Actinobacillus pleuropneumoniae Vaccine Strain Engineering

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Solution Overview

Problem

Current vaccines against Actinobacillus pleuropneumoniae (APP) lack satisfactory safety and efficacy profiles, particularly in providing cross-protection against heterologous serotypes and are costly to produce, with existing live attenuated and inactivated whole cell vaccines posing safety risks and subunit vaccines having limited immunogenicity due to toxin inactivation methods.

Innovation Solution

Development of APP strains expressing non-functional forms of ApxIA, ApxIIA, and ApxIIIA toxins, integrated into the chromosome using two-step natural transformation, allowing for a single live attenuated vaccine strain that induces antibodies against all known serovars and streamlines vaccine production for all three toxins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If chemically inactivated whole cell vaccines are used, then production is simplified, but immunogenicity is limited and cross-protection is insufficient

Engineering Contradiction:

Improvevaccine production simplicityVSAvoidimmunogenicity and cross-protection

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent extracts the Apx toxin genes (apxI, apxII, apxIII) from the APP genome and transfers them into a safe vaccine strain. This extraction of specific virulence factors allows the vaccine to provide targeted immunogenicity without the limitations of whole cell vaccines, enabling cross-protection against multiple serotypes while simplifying production compared to producing multiple separate vaccines.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent creates a universal vaccine strain that expresses multiple Apx toxin types (ApxI, ApxII, ApxIII) simultaneously. This multi-functional approach allows a single vaccine to provide cross-protection against all APP serotypes that produce these toxins, eliminating the need for separate vaccines for different serotypes and resolving the contradiction between production simplicity and immunogenicity breadth.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If live attenuated vaccines are used, then immunogenicity is improved, but safety risks increase due to virulence

Engineering Contradiction:

ImproveimmunogenicityVSAvoidvirulence and safety risks

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful Apx toxin genes into a benefit by transferring them into a safe vaccine strain. The same genes that cause disease in virulent strains are used to create immunogenicity in a safe strain, transforming the harmful factors into protective antigens. This resolves the contradiction by using the virulence factors themselves as vaccines in a controlled, safe context.

Inventive Principle:

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

Solution Approach 2:

The patent uses a safe APP strain as an intermediary vehicle to deliver the Apx toxin genes. This intermediary strain serves as a safe host that can express the virulence factors without causing disease, acting as a mediator between the harmful toxin genes and the vaccine application. The safe strain mediates the expression of protective antigens without the safety risks of using naturally virulent strains.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If subunit vaccines with chemically inactivated toxins are used, then safety is improved, but immunogenicity decreases due to denaturation

Engineering Contradiction:

Improvetoxin toxicityVSAvoidimmunogenicity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent uses a live bacterial cell as an intermediary carrier to present the Apx toxins in their native, immunogenic form. Instead of directly using chemically inactivated toxins that lose immunogenicity, the bacterial intermediary expresses and presents the toxins naturally, maintaining both safety (through controlled expression) and immunogenicity (through native protein structure).

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the state of the Apx toxins from chemically inactivated (denatured) to naturally expressed by the bacterial system. This parameter change in the physical-chemical state of the toxins maintains their native conformation and immunogenicity while controlling their expression through the safe vaccine strain, resolving the contradiction between safety and immunogenicity.

Inventive Principle:

Principle #35Parameter changes

4Reliability

If multiple separate vaccines are produced for different serotypes, then cross-protection is improved, but production cost and complexity increase

Engineering Contradiction:

Improvecross-protection coverageVSAvoidvaccine production complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges multiple Apx toxin genes (apxI, apxII, apxIII) into a single vaccine strain, combining the protective antigens for multiple serotypes into one product. This consolidation provides cross-protection against all APP serotypes that produce these toxins through a single vaccine, eliminating the need for multiple separate vaccines and reducing production complexity while maintaining broad cross-protection coverage.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20230322870A1Actinobacillus pleuropneumoniae vaccines

Publication Date: 2023.10.12 IMPERIAL COLLEGE INNVOATIONS LTD

AI summary

The present invention relates to microorganisms comprising each of each of an ApxIA, ApxIIA and ApxIIIA toxin, related vaccines and methods of production thereof, as well as uses thereof for the immunisation and protection of mammals.