Infectious DNA vaccines against chikungunya virus
Inventors
Pushko, Peter • Tretyakova, Irina • Lukashevich, Igor
Assignees
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Publication Number
US-9694065-B2
Publication Date
2017-07-04
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™) chikungunya vaccine platform in which DNA encoding an infectious CHIKV genomic RNA is delivered to recipients’ tissues. The DNA includes an operably linked eukaryotic RNA polymerase promoter so that transcription occurs in vivo by a eukaryotic RNA polymerase, and the resulting infectious RNA drives production of live attenuated, clonally purified CHIKV progeny intended to induce immunity against wild-type CHIKV.
The described DNA construct is based on DNA encoding an infectious RNA molecule with a eukaryotic RNA polymerase promoter, exemplified by a cytomegalovirus (CMV) RNA polymerase promoter. Additional embodiments address attenuated CHIKV, including chimeric alphavirus constructs containing CHIKV sequences and sequences from another alphavirus.
The platform further includes vector elements that support transcribed infectious RNA handling and replication, including sequence elements enabling transport of the transcribed infectious RNA molecule from the nucleus to the cytoplasm and/or enabling production of transcribed infectious RNA with functional 5′ and 3′ termini. The disclosed approach is associated with generating a homogeneous clonally purified live attenuated virus population, including considerations for homogeneity and genetic stability relative to classic 181/25 vaccine.
The described use includes in vivo delivery and also support for i-DNA-driven generation of live virus in vitro, together with an immunologic rationale that unmethylated CpG motifs in the administered DNA can activate innate immune signaling via toll-like receptor (TLR) pathways, including effects involving dendritic cells and type I interferons.
Claims Coverage
The claim set includes three independent claims. Across the independent claims, the shared coverage centers on producing or defining a homogeneous clonally purified live attenuated CHIKV in which DNA encoding an infectious CHIKV RNA is operably linked to a eukaryotic RNA polymerase promoter.
Attenuated CHIKV vaccine via operably linked infectious CHIKV RNA DNA and eukaryotic RNA polymerase promoter
A vaccine for chikungunya virus (CHIKV) comprising an attenuated CHIKV produced by isolating said CHIKV from cells transfected by a vector comprising DNA encoding an infectious RNA molecule and a eukaryotic RNA polymerase promoter, wherein the DNA encoding the infectious RNA molecule is operably linked to the eukaryotic RNA polymerase promoter and the infectious RNA molecule encodes a CHIKV.
Homogeneous clonally purified live attenuated CHIKV virus population prepared from vector-driven infectious CHIKV RNA transcription
A homogeneous clonally purified live attenuated virus population prepared from cells transfected with a vector comprising DNA encoding an infectious RNA molecule and a eukaryotic RNA polymerase promoter, wherein the DNA encoding the infectious RNA molecule is operably linked to the eukaryotic RNA polymerase promoter and the infectious RNA molecule encodes a CHIKV.
Homogeneous clonally purified live attenuated virus comprising infectious CHIKV RNA operably linked to a eukaryotic RNA polymerase promoter
A homogeneous clonally purified live attenuated virus comprising an infectious CHIKV RNA molecule operably linked to a eukaryotic RNA polymerase promoter.
Collectively, the independent claims cover producing and/or defining a homogeneous clonally purified live attenuated CHIKV in which DNA encoding an infectious CHIKV RNA is operably linked to a eukaryotic RNA polymerase promoter, yielding vaccine-relevant live virus for immunological effect.
Stated Advantages
Induces immunity against wild-type CHIKV.
Produces live attenuated, clonally purified CHIKV progeny.
Improves homogeneity, described as uniform plaque size, and addresses genetic stability considerations versus classic 181/25 vaccine.
Activates innate immune signaling via unmethylated CpG motifs and toll-like receptor (TLR) pathways, including involvement of dendritic cells and type I interferons.
Documented Applications
A vaccine for chikungunya virus (CHIKV), including immunizing a mammal by administering an effective amount of the vaccine.
Generation of live attenuated CHIKV progeny via i-DNA-driven transcription in recipient tissues.
Generation of live virus in vitro from i-DNA-driven constructs.
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