NA Mutations Stabilize HA in Recombinant Influenza Viruses for Egg Growth
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Solution Overview
Problem
Influenza vaccines produced in embryonated chicken eggs often acquire egg-adapting mutations in the hemagglutinin (HA) protein, altering antigenicity and reducing their effectiveness against circulating virus strains.
Innovation Solution
Introduce specific mutations in the neuraminidase (NA) protein to stabilize the HA protein during egg-passages, preventing HA mutations and enhancing vaccine virus yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If influenza viruses are passaged in embryonated chicken eggs for vaccine production, then vaccine virus yield is improved, but the HA protein acquires egg-adapting mutations that alter antigenicity and reduce effectiveness
Solution Approach 1:
The patent applies preliminary action by introducing specific mutations in the NA protein (such as T148K, D151E, H347G, T369K) before egg passage. These pre-introduced mutations stabilize the HA protein during subsequent egg passages, preventing the acquisition of egg-adapting mutations that would otherwise alter antigenicity. This allows the virus to be passaged in eggs for high yield while maintaining HA protein stability and antigenic integrity.
2Reliability
If serial passages in eggs are performed to allow virus adaptation, then efficient growth in eggs is achieved, but HA mutations occur that compromise antigenicity
Solution Approach 1:
The patent applies parameter changes by modifying the NA protein sequence (introducing specific amino acid substitutions) to change the biological parameters of virus stability and replication fidelity. These NA mutations alter the virus's interaction with the egg environment, enabling efficient growth while maintaining HA protein stability and preventing antigenic drift during passage.
3Productivity
If the virus is adapted to grow efficiently in eggs, then vaccine production is improved, but the HA protein undergoes mutations that reduce vaccine effectiveness
Solution Approach 1:
The patent uses the NA protein as an intermediary to mediate between the requirement for efficient egg growth and the need to maintain HA antigenic stability. By introducing specific mutations in NA (such as T148K, D151E, H347G, T369K), the NA protein acts as a mediator that enables efficient replication in eggs while simultaneously stabilizing the HA protein against egg-adapting mutations, thus preserving vaccine effectiveness.
Data Source
AI summary
Modified influenza virus neuraminidases are described herein that improve viral replication, thus improving the yield of vaccine viruses. Expression of such modified neuraminidases by influenza virus may also stabilize co-expressed hemagglutinins so that the hemagglutinins do not undergo mutation.