title: Bluetongue virus without NS3/NS3a expression is not virulent and protects against virulent bluetongue virus challenge.
abstract: Bluetongue is a disease in ruminants caused by the bluetongue virus (BTV), and is spread by Culicoides biting midges. Bluetongue outbreaks cause huge economic losses and death in sheep in several parts of the world. The most effective measure to control BTV is vaccination. However, both commercially available vaccines and recently developed vaccine candidates have several shortcomings. Therefore, we generated and tested next-generation vaccines for bluetongue based on the backbone of a laboratory-adapted strain of BTV-1, avirulent BTV-6 or virulent BTV-8. All vaccine candidates were serotyped with VP2 of BTV-8 and did not express NS3/NS3a non-structural proteins, due to induced deletions in the NS3/NS3a ORF. Sheep were vaccinated once with one of these vaccine candidates and were challenged with virulent BTV-8 3 weeks after vaccination. The NS3/NS3a knockout mutation caused complete avirulence for all three BTV backbones, including for virulent BTV-8, indicating that safety is associated with the NS3/NS3a knockout phenotype. Viraemia of vaccine virus was not detected using sensitive PCR diagnostics. Apparently, the vaccine viruses replicated only locally, which will minimize spread by the insect vector. In particular, the vaccine based on the BTV-6 backbone protected against disease and prevented viraemia of challenge virus, showing the efficacy of this vaccine candidate. The lack of NS3/NS3a expression potentially enables the differentiation of infected from vaccinated animals, which is important for monitoring virus spread in vaccinated livestock. The disabled infectious single-animal vaccine for bluetongue presented here is very promising and will be the subject of future studies.
authors.affiliation: Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Department of Virology, Central Veterinary Institute of Wageningen UR (CVI), Lelystad, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Feenstra
authors.affiliation: Department of Virology, Central Veterinary Institute of Wageningen UR (CVI), Lelystad, The Netherlands.
authors.forename: René G P
authors.initials: RGP
authors.lastname: van Gennip
authors.affiliation: Department of Virology, Central Veterinary Institute of Wageningen UR (CVI), Lelystad, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Maris-Veldhuis
authors.affiliation: Department of Virology, Central Veterinary Institute of Wageningen UR (CVI), Lelystad, The Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: Verheij
authors.affiliation: Department of Biochemistry, Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa.|Department of Virology, Central Veterinary Institute of Wageningen UR (CVI), Lelystad, The Netherlands.
authors.forename: Piet A
authors.initials: PA
authors.lastname: van Rijn
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D001819:Bluetongue / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D001820:Bluetongue virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D036022:Capsid Proteins / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D055786:Gene Knockout Techniques; D012756:Sheep / Q000276:immunology / Q000821:virology*; D014611:Vaccination / Q000662:veterinary*; D014758:Viral Core Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014765:Viral Vaccines / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000662:veterinary / Q000821:virology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D036022:Capsid Proteins; C075080:S10 protein, Bluetongue virus; C442520:VP2 protein, Bluetongue virus; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; C066862:VP7 protein, orbivirus