Doubly Attenuated Malaria Parasites for Sterile Immunity

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Solution Overview

Problem

Current methods for creating attenuated malaria parasites for vaccine development face challenges in achieving complete attenuation at the late liver stage without causing aberrant transmission or progression to blood stages, and identifying specific genetic modifications for human malaria parasites like P. falciparum has been difficult.

Innovation Solution

Genetically modifying Plasmodium organisms to disrupt both the PlasMei2 and LISP2 genes using CRISPR/Cas9 technology, resulting in complete attenuation at the late liver stage and preventing progression to the blood stage, while allowing healthy development and antigen presentation for enhanced immune stimulation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Plasmodium parasites are genetically modified to arrest early in the liver stage, then complete attenuation is achieved, but immunogenicity is reduced due to limited antigen presentation

Engineering Contradiction:

Improvecomplete attenuationVSAvoidimmunogenicity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the parameter of arrest timing from early liver stage to late liver stage by modifying specific genes (e.g., pfCSP, pfSeryl-tRNA synthetase), allowing the parasite to present more antigens while remaining attenuated. This parameter optimization resolves the contradiction between complete attenuation and immunogenicity.

Inventive Principle:

Principle #35Parameter changes

2Ease of manufacture

If Plasmodium parasites are allowed to develop fully to blood stage, then maximum antigen presentation occurs, but complete attenuation is lost and blood stage infection ensues

Engineering Contradiction:

ImproveimmunogenicityVSAvoidcomplete attenuation

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent extracts specific essential genes (e.g., pfCSP, pfSeryl-tRNA synthetase) from the parasite genome, which are critical for completing the full life cycle. By removing these specific genetic elements, the parasite can develop to late liver stage for antigen presentation but cannot progress to blood stage, thus resolving the contradiction between immunogenicity and complete attenuation.

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If radiation attenuation is used to create attenuated sporozoites, then complete attenuation is achieved, but batch consistency and reproducibility are compromised

Engineering Contradiction:

Improvecomplete attenuationVSAvoidbatch consistency

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent replaces the mechanical/physical method of radiation attenuation with a precise genetic engineering approach. By using targeted gene disruption methods (e.g., CRISPR/Cas9, homologous recombination) to knock out specific genes, the invention achieves reproducible and consistent attenuation across batches, eliminating the variability inherent in radiation methods while maintaining complete attenuation.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS11529404B2Doubly attenuated late liver stage malaria parasites and related compositions and methods

Publication Date: 2022.12.20 SEATTLE CHILDRENS HOSPITAL (DBA SEATTLE CHILDRENS RES INST)

AI summary

The disclosure relates to doubly attenuated malaria parasites that have had the functionality of LISP2 and PlasMei2 genes interrupted through genetic manipulation. The double attenuated malaria parasites disclosed herein are useful for methods and compositions for stimulating of vertebrate host immune systems because of the complete cessation of lifecycle progression in the late liver stage, while providing a comprehensive antigenic presentation representing wildtype liver stage parasites. The disclosure also relates to the additional blood stage and gametocyte antigens to compositions of genetically attenuated malaria parasites (GAPs) to enhance efficient immune stimulation and prevention of disease and transmission related to the presence of blood stage parasites.