss of time

Solution Approach 1:

The patent develops a universal vaccine platform based on the conserved HA stem region that can protect against multiple influenza subtypes (H1N1, H3N2, H5N1, H7N9) simultaneously. This multi-functional approach eliminates the need for annual updates by providing cross-subtype protection through a single vaccine formulation targeting the invariant stem region

Inventive Principle:

Principle #6Universality (Multi-functionality)

4Adaptability or versatility

If the HA protein is stabilized in pre-fusion conformation, then broadly neutralizing antibodies can be elicited, but the manufacturing process becomes more complex

Engineering Contradiction:

Improvebroad neutralization capabilityVSAvoidmanufacturing complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent incorporates stabilizing mutations (K394M, E446L, E448Q, R449W, D452L) directly into the HA gene sequence during the design phase. This preliminary action locks the HA protein in the desired pre-fusion conformation, ensuring that the protein maintains its immunogenic structure throughout production, purification, and storage without requiring complex post-manufacturing stabilization steps

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12268737B2Stabilized influenza hemagglutinin stem region trimers and uses thereof

Publication Date: 2025.04.08 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

Vaccines that elicit broadly protective anti-influenza antibodies. Some vaccines comprise nanoparticles that display HA trimers from influenza virus on their surface. The nanoparticles are fusion proteins comprising a monomeric subunit (e.g., ferritin) joined to the stem region of an influenza HA protein. The fusion proteins self-assemble to form the HA-displaying nanoparticles. The vaccines comprise only the stem region of an influenza HA protein joined to a trimerization domain. Also provided are fusion proteins, and nucleic acid molecules encoding such proteins, and assays using nanoparticles of the invention to detect anti-influenza antibodies.