Modified RdRp Vaccine Constructs for Stronger MHC I Presentation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for improved vaccines against viral infections, particularly for SARS-CoV-2, as existing vaccines may not effectively stimulate a robust immune response, especially through cytotoxic T lymphocyte (CTL) and Major Histocompatibility Complex (MHC) class I pathways.

Innovation Solution

Recombinant vectors are developed that encode modified RNA-dependent RNA polymerase (RdRp) with fragments, regulatory proteins for proteasomal degradation, or PEST sequences to enhance proteasomal degradation, which are fused or linked to RdRp, to increase MHC class I presentation and immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing vaccines are used, then basic vaccination coverage is achieved, but robust immune response through CTL and MHC class I pathways is insufficient

Engineering Contradiction:

Improveimmune response effectivenessVSAvoidCTL and MHC class I pathway stimulation

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent modifies the RdRp protein structure by fusing it with PEST sequences and regulatory proteins, changing its degradation parameters to enhance proteasomal processing. This structural modification transforms the antigen's ability to stimulate MHC class I presentation, thereby improving CTL response effectiveness without requiring entirely new vaccine platforms.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite antigen construct by fusing RdRp with PEST sequences and regulatory proteins. This composite structure combines the viral antigenic properties of RdRp with the degradation-enhancing properties of PEST sequences, resulting in improved immunogenicity through enhanced proteasomal degradation and MHC class I presentation.

Inventive Principle:

Principle #40Composite materials

2Reliability

If RdRp is modified with PEST sequences and regulatory proteins, then proteasomal degradation and MHC class I presentation are enhanced, but vaccine complexity increases

Engineering Contradiction:

ImproveMHC class I presentation efficiencyVSAvoidvaccine construct complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The PEST sequences and regulatory proteins are pre-fused to the RdRp antigen in the vaccine construct design phase. This preliminary incorporation ensures that once the vaccine is administered, the antigen is automatically directed toward proteasomal degradation pathways without requiring additional in vivo processing steps or complex delivery mechanisms, thereby simplifying the overall vaccine system despite the modified antigen structure.

Inventive Principle:

Principle #10Preliminary action

3Productivity

If proteasomal degradation is enhanced through regulatory proteins, then antigen processing for MHC class I is improved, but protein stability decreases

Engineering Contradiction:

Improveantigen processing efficiencyVSAvoidRdRp protein stability

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The PEST sequence-modified RdRp antigen is designed to be inherently unstable and rapidly degraded after vaccination. This short-lived antigen design is advantageous because it mimics natural viral protein turnover, provides strong initial immunogenicity signals, and reduces the risk of autoimmune reactions. The antigen performs its immunostimulating function effectively before being degraded, making its brief presence sufficient for achieving the desired immune response.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The recombinant vectors significantly enhance MHC class I presentation and CTL response, thereby improving the immune response to SARS-CoV-2, making them more effective in protecting against viral infections.

Implementation Method 1

RdRp and a regulatory protein that enhances proteasomal degradation, wherein the RdRp is conjugated or fused to the regulatory protein directly or indirectly via a linker

Methodology Applied

Scientific EffectProteasomal degradation: Decomposition (biological)

Implementation Method 2

RdRp and a peptide sequence rich in proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST sequence) that enhances proteasomal degradation

Methodology Applied

Scientific EffectProteasomal degradation: Decomposition (biological)

Implementation Method 3

increase MHC class I presentation and immune response

Methodology Applied

Scientific EffectMHC class I presentation:

Data Source

PatentUS20250352641A1Methods to increase immunogenicity of rdrp

Publication Date: 2025.11.20 UNIV OF PITTSBURGH OF THE COMMONWEALTH SYST OF HIGHER EDUCATION

AI summary

Disclosed are recombinant vectors comprising one or more polynucleotides encoding at least one modified ribonucleic acid (RNA) dependent RNA polymerase (RdRp), as well as pharmaceutical compositions and methods of their use.