Chitosan-Deficient Cryptococcus Vaccine via Inhalation

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Solution Overview

Problem

There is no effective vaccine available against Cryptococcus neoformans and Cryptococcus gattii infections, which are pathogenic fungi causing severe diseases in humans and animals, and current antifungals are inadequate in treating these infections due to toxicity and relapse issues.

Innovation Solution

Development of vaccines using Cryptococcus fungi strains deficient in chitosan production, specifically with deletions in chitin deacetylase and synthase genes, administered via inhalation to induce immunity, including the use of live or heat-killed strains in nasal formulations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current antifungals are used to treat Cryptococcus infections, then the fungus can be killed, but the treatment is inadequate due to inherent toxicities and inability to prevent relapse

Engineering Contradiction:

Improvecure rateVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses the fungus's own chitosan production pathway as a target for vaccination. By deleting chitin deacetylase genes (cda1, cda2, cda3) or chitin synthase genes (chs3), the invention creates attenuated strains that are less virulent but still immunogenic, converting the harmful chitosan production mechanism into a beneficial vaccine target that induces protective immunity without the toxicity of conventional antifungals

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent introduces chitosan-deficient mutant strains as intermediaries between the harmful wild-type fungus and the host immune system. These mutant strains serve as safe vaccine candidates that can induce protective immunity without causing severe disease, acting as mediators that bridge the gap between needing effective antifungal activity and avoiding toxicity

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If no vaccine is available against Cryptococcus infections, then treatment options are limited, but developing effective vaccines is needed to prevent infection and relapse

Engineering Contradiction:

Improveprotection against infectionVSAvoidvaccine development complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the complex problem of Cryptococcus vaccine development by targeting specific genes involved in chitosan production (cda1, cda2, cda3, chs3). By creating mutants with deletions in these individual genes or combinations thereof, the invention systematically reduces virulence while maintaining immunogenicity, breaking down the complex task of vaccine design into manageable genetic modifications

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the biochemical parameters of the fungus by deleting genes involved in chitosan synthesis. This alters the fungal cell wall composition and virulence characteristics, creating strains with modified properties that are suitable for vaccination. The parameter changes in chitosan content directly correlate with reduced virulence and improved safety profile

Inventive Principle:

Principle #35Parameter changes

3Reliability

If chitin deacetylase genes are deleted to reduce chitosan production, then virulence is reduced and immunity is induced, but the strain must be sufficiently attenuated to ensure safety

Engineering Contradiction:

Improveimmunity inductionVSAvoidvirulence

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies partial action by deleting only specific genes (cda1, cda2, cda3, or chs3) involved in chitosan production rather than eliminating all fungal functions. This partial genetic modification is sufficient to reduce virulence and induce immunity while maintaining enough fungal characteristics to serve as effective vaccine antigens, avoiding complete elimination of the organism

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS10092632B2Vaccination against <i>Cryptococcus</i>

Publication Date: 2018.10.09 WASHINGTON UNIV IN SAINT LOUIS

AI summary

Vaccines and methods of inoculation for conferring immunity to Cryptococcus infection are disclosed. Strains of Cryptococcus fungi, including Cryptococcus neoformans and Cryptococcus gattii, can be administered to a human or animal subject via inhalation. Cryptococcus fungi that can be used to confer immunity can comprise one or more mutations in genes that contribute to chitosan production, such as genes encoding a chitin deacetylase (cda), a chitin synthase (chs) and/or a regulator of chitin synthase (csr). Inhalation administration of heat-killed Cryptococcus harboring deletions in cda1, cda2 and cda3 genes can confer immunity. In a murine model system, inhalation administration of Cryptococcus neoformans harboring deletions in cda1, cda2 and cda3 genes conferred immunity against subsequent exposure to wild type Cryptococcus neoformans in 100% of test animals. Inhalation administration of heat-killed Cryptococcus grown under conditions leading to reduced chitosan production can also confer immunity.