Infectious DNA vaccines against chikungunya virus
Inventors
Pushko, Peter • Tretyakova, Irina • Lukashevich, Igor
Assignees
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Publication Number
US-9101572-B2
Publication Date
2015-08-11
Expiration Date
Abstract
Described herein are i-DNA™ vectors and vaccines and methods for using the same. The i-DNA™ generates live attenuated vaccines in eukaryotic cells in vitro or in vivo for pathogenic RNA viruses, particularly chikungunya virus (CHIKV). 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 provides an infectious DNA (i-DNA) vaccination platform in which a vector comprises DNA encoding an infectious RNA molecule. The DNA encoding the infectious RNA molecule is operably linked to a eukaryotic RNA polymerase promoter so that, upon administration to a recipient, in vivo transcription generates infectious RNA and live attenuated virus. The infectious RNA molecule encodes chikungunya virus (CHIKV).
In one embodiment, the eukaryotic RNA polymerase promoter is a cytomegalovirus (CMV) RNA polymerase promoter positioned about 13 to about 17 nucleotide residues upstream of the CHIKV 5′ end of the DNA encoding the infectious RNA molecule. The described platform can also generate progeny attenuated CHIKV and, optionally, chimeric alphavirus variants containing CHIKV sequences. The resulting live attenuated virus is used to induce protective immunity against wild-type CHIKV.
The platform further describes production of homogeneous clonally purified live attenuated CHIKV from transfected cells, including formulations and immunizing a mammal with an effective amount of the vaccine. The disclosure also states advantages related to genetic stability and reduced risk of reduced quasispecies and reversion to virulent virus, including reduced host DNA mutagenesis risk compared with conventional DNA vaccines.
Claims Coverage
The independent claims cover vectors that express an infectious RNA from DNA under a eukaryotic RNA polymerase promoter, including CHIKV-encoded infectious RNA and CHIKV-containing alphavirus/chimeric alphavirus constructs, as well as vectors defined by specific sequence IDs that generate live attenuated, clonally purified CHIKV. Across the independent claims, the inventive features center on promoter-linked infectious RNA encoding CHIKV or CHIKV-containing alphavirus sequences and defining specific vector sequence identities.
Eukaryotic RNA polymerase promoter-linked infectious RNA encoding CHIKV
A vector comprising DNA encoding an infectious RNA molecule and a eukaryotic RNA polymerase promoter, wherein the DNA encoding an infectious RNA molecule is operably linked to the eukaryotic RNA polymerase promoter and the infectious RNA molecule encodes a chikungunya virus (CHIKV).
CHIKV-containing alphavirus infectious RNA under eukaryotic promoter control
A vector comprising DNA encoding an infectious RNA molecule and a eukaryotic RNA polymerase promoter, wherein the DNA encoding an infectious RNA molecule is operably linked to the eukaryotic RNA polymerase promoter and the infectious RNA molecule encodes an alphavirus and contains sequences from CHIKV as well as from another alphavirus.
Vectors defined by selectable SEQ ID nucleic-acid sequences
A vector comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5.
Overall claim coverage is directed to promoter-linked expression of infectious RNA from DNA, specifically infectious RNA encoding CHIKV or alphavirus constructs containing CHIKV sequences, and to vectors defined by selected sequence identifiers.
Stated Advantages
Single-dose immunity.
Genetic stability.
Reduced quasispecies and reduced risk of reversion to virulent virus.
Reduced host DNA mutagenesis risk compared with conventional DNA vaccines.
Documented Applications
Producing protective immunity against wild-type CHIKV by inducing live attenuated CHIKV (and optionally chimeric alphavirus variants) generated through in vivo transcription from the infectious DNA platform.
Preparation of homogeneous clonally purified live attenuated CHIKV from transfected cells and use as a vaccine composition.
Immunizing a mammal against CHIKV by administering a vaccine composition comprising the described vector or the live attenuated virus produced from transfected cells.
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