Headless Hemagglutinin Serial Immunization for Cross-Protective Immunity
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Solution Overview
Problem
Current influenza vaccines primarily induce isolate-specific antibodies, failing to elicit cross-protective antibodies that can neutralize multiple strains and subtypes of influenza viruses due to competition from memory B cells activated by immunodominant epitopes, limiting their effectiveness against antigenic drift and shift.
Innovation Solution
A method involving serial immunization with unique hemagglutinin molecules that expose conserved sites not normally immunogenic, avoiding activation of dominant memory B cells and allowing T cell help for cross-reactive, cross-protective antibody production by administering distinct antigens that share conserved but immunologically distinct sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current influenza vaccines induce isolate-specific antibodies through conventional immunization, then strain-specific protection is achieved, but cross-protective antibody production is suppressed due to competition from memory B cells activated by immunodominant epitopes
Solution Approach 1:
The patent extracts the immunodominant head region of hemagglutinin that causes competitive inhibition of cross-reactive B cells, and removes it from the vaccine antigen. By using only the stem region or headless hemagglutinin, the vaccine eliminates the harmful immunodominant epitopes while preserving the conserved protective epitopes, thereby resolving the contradiction between strain-specific and cross-protective immunity
Solution Approach 2:
The patent applies local quality by modifying specific regions of the hemagglutinin molecule - specifically reducing or eliminating the immunogenicity of the head region while enhancing or preserving the immunogenicity of the stem region. This localized modification allows different parts of the antigen to have different immunogenic properties, enabling cross-protective antibody production without suppressing it through competitive inhibition
2Adaptability or versatility
If memory B cells targeting conserved regions are rare and normally outcompeted by B cells responding to variable epitopes, then cross-reactive antibody production is limited, but serial immunization with unique hemagglutinin molecules can prioritize T cell help for these rare memory B cells
Solution Approach 1:
The patent applies preliminary action by conducting serial immunizations with unique hemagglutinin molecules before the rare cross-reactive memory B cells need to be activated. The first immunization primes the immune system with a unique HA molecule, and subsequent immunizations with different unique HA molecules build up T cell help that preferentially supports cross-reactive B cells, preparing the immune system in advance to produce cross-protective antibodies when needed
Solution Approach 2:
The patent uses periodic action through serial immunizations administered at specific time intervals (e.g., 3-52 weeks apart). This periodic stimulation with unique hemagglutinin molecules allows the immune system to process each antigen separately, building cumulative T cell help that preferentially supports rare cross-reactive memory B cells over time, thereby resolving the contradiction between cross-reactive antibody production and protocol complexity
3Productivity
If conventional vaccines use dominant strain-specific epitopes as immunogens, then strong strain-specific immune response is generated, but cross-protective antibodies are not elicited due to competitive inhibition from dominant memory B cells
Solution Approach 1:
The patent extracts and removes the immunodominant head region of hemagglutinin that generates strong strain-specific responses but inhibits cross-protective antibody production. By using vaccines based on headless hemagglutinin or stem-only regions, the harmful immunodominant epitopes are eliminated while the conserved protective epitopes in the stem region are preserved, resolving the contradiction between immune response strength and cross-subtype protection
Solution Approach 2:
The patent applies local quality by creating vaccines with non-uniform immunogenicity across the hemagglutinin molecule - specifically making the head region immunologically invisible or minimally immunogenic while making the stem region highly immunogenic. This localized differentiation allows the vaccine to generate strong immune responses against conserved stem epitopes without the competitive inhibition from head-region-specific memory B cells, thereby achieving both strong productivity and cross-subtype adaptability
Data Source
AI summary
The present disclosure provides a method of inducing a cross-protective immune response in a subject against a pathogen, such as influenza, comprising administering a first unique pathogen antigen to the subject; and administering a second unique pathogen antigen 3-52 weeks after a); wherein the second unique pathogen antigen and the first unique pathogen antigen are immunologically distinct but share conserved sites that are not normally immunogenic for antibodies. Also disclosed herein are assays for detecting cross-protective antibodies, methods of generating novel cross-protective antibodies. Further provided are novel antibodies against influenza.