Stabilized Coronavirus Spike Immunogens for Prefusion Vaccine Design
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Solution Overview
Problem
There are no approved therapeutics or vaccines for treating or preventing human-infecting coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2, necessitating the development of effective vaccines.
Innovation Solution
Engineered immunogen polypeptides derived from the spike glycoprotein of coronaviruses with stabilizing mutations, such as inactivating the S1/S2 cleavage site and preventing HR1 and CH helix formation, and displayed on self-assembling nanoparticles like ferritin, E2p, or I3-01, to enhance vaccine efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If wildtype soluble S protein is used, then the protein structure is native and immunogenic, but the structure is metastable and prone to degradation during storage and production
Solution Approach 1:
The patent applies parameter changes by introducing specific point mutations (K986P/V987P, A942P, A944P, S943P) at critical positions in the spike protein structure. These mutations alter local structural parameters to stabilize the prefusion conformation without changing the overall immunogenic properties, resolving the contradiction between stability and immunogenicity
Solution Approach 2:
The patent extracts and removes the HR2 region from the spike protein construct. This extraction prevents HR2-mediated stabilization of the postfusion state, thereby locking the protein in the prefusion conformation and enhancing structural stability while maintaining immunogenicity through the preserved RBD and HR1 regions
2Reliability
If the spike protein is stabilized in prefusion conformation, then vaccine efficacy is enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent applies preliminary action by pre-stabilizing the spike protein in its prefusion conformation through genetic mutations before production. This preliminary structural stabilization simplifies downstream manufacturing processes by reducing aggregation and degradation, thereby enhancing vaccine efficacy without significantly increasing manufacturing complexity
Solution Approach 2:
The patent applies local quality by introducing mutations at specific local positions (K986P, V987P, A942P, A944P, S943P) rather than throughout the entire protein. This localized modification approach maintains overall protein simplicity while achieving the desired stabilization effect, balancing manufacturing feasibility with enhanced vaccine efficacy
3Stability of the object's composition
If mutations are introduced to stabilize the S protein structure, then the prefusion conformation is maintained, but the protein sequence diverges from wildtype
Solution Approach 1:
The patent applies parameter changes by making targeted amino acid substitutions at specific positions (K986P, V987P, A942P, A944P, S943P) that locally alter structural parameters to stabilize the prefusion conformation. These minimal, precise changes maintain high sequence fidelity to wildtype while achieving the desired conformational stability
Solution Approach 2:
The patent applies local quality by limiting mutations to specific critical regions (turn region between HR1 and CH, and positions in HR1) rather than throughout the entire sequence. This localized mutation strategy preserves overall sequence fidelity to wildtype spike protein while achieving preferential stabilization of the prefusion conformation
Data Source
AI summary
The present invention provides redesigned soluble coronavirus S protein derived immunogens that are stabilized via specific modifications in the wildtype soluble S sequences. Also provided in the invention are nanoparticle vaccines that contain the redesigned soluble S immunogens displayed on self-assembling nanoparticles. Polynucleotide sequences encoding the redesigned immunogens and the nanoparticle vaccines are also provided in the invention. The invention further provides methods of using the vaccine compositions in various therapeutic applications, e.g., for preventing or treating coronaviral infections.