Adapted Filovirus Models for Predictive Human Outcomes
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Solution Overview
Problem
Current filovirus models in small mammals, such as guinea pigs and mice, lack predictive value for human outcomes, failing to accurately replicate the severity of filovirus infections and the efficacy of countermeasures, particularly in terms of coagulopathies and vascular leak syndromes.
Innovation Solution
Development of uniformly lethal filovirus strains adapted for virulence in outbred guinea pigs through serial passages and sequencing, focusing on mutations in genes like NP, VP24, and glycoprotein, which are then used to assess candidate drugs' effectiveness by comparing treated and placebo groups for symptoms like fever, weight loss, and coagulopathy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current filovirus models in small mammals are used, then the model system is available for studying filovirus infection, but the models lack predictive value for human outcomes and fail to accurately replicate the severity of filovirus infections
Solution Approach 1:
The patent applies parameter changes by serially passaging filovirus in outbred guinea pigs to select for virulent variants with specific genetic mutations. This evolutionary selection process changes viral parameters (virulence, pathogenicity) to achieve uniform lethality and human-relevant disease features including coagulopathies and vascular leak syndromes, thereby improving predictive value for human outcomes
2Reliability
If filovirus models are adapted for virulence in small mammals, then the models can replicate severe infection features, but the complexity of adapting and characterizing the virus strains increases
Solution Approach 1:
The patent employs self-service by allowing the filovirus to undergo natural evolutionary adaptation through serial passage in outbred guinea pigs. The virus autonomously develops virulent variants with human-relevant pathogenicity features without requiring complex external manipulation, thereby achieving severe infection replication while reducing adaptation complexity
Solution Approach 2:
The patent implements feedback through systematic monitoring and characterization of viral variants during serial passage. By tracking genetic mutations and phenotypic changes, researchers can identify uniformly lethal variants with desired features, creating a feedback loop that guides the adaptation process and reduces overall complexity
3Reliability
If uniformly lethal filovirus strains are developed through serial passages, then the models demonstrate hallmark features of Ebola hemorrhagic fever, but the time and resources required for virus adaptation increase
Solution Approach 1:
The patent applies preliminary action by conducting serial passages of filovirus in outbred guinea pigs before using the adapted strains for therapeutic or vaccine efficacy studies. This pre-adaptation process establishes uniformly lethal variants with human-relevant pathogenicity, ensuring that subsequent experiments use viruses that already exhibit hallmark disease features, thereby reducing the time needed for validation in later studies
Data Source
AI summary
The present invention includes methods of making, and compositions comprising, a uniformly lethal filovirus for outbred small mammals by mutation of the viral genome through serial passages in a small mammal, the method comprising the steps of: obtaining a filovirus strain from a human subject; passing the filovirus strain one or more times by intramuscular injection of one or more filovirus infected tissues into an inbred small mammal until uniform lethality is obtained; passing the filovirus strain in one or more human cell lines; passing the filovirus strain one or more times by intraperitoneal injection of one or more filovirus infected tissues into an outbred small mammal until uniform lethality is obtained; and isolating the uniformly lethal filovirus obtained thereby.