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Engineered respiratory syncytial viruses with control of cell-to-cell virus transmission for enhanced safety of live virus vaccines

a technology of respiratory syncytial viruses and cell-to-cell virus transmission, which is applied in the field of vaccines against diseases caused by paramyxoviridae viruses, can solve the problems of large amount of antigen production, and achieve the effect of high levels of rsv antigens

Inactive Publication Date: 2014-07-24
BOARD OF REGENTS FOR OKLAHOMA STATE UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a new system for designing a live vaccine that controls the production and transmission of viral cells. By controlling cell-cell transmission, the system ensures that the live vaccine virus does not spread too quickly or cause excessive damage. The patent also explains a method for identifying mutations in a protein that affect the production of infectious viral particles. Overall, this patent provides new tools for developing safer and effective live vaccines.

Problems solved by technology

Thus, normal or above normal levels of replication / transcription by viruses expressing modified M proteins results in the production of large amounts of antigens when the virus infects host cells.
However, because cell-to-cell transmission of the virus is impaired or controlled, the development of a full blown viral infection (including dissemination within the lung) is precluded (or at least lessened), making the vaccine safe for administration.

Method used

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  • Engineered respiratory syncytial viruses with control of cell-to-cell virus transmission for enhanced safety of live virus vaccines
  • Engineered respiratory syncytial viruses with control of cell-to-cell virus transmission for enhanced safety of live virus vaccines
  • Engineered respiratory syncytial viruses with control of cell-to-cell virus transmission for enhanced safety of live virus vaccines

Examples

Experimental program
Comparison scheme
Effect test

example 1

REFERENCES FOR EXAMPLE 1

[0106]1. Bachi, T., and C. Howe. 1973. Morphogenesis and ultrastructure of respiratory syncytial virus. J Virol 12:1173-80.[0107]2. Batonick, M., A. G. Oomens, and G. W. Wertz. 2008. Human respiratory syncytial virus glycoproteins are not required for apical targeting and release from polarized epithelial cells. J Virol 82:8664-72.[0108]3. Batonick, M., and G. W. Wertz. 2011. Requirements for Human Respiratory Syncytial Virus Glycoproteins in Assembly and Egress from Infected Cells. Adv Virol 2011.[0109]4. Bitko, V., A. Oldenburg, N. E. Garmon, and S. Batik. 2003. Profilin is required for viral morphogenesis, syncytium formation, and cell-specific stress fiber induction by respiratory syncytial virus. BMC Microbiol 3:9.[0110]5. Branigan, P. J., C. Liu, N. D. Day, L. L. Gutshall, R. T. Sarisky, and A. M. Del Vecchio. 2005. Use of a novel cell-based fusion reporter assay to explore the host range of human respiratory syncytial virus F protein. Virol J 2:54.[011...

example 2

Scan Mutations of M Protein

[0167]FIG. 6 shows the nucleotide sequence encoding the unmodified M gene from RSV A2 strain (FIG. 6A) and the sequence of the codon-optimized M gene used to generate M-expressing cells (FIG. 6B). FIG. 7 shows the amino acid sequence of unmodified M protein from the RSV A2 strain.

[0168]Scan mutation assays, which replace selected amino acids in the primary sequence of a protein with different amino acids, usually sequentially along the length of the protein sequence, are known in the art and are used to identify sections of the protein that are required or important for activity. FIGS. 8A and B show exemplary mutants of M protein derived by inserting an epitope of 9 amino acids in a scanning fashion at various positions along the length of the M protein.

[0169]As recognized in the art, alanine scanning mutations are a more specific type of scanning assay. In this method, each (or selected) amino acid residues of a protein sequence of interest are replaced w...

example 3

[0173]In Examples 1 and 2, a system was used to test mutant M protein in which a recombinant attenuated virus with a “first generation” mutant M-null protein also expressed a tet transactivating protein, and induction of expression of M was carried out in a cell line carrying the M gene under control of tet-responsive elements (TRE). The first generation M-null construct to is depicted schematically in FIG. 11 (see middle section of figure). In this system, the M protein is expressed from the plasmids in all cells after induction with doxycyclin, whether or not virus from a mutant M sequence is replicating in the cells, resulting in cytotoxic effects to the cell culture prior to the viral exploitation of the cell for amplification of the mutant M protein. The titers obtained in such systems are generally low (−105 PFU / ml) and the cytotoxic effect on H2-M cells is most likely the reason, or one of the reasons, underlying the low titers. The problems / challenges of the first generation...

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Abstract

Highly antigenic yet safe vaccines against diseases caused by Paramyxoviridae viruses such as respiratory syncytial virus (RSV) are provided. The vaccines comprise attenuated Paramyxoviridae viruses with high antigenicity but which display impaired cell-to-cell transmission as a result of genetic manipulation of the gene encoding the matrix (M) protein. In the viruses, the M protein is absent or mutated to a less active form. Screening or assay systems and methods for evaluating the infectivity of mutant M proteins and for identifying suitable M candidates for live-attenuated vaccine virus and VLP production, are also provided.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 492,261 filed Jun. 1, 2011, herein incorporated by reference in its entirety for all purposes.SEQUENCE LISTING[0002]This application includes as the Sequence Listing the complete contents of the accompanying text file “Sequence.txt”, created Jun. 1, 2011, containing 64,808 bytes, hereby incorporated by reference.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention generally relates to vaccines against diseases caused by Paramyxoviridae viruses such as respiratory syncytial virus (RSV), as well as Retroviridae members and Mononegavirales order members. In one embodiment, the invention provides attenuated Paramyxoviridae which display high antigenicity but are nevertheless safe for use in vaccines due to their low level of cell-to-cell transmission, as a result of genetic manipulation of the gene encoding the matrix (M) protein, and to methods...

Claims

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Application Information

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IPC IPC(8): C12N7/00C12Q1/06
CPCC12Q1/06C12N7/00A61K2039/5254A61K2039/5258C07K14/005C12N2760/18511C12N2760/18522C12N2760/18523C12N2760/18534C12N2760/18562G01N2333/115G01N2500/00
Inventor OOMENS, ANTONIUS G.P.
Owner BOARD OF REGENTS FOR OKLAHOMA STATE UNIVERSITY
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