Treated Gram-Negative Bacteria With Reduced LPS for Immune Activation
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Solution Overview
Problem
Existing TLR agonists used in therapeutic vaccines face challenges of lack of potency and excessive toxicity, limiting their effectiveness in treating viral infections such as hepatitis B and HIV, despite the need for both innate and adaptive immune responses.
Innovation Solution
Treatment of Gram-negative bacteria to reduce LPS-associated endotoxin activity using polymyxin and glutaraldehyde, maintaining bacterial integrity while significantly reducing LPS levels, enhances their ability to induce cytokine secretion from immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type Gram-negative bacteria are administered intravenously, then significant TLR agonist-associated immune responses are induced, but excessive toxicity occurs due to high LPS levels
Solution Approach 1:
The patent extracts and removes LPS (lipopolysaccharide) from Gram-negative bacteria through chemical treatment methods, specifically using polymyxin B and/or glutaraldehyde to reduce LPS levels by at least 50% while maintaining bacterial integrity and other TLR agonists, thereby reducing toxicity while preserving immune response potency
Solution Approach 2:
The patent changes the chemical parameters of the bacterial surface by treating with polymyxin B and/or glutaraldehyde, which modifies the LPS content and structure, reducing endotoxin activity while maintaining the bacteria's ability to stimulate immune responses through other TLR agonists
2Object-affected harmful factors
If LPS levels are reduced in treated bacteria, then systemic toxicity is reduced, but immune response potency may be compromised
Solution Approach 1:
The patent utilizes the multi-functionality of Gram-negative bacteria as a platform that provides multiple TLR agonists simultaneously (TLR2, TLR4, TLR5, TLR9 agonists), where reducing LPS (TLR4 agonist) while maintaining other agonists creates a balanced multi-target immune stimulation that preserves overall potency while reducing specific toxicity pathways
3Reliability
If TLR agonist adjuvants are used in therapeutic vaccines, then immune activation is enhanced, but excessive toxicity and lack of potency are encountered
Solution Approach 1:
The patent creates a composite therapeutic vaccine system that combines TLR agonist-adjuvanted vaccines with treated Gram-negative bacteria (having reduced LPS levels), where the treated bacteria serve as a multi-TLR agonist adjuvant platform that enhances immune activation while maintaining improved safety profile compared to wild-type bacteria
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
The treated bacteria induce higher levels of cytokines than mono-specific TLR agonists with reduced systemic toxicity, effectively inhibiting HBV and HIV infections, even after treatment cessation, and synergistic effects with NSAIDs enhance efficacy.
Implementation Method 1
Treatment of Gram-negative bacteria to reduce LPS-associated endotoxin activity using polymyxin and glutaraldehyde, maintaining bacterial integrity while significantly reducing LPS levels
Implementation Method 2
enhances their ability to induce cytokine secretion from immune cells
Implementation Method 3
Gram-negative bacteria also contain agonists for TLRs 1/2, 5 and 9, which can contribute to both immune system stimulation and systemic toxicity
Data Source
AI summary
The present disclosure relates generally to compositions, dosage forms, and methods for preventing and treating infections. The compositions include intact and substantially non-viable Gram-negative bacterial cells which have been treated to reduce lipopolysaccharide (LPS)-associated endotoxin activity, which surprisingly have increased activity to trigger immune cell production of cytokines.