Modified Immunogenic Proteins for Germline-Targeted HIV bnAb Priming
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Solution Overview
Problem
Existing HIV vaccines struggle to elicit broadly neutralizing antibodies (bnAbs) due to the high variability and glycan shielding of viral surface proteins, making it difficult to expose conserved protein epitopes for antibody recognition.
Innovation Solution
Development of non-naturally occurring proteins with specific modifications, including germline-targeting designs and trimer stabilization, to prime precursor B cells and guide maturation of bnAbs, using trimer nanoparticles and membrane-anchored immunogens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If viral surface proteins are used as vaccine antigens, then the vaccine can recognize viral structures, but the high variability and glycan shielding prevent effective antibody recognition of conserved epitopes
Solution Approach 1:
The patent extracts and removes the variable and glycan-shielded regions from the viral envelope protein, retaining only the conserved core epitopes that are essential for neutralization. This extraction eliminates the harmful variability and glycan shielding while preserving the functional antigenic determinants, allowing antibodies to access previously hidden conserved regions.
Solution Approach 2:
The patent applies local quality modification by selectively modifying specific regions of the envelope protein while preserving others. The variable regions and glycan-shielded areas are removed or stabilized, while the conserved core epitopes are maintained in their native conformation. This localized modification strategy exposes critical epitopes without compromising the essential antigenic properties needed for bnAb induction.
2Stability of the object's composition
If native envelope proteins are used to maintain natural conformation, then the protein structure is preserved, but the flexibility and variability prevent consistent epitope exposure
Solution Approach 1:
The patent segments the envelope protein into distinct functional domains, separating the conserved core epitopes from the variable extracellular regions. By dividing the protein structure, the patent can stabilize the conserved core while allowing the variable regions to be removed or modified, thereby achieving consistent epitope exposure without compromising the essential conformational integrity of the antigenic determinants.
Solution Approach 2:
The patent applies parameter changes by modifying the structural parameters of the envelope protein, specifically stabilizing the transmembrane and cytoplasmic domains while removing or fixing the variable extracellular loops. This parameter modification approach locks the protein into a conformation that consistently exposes the conserved core epitopes, eliminating the variability present in native proteins while maintaining the essential three-dimensional structure needed for antibody recognition.
3Reliability
If germline-targeting designs are implemented to prime precursor B cells, then the maturation of bnAbs is guided, but the complexity of the immunogen design increases
Solution Approach 1:
The patent applies preliminary action by designing immunogens that pre-target germline precursor B cells with simplified antigen structures. The immunogens are engineered in advance to present conserved epitopes in a conformation that specifically binds to germline-stage B cell receptors, guiding the maturation process from the outset. This preliminary targeting simplifies the overall immunogen design by focusing on a single conserved epitope configuration rather than attempting to present multiple variable regions.
Data Source
AI summary
The invention relates to germline-targeting designs, stabilization designs, and/or combinations thereof, of proteins designed with modified surfaces helpful for immunization regimens, other protein modifications and/or development of nanoparticles, methods of making and using the same, and to (a) germline-targeting priming or boosting/shepherding immunogens to initiate or guide maturation of VRC01-class responses (b) PCT64/PG9-germline-targeting designs (c) BG18-germline-targeting designs or boosting/shepherding immunogens to initiate or guide maturation of BG18-like responses, and/or (d) trimer stabilization and presentation in a membrane-bound format.