Native OMV Antigen Conjugation via Bivalent Linker
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Solution Overview
Problem
Existing methods for conjugating antigens to carriers, such as Outer Membrane Protein Complex (OMPC), face challenges in obtaining pure native outer membrane vesicles (nOMVs) and require detergent use, which alters surface proteins and complicates antigen conjugation, leading to aggregation issues and limited selection of suitable linkers for vesicle and antigen coupling.
Innovation Solution
The development of a method using native, detergent-free outer membrane vesicles (nOMVs) for conjugation with antigens through a bivalent linker, allowing for selective connection of surface saccharides and proteins, avoiding vesicle aggregation and enabling multi-functionalization without cross-linking issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If detergent extraction is used to obtain outer membrane vesicles, then vesicle purity is improved, but surface protein composition is altered and aggregation issues occur
Solution Approach 1:
The patent extracts and removes detergents from the vesicle preparation process, obtaining native outer membrane vesicles without detergent extraction. This eliminates the harmful effect of detergent-induced protein alteration while maintaining vesicle integrity and surface protein composition.
Solution Approach 2:
The patent converts the previously harmful detergent extraction step into a beneficial native vesicle isolation method. By avoiding detergent use, the natural surface protein composition is preserved, transforming a harmful process into a beneficial one that maintains immunogenicity.
2Manufacturing precision
If bivalent heterobifunctional linkers are used for antigen conjugation, then selective reaction is improved, but linker selection and functionalization complexity increases
Solution Approach 1:
The patent employs a universal bivalent homobifunctional linker that can react with both the vesicle surface protein and the antigen using identical functional groups. This eliminates the need for complex heterobifunctional linker selection while maintaining conjugation selectivity through the native vesicle surface chemistry.
Solution Approach 2:
The patent changes the linker functional group parameters from heterobifunctional to homobifunctional, using identical reactive groups (e.g., both ends with amine or thiol groups) that can react with complementary groups on both the vesicle and antigen, simplifying the selection process while maintaining specificity.
3Ease of manufacture
If conventional conjugation methods are used, then antigen carrier conjugation is achieved, but vesicle aggregation and side products form
Solution Approach 1:
The patent uses a bivalent linker as an intermediary that bridges the vesicle surface protein and the antigen without causing aggregation. The linker mediates the conjugation reaction while maintaining vesicle dispersion and preventing harmful side products through controlled monovalent attachment.
4Adaptability or versatility
If multiple antigens are conjugated to nOMV, then multivalent vaccine capability is improved, but conjugation process complexity increases
Solution Approach 1:
The patent segments the conjugation process into independent steps for each antigen, using the bivalent linker to sequentially attach different antigens to the vesicle surface. This segmentation allows multivalent vaccines to be constructed through a systematic, manageable process rather than a complex simultaneous conjugation.
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
This approach results in immunogenic nOMV-antigen conjugates that maintain native protein conformation, improve immunogenicity, and simplify the conjugation process, providing a reliable and efficient method for producing multivalent vaccines with enhanced immune response.
Implementation Method 1
having at least a surface saccharide moiety connected to at least a foreign antigen
Implementation Method 2
having at least a surface protein residue connected to at least a different foreign antigen through a bivalent Linker
Implementation Method 3
activating at least a nOMV saccharide moiety, generally bond to the nOMV surface
Data Source
AI summary
The present invention is in the field of conjugating native, non-detergent extracted, outer membrane vesicles (nOMV) to multiple antigens to form multi functionalized nOMV-antigen conjugated derivatives, which are particularly useful for immunogenic compositions and immunisation; processes for the preparation and use of such conjugates are also provided.