Prefusion RSV F Trimer Stabilization for Stronger Infant Immunity
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Solution Overview
Problem
Existing RSV F-based immunogens do not induce a sufficient immune response for preventing severe RSV disease, particularly in infants, and lack stability during heat inactivation.
Innovation Solution
Development of recombinant RSV F proteins through iterative structure-based design, incorporating specific substitutions and disulfide bonds to stabilize the prefusion conformation, enhancing immunogenicity and stability, including a C-terminal trimerization domain for improved antigen presentation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing RSV F-based immunogens are used, then the immune response is elicited, but the response is insufficient for preventing severe RSV disease
Solution Approach 1:
The patent applies parameter changes by modifying the conformational state of the RSV F protein from post-fusion to prefusion through specific amino acid substitutions (155C, 290C, 190F, 207L). This conformational parameter change results in a multi-fold greater neutralizing immune response, directly addressing the insufficient magnitude of immune response while improving effectiveness in preventing severe disease.
Solution Approach 2:
The patent creates a composite immunogen structure by combining the RSV F ectodomain with the DS-Cav1 substitutions and a T4 fibritin trimerization domain. This composite construction stabilizes the prefusion conformation and enhances both the magnitude and quality of the immune response, resolving the contradiction between response magnitude and disease prevention effectiveness.
2Stability of the object's composition
If existing RSV F immunogens are used, then immunogenicity is achieved, but stability during heat inactivation is insufficient
Solution Approach 1:
The patent applies beforehand cushioning by introducing stabilizing disulfide bonds (155C-290C) and cavity-filling substitutions (190F, 207L) into the RSV F protein structure before heat inactivation occurs. These preemptive structural modifications cushion the protein against thermal denaturation, maintaining antigenic stability and immunogenicity even after heat exposure, thus resolving the contradiction between heat stability and overall antigenic stability.
3Productivity
If recombinant RSV F proteins with stabilizing substitutions are developed, then immunogenicity is enhanced, but the complexity of protein engineering increases
Solution Approach 1:
The patent applies segmentation by dividing the RSV F protein into functional domains (ectodomain, transmembrane domain, cytoplasmic tail) and selectively modifying only the ectodomain with specific substitutions (155C, 290C, 190F, 207L). This segmented approach enhances immunogenicity through targeted engineering while avoiding unnecessary complexity in other regions of the protein, resolving the contradiction between improved immunogenicity and engineering complexity.
Data Source
AI summary
Embodiments of a recombinant Respiratory Syncytial Virus (RSV) F ectodomain trimer stabilized in a prefusion conformation are provided. Also disclosed are nucleic acids encoding the RSV F ectodomain trimer and methods of producing the RSV F ectodomain trimer. Methods for inducing an immune response in a subject are also disclosed. In some embodiments, the method can be a method for treating or preventing a RSV infection in a subject by administering a therapeutically effective amount of the recombinant RSV F ectodomain trimer to the subject.