HCMV Polyepitope Protein Conjugated to Glycoprotein B
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Solution Overview
Problem
Current vaccines for Human Cytomegalovirus (HCMV) fail to effectively elicit both cytotoxic T-lymphocyte and neutralizing antibody responses, particularly due to limitations in antigen processing and presentation, which can lead to inadequate immune responses in preventing fetal infection and other clinical challenges.
Innovation Solution
A recombinant protein comprising a polyepitope sequence derived from multiple HCMV antigens conjugated to the extracellular domain of glycoprotein B, designed to elicit both cytotoxic T-lymphocyte and neutralizing antibody responses, is developed. This protein includes a plurality of CTL epitopes and B cell epitopes, optimized for broad HLA coverage and processed efficiently by human cells to stimulate strong immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full-length HCMV antigens are used in vaccine formulations, then the immune response is enhanced, but normal cellular processing is interrupted affecting epitope presentation
Solution Approach 1:
The patent divides full-length HCMV antigens into multiple smaller epitope fragments (peptides) that are linked together in a polyepitope construct. This segmentation allows the vaccine to present multiple immunogenic regions without the problems of full-length antigen processing, enabling effective epitope presentation to both CD8+ and CD4+ T cells while avoiding the cellular processing interruptions that occur with intact viral proteins.
Solution Approach 2:
The patent extracts specific immunogenic epitopes from full-length HCMV antigens and isolates them into a dedicated polyepitope construct. By taking out only the essential T-cell epitopic regions and removing the problematic full-length antigen structure, the vaccine achieves effective immune stimulation without the cellular processing interference that characterizes whole-antigen approaches.
2Device complexity
If a single HCMV antigen is used in subunit vaccines, then the vaccine formulation is simplified, but the immune response coverage is limited
Solution Approach 1:
The patent merges multiple different HCMV epitopes from various viral antigens into a single polyepitope construct. This combining approach allows the vaccine to target multiple viral proteins simultaneously (enhancing immune response coverage and adaptability) while maintaining a unified, relatively simple formulation structure that can be produced and administered as a single vaccine preparation.
Solution Approach 2:
The polyepitope construct is designed to serve multiple immune functions simultaneously: it presents epitopes to both CD8+ cytotoxic T cells and CD4+ helper T cells, targets multiple different HCMV antigens, and can be restricted by various HLA class I and class II molecules. This multi-functionality achieves broad immune coverage without requiring separate vaccine formulations for each antigen or cell type.
3Productivity
If HCMV proteins are expressed to inhibit proteasomal processing, then viral replication is enhanced, but epitope presentation is reduced
Solution Approach 1:
The patent extracts epitopes from the context of full-length viral proteins that contain kinase activities capable of inhibiting proteasomal processing. By isolating just the epitopic sequences into a polyepitope construct, the vaccine eliminates the problematic viral protein structures and enzymatic activities that would otherwise interfere with MHC class I presentation, while retaining the essential T-cell recognition sequences.
Solution Approach 2:
The patent creates an artificial copy of the essential immunogenic information contained in HCMV antigens, but in a simplified polyepitope format that lacks the viral protein structures responsible for inhibiting proteasomal processing. This copied epitopic information maintains T-cell recognition capability while removing the harmful proteasomal inhibition function, enabling effective vaccine-induced epitope presentation.
Data Source
AI summary
An isolated protein construct comprising a polyepitope derived from multiple human cytomegalovirus protein antigen epitopes conjugated to an extracellular domain of glycoprotein B, which isolated protein is capable of eliciting a cytotoxic T-lymphocyte immune response as well as a neutralizing antibody response to human cytomegalovirus. Also provided are pharmaceutical compositions comprising the isolated protein or an adenoviral expression construct for delivery and expression of a nucleic acid encoding the isolated protein for prophylactic and/or therapeutic treatment of human cytomegalovirus infection, particularly in humans.