Fusion Protein Oligomerization Enhances Immunogenicity
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Solution Overview
Problem
Developing effective antigens for vaccines is challenging due to the need for specific, stable targets that elicit protective immune responses, especially against rapidly mutating pathogens, which requires extensive research and identification of optimal molecular structures.
Innovation Solution
The development of fusion proteins comprising oligomerization, spacer, and antigenic domains, including sequences from flaviviruses, influenza, and SARS-CoV-2, which oligomerize to enhance immunogenicity and include purification tags for ease of use in immunization protocols.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If fusion proteins are designed with specific oligomerization domains and spacer sequences to enhance immunogenicity, then antibody response strength is improved, but protein structure complexity increases
Solution Approach 1:
The fusion protein is divided into distinct functional segments: an oligomerization domain (e.g., ferritin, hepatitis B surface antigen) that self-assembles into stable structures, spacer domains (e.g., (GGGGS)n repeats) that provide flexibility and proper spacing, and antigenic domains from target pathogens. This segmentation allows each component to perform its specific function while maintaining overall structural organization and immunogenicity.
Solution Approach 2:
The invention combines multiple protein domains with different properties into a single fusion protein construct. The oligomerization domain provides stable self-assembly, the spacer domains provide structural flexibility and spacing, and the antigenic domains provide pathogen-specific immunogenicity. This composite approach creates a protein that integrates multiple functions (self-assembly, structural organization, and immune recognition) into one molecule, enhancing overall immunogenicity while maintaining designable complexity.
2Ease of manufacture
If purification tags are added to fusion proteins to enable easy purification, then ease of manufacture is improved, but protein size increases
Solution Approach 1:
A purification tag (such as a polyhistidine tag or other affinity tag) is added to the fusion protein construct, typically at the N- or C-terminus. This tag can be easily removed after purification if needed, as it serves only the temporary function of enabling affinity purification during manufacturing. The tag allows rapid purification through immobilized metal affinity chromatography or other tag-specific methods, significantly simplifying the manufacturing process while adding minimal sequence.
Solution Approach 2:
The purification tag provides a universal solution for purifying diverse fusion proteins regardless of their specific antigenic domain. The same tag sequence can be used across different vaccine candidates, allowing standardized purification protocols and reagents to be applied universally. This multi-functional approach simplifies manufacturing across multiple protein products while the tag itself remains a small, well-characterized sequence.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These fusion proteins induce strong antibody responses capable of neutralizing viruses, as demonstrated by high neutralizing titers in animal models, facilitating effective immunization against various pathogens.
Implementation Method 1
an oligomerization domain having an oligomerization amino acid sequence that oligomerizes with other polypeptides having the oligomerization amino acid sequence
Data Source
AI summary
A fusion protein can include: a series of polypeptide domains starting from an N-terminus or C-terminus, the series of polypeptide domains comprising in order: an oligomerization domain having an oligomerization amino acid sequence that oligomerizes with other polypeptides having the oligomerization amino acid sequence; a first spacer domain having a first spacer amino acid sequence of at least 6 amino acids; an antigenic domain having an antigenic amino acid sequence of an antigen that is immunogenic, wherein the antigen is from one of: Domain III of an envelope glycoprotein of a flavivirus; hemagglutinin of a H5 influenza virus, or receptor binding domain of a SARS-COV-2 virus; a second spacer domain having a second spacer amino acid sequence of at least 6 amino acids; and optionally a purification tag having a purification amino acid sequence that binds with a purification substrate.