Recombinant Bacteria Expressing Heterologous Proteins in Outer Membrane Vesicles
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Solution Overview
Problem
Current vaccine delivery systems, particularly for mucosal sites, face challenges in preserving antigen integrity and safety, leading to limited availability and effectiveness against intestinal infections, and there is a need for improved delivery methods for therapeutic peptides and proteins that can target mucosal sites without the drawbacks of injection.
Innovation Solution
A recombinant gram-negative commensal gut bacterium, such as Bacteroides thetaiotaomicron, is engineered to express therapeutic peptides, proteins, or antigens in outer membrane vesicles (OMVs) for stable and targeted delivery to mucosal sites, using an inducible expression system to control the production of OMVs containing these molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If injection-based vaccine delivery is used, then vaccine can be delivered effectively, but safety issues arise and mucosal sites remain unprotected
Solution Approach 1:
The patent uses commensal bacteria as intermediary carriers to deliver vaccines to mucosal sites. These bacteria naturally inhabit the gut and can transport the vaccine antigen through the gastrointestinal tract to target mucosal immune cells, avoiding the need for injection while ensuring safe and effective delivery to the intended site.
Solution Approach 2:
The commensal bacteria utilize their natural ability to colonize and traverse the gastrointestinal tract to deliver the vaccine. The bacteria's inherent biological functions are harnessed to perform the delivery task, eliminating the need for invasive injection methods while maintaining effective vaccine delivery to mucosal sites.
2Ease of operation
If oral vaccine delivery systems are used, then mucosal sites can be targeted, but antigen integrity is not preserved during transit through the GI tract
Solution Approach 1:
The commensal bacteria serve as protective intermediaries that carry the vaccine antigen through the harsh gastrointestinal environment. The bacterial cell structure and outer membrane vesicles protect the antigen from degradation by digestive enzymes and acidic conditions, ensuring integrity is maintained during transit to the target site.
Solution Approach 2:
The patent utilizes the bacterial outer membrane and outer membrane vesicles as flexible protective shells. These membrane structures encapsulate and protect the antigen from the harsh gastrointestinal environment, maintaining antigen integrity while allowing the delivery system to navigate the GI tract effectively.
3Stability of the object's composition
If complex delivery systems like polymer microparticles are used, then antigen can be protected, but manufacturing complexity increases
Solution Approach 1:
The commensal bacteria naturally produce outer membrane vesicles as part of their normal biological function. This self-organizing biological process creates protective structures without requiring complex external manufacturing steps, simplifying production while maintaining antigen protection during GI tract transit.
Solution Approach 2:
The patent exploits natural variations in bacterial physiology and outer membrane vesicle formation under different growth conditions. By adjusting cultivation parameters, the bacteria naturally produce optimized vesicles for antigen delivery, eliminating the need for complex purification and encapsulation steps required by synthetic delivery systems.
4Ease of operation
If live attenuated pathogens are used as vectors, then vaccine delivery to mucosal sites is effective, but safety risks arise from reversion and contamination
Solution Approach 1:
The patent extracts and utilizes only the beneficial delivery capabilities of pathogenic bacteria by using harmless commensal species. The dangerous virulence factors are completely removed, retaining only the ability to colonize and deliver antigens to mucosal sites, thereby eliminating reversion and contamination risks while maintaining delivery effectiveness.
Solution Approach 2:
The commensal bacteria are used as single-use, non-replicating delivery vehicles that are safely eliminated after delivering the antigen. This approach avoids the long-term safety concerns associated with live attenuated pathogens, as the commensal bacteria do not persist or revert to virulent forms, eliminating contamination risks.
Data Source
AI summary
This invention relates to the delivery of heterologous peptides or proteins such as therapeutic peptides, therapeutic proteins or antigens to mucosal sites using vesicles derived from the outer membrane of commensal bacteria, recombinant bacteria capable of producing such vesicles, and methods for the production of such vesicles. The invention further relates to an inducible expression system for use in recombinant bacteria.