Attenuated dengue virus

A dengue virus and protein technology, applied in the direction of viruses, antiviral agents, viruses/bacteriophages, etc., can solve the problems of enhancing DENV vaccine strains and increasing adverse events

Pending Publication Date: 2022-04-08
CODAGENIX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Of note, individuals with latent DENV immunity may experience increased adverse events from live DENV vaccines, as their DENV immunity may enhance the infectivity of DENV vaccine strains, resulting in increased adverse events

Method used

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  • Attenuated dengue virus
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  • Attenuated dengue virus

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0297] Rapid design and construction of SAVE deoptimized live attenuated dengue vaccine candidates. To select our target sequences, we started with all prM-E sequences of all DENV virus isolates from the past decade and performed an amino acid consensus sequence analysis, available in the NCBI virus variant database. Since the consensus sequence usually never exists as an actual virus, it would be unwise to use it as the basis for our design. We prefer natural viral evolution to tell us what works and what doesn't. Therefore, the consensus sequence of each serotype was then searched against the entire Genbank using the tblastn algorithm to identify the actual genome of the replicating virus most identical to the consensus sequence; we then used this sequence as our target sequence. Furthermore, the target sequence must not be unique in the database (possible sequencing artifacts), in which case we chose the sequence with the next highest identity to the consensus sequence rep...

Embodiment 2

[0299] Leveraging the flexibility of the SAVE platform to create second-generation dengue virus vaccine candidates

[0300] To fine-tune attenuation and immunogenicity, a second-generation dengue virus vaccine candidate was constructed using the SAVE platform ( figure 2 ). Second-generation dengue vaccine candidates leverage the flexibility of the SAVE platform to reduce deoptimized regions from 2014bp (E-min) to 997bp (W-E-Min) or further down to 664bp (W-W-E-Min) while maintaining a homologous backbone The amino acid sequences in are 100% identical.

Embodiment 3

[0302] Growth of a heterologous backbone dengue vaccine candidate in Vero cells under animal component-free conditions

[0303] To optimize production conditions for future cGMP production and test attenuation in vitro, DENV1-4 E-Min was used to infect Vero cells at an MOI of 0.01 under animal component-free Supernatants were titrated daily for multi-step growth curves. DENV2, DENV3 and DENV4 candidates reached titers of 1-2 × 10 5 FFU / mL, while DENV1E-Min titers were ~1 log lower compared to other candidates 10 ( image 3 ).

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Abstract

The present invention provides a modified flavivirus, such as a modified type 1, type 2, type 3, type 4 dengue virus, a combination of these viruses, or a tetravalent combination of these viruses. The modifications according to various aspects of the invention result in reduced expression of the viral protein as compared to the parent virus, where the expression reduction is the result of recoding one or more regions of the virus. For example, a prM or envelope (E) region may be recoded. In various embodiments, the one or more regions are recoded by reducing the codon pair preference or codon use preference of the protein coding sequence. These modified flaviviruses are useful as vaccine compositions to provide protective immune responses.

Description

[0001] Cross References to Related Applications [0002] This application includes the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 866,477 filed June 25, 2019, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention provides highly attenuated flaviviruses, particularly attenuated dengueviruses, and vaccines. Attenuated viruses provide protective immunity against challenge by viruses of the same lineage, as well as cross-protection against heterologous viruses. Background technique [0004] Dengue virus (DENV) is a single-stranded positive-sense RNA virus belonging to the Flaviviridae family (Flaviviridae), including Zika virus (ZIKV), West Nile virus (West Nilevirus) in the same genus (Flavivirus, Flavivirus) , WNV) and yellow fever virus (yellow fever virus, YFV). According to the World Health Organization (WHO), approximately 2.5 billion people (nearly half of the world's popu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/12C12N7/00A61K39/00A61P31/14
CPCA61K39/12A61P31/14C12N7/00C12N2770/24134A61K2039/5254C12N2770/24121C12N2770/24162Y02A50/30C12N7/04A61K2039/545C12N2770/24122
Inventor 斯特芬·穆勒约翰·罗伯特·科尔曼查尔斯·斯塔夫王颖
Owner CODAGENIX INC
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