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Publication Number
US-10653769-B2
Publication Date
2020-05-19
Expiration Date
Abstract
Described herein are iDNA vectors and vaccines and methods for using the same. The iDNA generates live attenuated vaccines in eukaryotic cells in vitro or in vivo for pathogenic RNA viruses, particularly yellow fever virus and Venezuelan equine encephalitis virus. When iDNA is injected into the vaccine recipient, RNA of live attenuated virus is generated by in vivo transcription in the recipient's tissues. This initiates production of progeny attenuated viruses in the tissues of the vaccine recipient, as well as elicitation of an effective immune response protecting against wild-type, non-attenuated virus.
Core Innovation
The invention relates to iDNA (infectious DNA) vaccine vectors that encode full-length live attenuated alphavirus RNA genomes. The vectors include an infectious RNA molecule that encodes a non-pathogenic alphavirus and is linked for in vivo transcription in recipient tissues and/or in vitro transcription in cultured cells under control of a DNA/RNA polymerase promoter.
A key feature is the generation of homogeneous, clonally pure or clonally purified live attenuated viruses from cultured transfected cells or directly in recipient tissues. The viral genome is configured with two RNA dependent RNA polymerase promoters operatively linked to one or more portions of a capsid and a glycoprotein of the infectious RNA molecule, providing additional attenuation through promoter-capsid/glycoprotein expression arrangements using duplicated promoter elements.
The disclosed DNA constructs further include operable linkage of infectious RNA DNA to RNA-dependent RNA polymerase promoters and downstream transcription control elements including ribozymes, transcription termination, and poly-A site. The patent describes attenuated viruses derived from iDNA by inserting two RNA-dependent RNA promoters into viral cDNA, and illustrates iDNA-driven VEE TC-83 and YF17D antigen expression with avirulence of iDNA-derived TC-83 relative to virulent wild-type control.
Claims Coverage
The document includes three independent claims. Across them, the inventive features focus on a homogeneous clonally pure/clonally purified live attenuated virus and a vaccine that administers a therapeutically effective amount of that virus, where the virus is encoded by a DNA vector having two RNA dependent RNA polymerase promoters operatively linked to capsid and glycoprotein portions.
Homogeneous clonally pure live attenuated alphavirus virus with two RNA dependent RNA polymerase promoters linked to capsid and glycoprotein
A homogeneous clonally pure live attenuated virus prepared from cultured cells transfected with a vector comprising DNA encoding an infectious RNA molecule that encodes a non-pathogenic alphavirus and two RNA dependent RNA polymerase promoters, wherein the two RNA dependent RNA polymerase promoters are operatively linked to one or more portions of a capsid and a glycoprotein of the infectious RNA molecule.
Vaccine comprising therapeutically effective amount of homogeneous clonally pure live attenuated virus encoded by two RNA dependent RNA polymerase promoters linked to capsid and glycoprotein
A vaccine for an infectious RNA virus comprising a therapeutically effective amount of a homogeneous clonally pure live attenuated virus prepared from cultured cells transfected with a vector comprising DNA encoding an infectious RNA molecule that encodes a non-pathogenic alphavirus and two RNA dependent RNA polymerase promoters, wherein the two RNA dependent RNA polymerase promoters are operatively linked to one or more portions of a capsid and a glycoprotein of the infectious RNA molecule.
Homogeneous clonally purified live attenuated alphavirus virus with two RNA dependent RNA polymerase promoters linked to capsid and glycoprotein
A homogeneous clonally purified live attenuated virus comprising an infectious RNA molecule, and two RNA dependent RNA polymerase promoters, the two RNA dependent RNA polymerase promoters being operatively linked to one or more portions of a capsid and a glycoprotein of the infectious RNA molecule, wherein the infectious RNA molecule encodes a non-pathogenic alphavirus.
All independent claims require an infectious RNA molecule encoding a non-pathogenic alphavirus, together with two RNA dependent RNA polymerase promoters operatively linked to capsid and glycoprotein portions, either expressed as a homogeneous clonally pure/clonally purified live attenuated virus prepared from transfected cultured cells or used as the therapeutically administered vaccine component.
Stated Advantages
Provides avirulence for iDNA-derived TC-83 in BALB/c mice, relative to virulent wild-type control causing mortality.
Enables protective immunity against wild-type VEE/YF, as described for the iDNA approaches.
Enables production of infectious attenuated virus RNA and progeny virus after administration.
Documented Applications
Vaccination/immunization using the disclosed vaccine for an infectious RNA virus, including preventing a VEE virus-associated disease by administering a vaccine, a DNA vector, and/or the virus.
Generation and use of iDNA-derived live attenuated viruses (e.g., VEE TC-83 and YF17D) for antigen expression and immunogenicity evaluation, including serum antibody detection after mouse vaccination.
In vivo expression/viral progeny generation in recipient tissues after administration, as described for the iDNA system producing infectious attenuated virus RNA and progeny virus.
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