Nucleoside-Modified RNA for Stable Adaptive Immunity
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Solution Overview
Problem
Current mRNA vaccine development is hindered by issues with mRNA stability, delivery, and immunogenicity, particularly due to innate immune responses against the mRNA itself, leading to poor antibody and CD8+ T-cell responses when administered in vivo.
Innovation Solution
The use of nucleoside-modified RNA, such as pseudouridine or 1-methyl-pseudouridine, encapsulated in lipid nanoparticles (LNPs), to enhance stability and delivery, thereby reducing innate immune activation and improving immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If mRNA is used as a vaccine candidate, then the vaccine can be developed quickly and provided in cytoplasm, but mRNA stability is poor and it triggers innate immune responses
Solution Approach 1:
The patent modifies the chemical structure of mRNA by incorporating nucleoside analogs (pseudouridine, 1-methyl-pseudouridine, 5-methyl-cytidine, 5-hydroxymethyl-cytidine) at specific positions within the mRNA sequence. These parameter changes in nucleoside composition improve mRNA stability and reduce innate immune activation while maintaining translation efficiency, directly resolving the contradiction between rapid development and stability/reliability.
Solution Approach 2:
The patent creates a composite mRNA molecule combining wild-type nucleosides with modified nucleosides in a specific ratio (e.g., 1:4 to 1:9). This composite structure leverages the advantages of both stable natural nucleosides and immunomodulatory modified nucleosides, achieving improved stability and reduced immunogenicity while maintaining vaccine efficacy.
2Ease of operation
If mRNA is administered in vivo, then the vaccine can be delivered directly, but it triggers innate immune responses against the mRNA itself
Solution Approach 1:
The patent converts the harmful effect of mRNA recognition by innate immune systems into a benefit by strategically incorporating modified nucleosides that are recognized as non-pathogenic. The modified nucleosides (pseudouridine, 1-methyl-pseudouridine, etc.) are naturally occurring modifications that when introduced, reduce recognition by pattern recognition receptors, thereby converting potential harmful immune activation into a beneficial reduction of unwanted immune responses while maintaining adaptive immunity.
Solution Approach 2:
By changing the nucleoside composition parameters of the mRNA molecule, the patent alters its interactome with the host immune system. The specific incorporation of modified nucleosides changes the molecular recognition parameters, reducing activation of innate immune pathways while preserving the ability to induce adaptive immune responses against the vaccine antigen.
3Ease of manufacture
If current mRNA vaccine methods are used, then the vaccine can be produced, but antibody and CD8+ T-cell responses are poor
Solution Approach 1:
The patent systematically modifies nucleoside parameters within the mRNA sequence to optimize immunogenicity. By adjusting the type and position of modified nucleosides (pseudouridine, 1-methyl-pseudouridine, 5-methyl-cytidine, 5-hydroxymethyl-cytidine), the patent enhances both antibody and CD8+ T-cell responses while maintaining ease of manufacture through in vitro transcription methods.
Solution Approach 2:
The patent applies local quality modification by introducing modified nucleosides at specific positions within the mRNA sequence rather than uniformly throughout. This localized modification strategy optimizes the balance between translation efficiency and immunogenicity, with different modified nucleosides placed at positions that maximize adaptive immune response while minimizing unwanted effects.
Data Source
AI summary
The present invention relates to compositions and methods for inducing an adaptive immune response in a subject. In certain embodiments, the present invention provides a composition comprising a nucleoside-modified nucleic acid molecule encoding an antigen, adjuvant, or a combination thereof. For example, in certain embodiments, the composition comprises a vaccine comprising a nucleoside-modified nucleic acid molecule encoding an antigen, adjuvant, or a combination thereof.