Influenza B Virus Internal Gene Mutations for High-Titer Vaccine Production
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Solution Overview
Problem
Existing influenza B virus vaccines often fail to match the dominant strain of the season, and there is a need for more efficient and cost-effective production methods to enhance viral titers in cultured cells and embryonated chicken eggs.
Innovation Solution
Introduction of specific mutations in the internal genes and viral glycoproteins HA and NA of influenza B viruses, combined with selected HA and NA genes, to enhance viral growth in cells and eggs, using reassortant or recombinant viruses with amino acid and nucleotide substitutions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional influenza B virus vaccine production methods are used, then vaccine production can proceed with standard processes, but viral titers remain low and production efficiency is poor
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions in the internal genes of influenza B virus (such as PB2, PB1, PA, NP, M, and NS genes) to enhance viral replication efficiency. These genetic parameter modifications result in significantly higher viral titers (up to 10^8 PFU/mL in cultured cells and 10^7 EID50/mL in eggs) compared to wild-type viruses, thereby improving productivity and reducing production time.
2Quantity of substance
If wild-type influenza B viruses are used for vaccine production, then the process is simple and cost-effective, but the viral yield is insufficient for efficient vaccine manufacturing
Solution Approach 1:
The patent utilizes segmentation by working with the eight segmented RNA genes of influenza B virus. Specific internal genes (PB2, PB1, PA, NP, M, NS) are modified with amino acid substitutions while keeping the segmentation structure intact. This approach enables enhanced viral yield through genetic optimization without requiring complete reconstruction of the virus, balancing complexity and productivity.
Solution Approach 2:
The patent applies parameter changes by introducing specific amino acid substitutions in the internal genes of influenza B virus (such as PB2, PB1, PA, NP, M, and NS genes) to enhance viral replication efficiency. These genetic parameter modifications result in significantly higher viral titers (up to 10^8 PFU/mL in cultured cells and 10^7 EID50/mL in eggs) compared to wild-type viruses, thereby improving productivity and reducing production time.
3Reliability
If influenza B virus vaccines are produced using conventional methods, then standard production protocols can be followed, but the vaccines may not match the dominant seasonal strain
Solution Approach 1:
The patent applies preliminary action by pre-modifying the internal genes of influenza B virus with amino acid substitutions that enhance replication efficiency before vaccine production. This preliminary genetic optimization ensures that the virus backbone can efficiently produce high yields of the desired seasonal strain antigens, improving strain matching accuracy while maintaining ease of manufacture through standardized production protocols.
Data Source
AI summary
The invention provides a composition useful to prepare high titer influenza B viruses, e.g., in the absence of helper virus, which includes internal genes from an influenza B virus vaccine strain or isolate, e.g., one that is safe in humans, for instance, one that does not result in significant disease, that confer enhanced growth in cells in culture, such as MDCK cells, or in eggs.