Split RNA Replicon Architecture for Lower-Dose Multivalent Vaccines
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Solution Overview
Problem
Current mRNA vaccines face challenges in balancing high administration doses with adverse effects, require prime-boost vaccinations, and necessitate cold-chain storage, while self-amplifying RNA (saRNA) vaccines encounter issues with production, delivery, and stability due to very long RNA sequences.
Innovation Solution
A split replicon system comprising a cisreplicon encoding replicase and transreplicon encoding the gene of interest (GOI), where the GOI is inserted in the non-structural protein region, utilizing the same molecular chassis for both, allowing self-amplification and trans-amplification, respectively, to facilitate rapid and efficient expression of immunogens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If self-amplifying RNA (saRNA) vaccines are used to reduce administration dose, then the required RNA dose is reduced, but the RNA sequence length becomes very long causing production, delivery, and stability issues
Solution Approach 1:
The patent divides the saRNA vaccine into two separate RNA components: a replicase RNA (encoding the RNA-dependent RNA polymerase) and a GOI RNA (encoding the gene of interest). The replicase RNA contains the 5' UTR, 3' UTR, and replicase coding sequence, while the GOI RNA contains the 5' UTR, 3' UTR, and GOI coding sequence. This segmentation reduces the complexity of individual RNA molecules while maintaining the self-amplifying capability through trans-replication.
2Ease of manufacture
If conventional mRNA vaccines are used, then production and delivery are simpler, but high administration doses are required which cause adverse effects
Solution Approach 1:
The patent employs self-amplifying RNA technology where the replicase RNA encodes an RNA-dependent RNA polymerase that automatically replicates the GOI RNA within host cells. This self-service mechanism amplifies the gene of interest without requiring additional external intervention or high initial doses, thereby reducing adverse effects while maintaining production simplicity.
3Productivity
If saRNA vaccines are used to achieve rapid amplification, then expression of immunogen is enhanced, but storage and stability issues arise
Solution Approach 1:
By segmenting the saRNA into replicase RNA and GOI RNA, the patent reduces the molecular complexity and potential secondary structures in each individual RNA molecule. This segmentation improves storage stability while maintaining the rapid amplification capability, as the separate RNA components are easier to stabilize and store without compromising their functional interactions.
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 system enables rapid and efficient expression of multiple immunogens with reduced RNA load, overcoming storage and stability issues, and allowing for rapid development of personalized cancer vaccines and multivalent vaccines.
Implementation Method 1
a first positive sense RNA, herein identified as self-amplifying (sa)RdRp-RNA, encodes a functional RNA-dependent RNA polymerase (RdRp)-gene derived from said virus and allows self-amplification in cis by said RdRp derived from said first RNA, and wherein at least a second (positive or negative sense) RNA, herein identified as GOI-RNA
Data Source
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AI summary
The invention embraces an advantageous split replicon system allowing easy, plug-and-play, multivalency of RNA-therapeutics as well as RNA-vaccines. The system as provided herein comprises combining essentially purified RNA derived from a positive strand RNA virus and encoding self-amplifying or self-replicating RdRp in a split-replicon fashion with one or more essentially purified RNAs having a GOI, or different GOIs inserted in the area of the RdRp-gene(s), and preferably structurally deleting viral structural proteins by avoiding use of nucleic acid encoding said structural protein(s) all together, and therewith rendering the system small, versatile, safe and propagation defective.