Prefusion MPV F Protein Stabilization for Vaccine Immunogenicity
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Solution Overview
Problem
Current efforts to develop an MPV F protein-based vaccine have proven unsuccessful due to incorrect structural models of the membrane-distal aspect of the MPV F protein, which is a key target for neutralizing antibodies and vaccine development.
Innovation Solution
A refined structural model of the MPV F protein in its prefusion conformation is developed, allowing for the design and generation of recombinant MPV F proteins stabilized in this conformation, which can be used as immunogens to generate an immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If prior structural models of MPV F protein were used for vaccine development, then vaccine design could proceed, but the structural accuracy was incorrect leading to unsuccessful vaccine development
Solution Approach 1:
The patent applies parameter changes by refining the structural model parameters through re-refinement of deposited structure data (PDB No. 4DAG). This involves adjusting computational parameters and methods to achieve a corrected structural model that accurately represents the prefusion conformation of MPV F protein, thereby resolving the contradiction between model accuracy and vaccine development success
Solution Approach 2:
The patent creates a corrected copy of the previously published structural model through re-refinement processes. This corrected structural model serves as an accurate template for subsequent vaccine design, eliminating the errors present in the original model and enabling successful vaccine development
2Reliability
If recombinant MPV F proteins are designed based on corrected structural model, then immune response can be generated, but protein production and stabilization becomes complex
Solution Approach 1:
The patent applies preliminary action by stabilizing the MPV F protein in its prefusion conformation through site-directed mutagenesis before vaccine application. Specific amino acid substitutions are introduced in advance to lock the protein in the desired conformation, eliminating the need for complex stabilization conditions during subsequent vaccine production and administration
Solution Approach 2:
The patent applies local quality by introducing specific point mutations at particular locations within the MPV F protein sequence. These localized changes (e.g., substitutions at specific residues) modify only the necessary regions to stabilize the prefusion conformation while leaving the rest of the protein structure intact, thereby achieving immune response generation without excessive complexity
Data Source
AI summary
Metapneumovirus (MPV) F proteins stabilized in a prefusion conformation, nucleic acid molecules and vectors encoding these proteins, and methods of their use and production are disclosed. In several embodiments, the MPV F proteins and/or nucleic acid molecules can be used to generate an immune response to MPV in a subject. In additional embodiments, the therapeutically effective amount of the MPV F ectodomain trimers and/or nucleic acid molecules can be administered to a subject in a method of treating or preventing MPV infection.