Cleavage-Resistant RSV G Protein Mutants
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Solution Overview
Problem
Current vaccines for respiratory syncytial virus (RSV) face challenges, including the issue of protease cleavage of the G protein, which reduces the effectiveness of live, attenuated vaccines produced in Vero cells, leading to lower infectivity and increased costs due to the need for higher doses to induce an immune response.
Innovation Solution
Development of RSV with cleavage-resistant mutated attachment (G) glycoproteins that are more resistant to protease cleavage, allowing for increased production and formulation into immunogenic compositions, such as vaccines, which can induce an effective immune response with reduced inoculum volume and improved infectivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If live, attenuated RSV vaccines are produced in Vero cells, then vaccine production is achieved, but the G protein undergoes protease cleavage which reduces infectivity and requires higher doses
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the G protein at the protease cleavage site. Specifically, it replaces basic amino acids (lysine or arginine) with non-basic amino acids to prevent protease recognition and cleavage. This chemical parameter change in the protein structure maintains full-length G protein integrity during Vero cell production, thereby preserving vaccine infectivity while enabling efficient production.
2Reliability
If higher doses of vaccine are administered to compensate for G protein cleavage, then immune response is achieved, but the volume of vaccine required increases leading to higher costs
Solution Approach 1:
By changing the amino acid parameters at the cleavage site to prevent proteolytic processing, the patent ensures that the G protein remains in its full-length, immunogenic form. This eliminates the need to administer higher doses to compensate for cleavage-induced loss of immunogenicity, thereby reducing the quantity of vaccine material required per dose while maintaining effective immune response.
3Ease of manufacture
If protease cleavage of G protein occurs during vaccine production, then vaccine can be manufactured, but the cleaved G protein has reduced immunogenicity requiring more complex formulations
Solution Approach 1:
The patent simplifies the formulation by preventing protease cleavage through amino acid parameter changes. This ensures that the G protein remains intact without requiring additional formulation steps to stabilize or compensate for cleaved fragments, thereby reducing formulation complexity while maintaining ease of manufacture.
Data Source
AI summary
Embodiments disclosed herein provide compositions, methods, and uses for respiratory syncytial viruses (RSV) and immunogenic compositions thereof. Certain embodiments provide RSV having cleavage-resistant mutated attachment (G) glycoproteins. In some embodiments, the cleavage-resistant G protein mutants increase production of live attenuated RSV in host cells. Also provided are methods for amplifying RSV in host cells, wherein the amplified RSV has full length G protein. In certain embodiments, the amplified RSV having full length G protein is formulated into immunogenic compositions, including vaccines. Other embodiments provide methods for inducing an effective immune response against RSV infection in a subject.