National Institutes of Health, a Component of the US Dept. of Health & Human Services

US Government As Represented by the Secretary of the Army

The Walter Reed Army Institute of Research

Alexander G Pletnev

Robert M Chanock

Brian R Murphy

Stephen Whitehead

Joseph R Putnak

Ching-Juh Lai

Joseph E Blaney

Ruhe Men

Kenneth H Eckels

Michael Bray

Amber R Engel

Yi-Ming Zhang

Joseph E Blaney, Jr

Stephen S Whitehead

The present invention relates to attenuated, immunogenic West Nile virus chimeras built on a dengue virus backbone for the production of immunogenic, live, attenuated West Nile virus vaccines,

Construction of West Nile virus and dengue virus chimeras for use in a live virus vaccine to prevent disease caused by West Nile virus

The present invention relates to attenuated, immunogenic West Nile virus chimeras built on a dengue virus backbone for the production of immunogenic, live, attenuated West Nile virus vaccines.

Disclosed herein are chimeric TBEV/DEN4 flaviviruses including a first nucleic acid molecule including a 5' non-coding region (NCR) from a DEN4 virus, a nucleic acid encoding a C protein and non-structural proteins from a DEN4 virus, and a 3&#x2032; NCR from a DEN4 virus, wherein nonstructural protein NS4B includes a phenylalanine at amino acid position 112, nonstructural protein NS5 includes an alanine at amino acid position 654 and an alanine at amino acid position 655, and the 3&#x2032; NCR includes a deletion of nucleotides 10478-10507. The chimeric construct also includes a second nucleic acid molecule, which is operably linked to the first nucleic acid molecule, encoding a prM protein and an E protein from a TBEV, wherein the E protein includes an amino acid substitution that differs from the wild type TBEV at amino acid position 315 and a tryptophan at amino acid position 240. Also disclosed are methods of eliciting an immune response using the disclosed TBEV/DEN4 chimeric flaviviruses and immunogenic compositions including the disclosed chimeric flaviviruses and a pharmaceutically acceptable carrier.

Antigenic chimeric tick-borne encephalitis virus/dengue virus type 4 recombinant viruses

Embodiments described herein include full-length infectious cDNA clones of Langat tick-borne flavivirus.

Full-length infectious cDNA clones of tick borne flavivirus

The invention includes a chimeric virus for use in a vaccine preparation having a genome comprising nucleic acid sequences encoding at least one structural protein from one flavivirus and nucleic acid sequences encoding nonstructural protein from another flavivirus. The genome preferably includes mutations within the viral genome that reduce virus virulence and in a particularly preferred embodiment these vaccines are directed to flaviviruses such as dengue virus, tick-borne encephalitis virus and Japanese encephalitis virus. The invention also includes a baculovirus having a recombinant dengue cDNA sequence which encodes: (1) dengue virus capsid protein, pre-matrix protein, envelope glycoprotein and NS1 and NS2a nonstructural proteins or (2) dengue envelope glycoprotein or (3) dengue non-structural proteins NS1 and NS2a. The invention further includes a baculovirus having a recombinant Japanese B encephalitis virus cDNA sequence which encodes the Japanese B encephalitis virus capsid protein, pre-matrix protein, envelope glycoprotein and non-structural proteins NS1 and NS2a. The invention further includes a vaccine and a method to produce that vaccine.

Chimeric and/or growth-restricted flaviviruses

A live, attenuated chimeric virus vaccine against tick-borne encephalitis virus comprising the preM and E structural genes of the tick-borne encephalitis Langat virus and the non-structural genes of the mosquito-borne dengue virus. The live chimeric vaccine was administered intraperitoneally and exhibited complete attenuation in mice while at the same time providing protection against subsequent challenge with the virulent parental Langat virus.

Growing community of inventors

Gaithersburg, MD, United States of America

Alexander G Pletnev