Method for Generating PRRS Vaccination Strains
Porcine reproductive and respiratory syndrome (PRRS) is the leading threat to the swine industry worldwide. Live-attenuated and inactivated vaccines are now commercially available, but are not without limitations, including concerns on reversion to virulence and insufficient level of protection. The co-existence of different PRRSV strains and subtypes emphasizes the need for cross-protective vaccines. PRRS is the result of infection with a small, enveloped virus (PRRSV) containing a single positive-stranded RNA genome that can be divided into 2 major genotypes: Type I (European) and Type II (North American). Highly pathogenic variants that emerged in China and other Asian countries originated from the Type II genotype.
The PRRSV genome is about 15kb in length and contains at least 10 open reading frames. Situated in the 5’-proximal region of the genome are the PRRSV replicase genes, ORF1a and ORF1b, which represent nearly 75% of the viral genome. These replicase genes encode long polyproteins that are proteolytically processed into at least 14 nonstructural protein (nsp) products, the largest of which is nsp2. The invention provides the discovery and characterization of arterivirus protein, nsp2TF, the expression of which is dependent upon -2 ribosomal frameshifting at a site located in the nsp2 coding region. This coding region overlaps the portion of ORF1a that encodes the transmembrane region of nsp2 in PRRS and other arteriviruses, including lactate dehydrogenase-elevating virus (LDV) and simian haemorrhagic fever virus (SHFV). Mutations affecting the expression of nsp2TF impair PRRSV replication and result in a smaller plaque phenotype. Provided here are arteriviruses that display reduced translation of nsp2TF and/or altered translation of one or more downstream products, arteriviruses in which nsp2TF function is reduced and/or absent, and vaccines or immunogenic compositions that comprise these arteriviruses. Also provided are diagnostic methods, methods for identifying compounds that inhibit -2 frameshifting, and gene expression tools for eukaryotic systems utilizing -2 frameshifting.
PRRSV infection in swine is characterized by later term reproductive failure in sows and severe pneumonia in neonatal pigs, and is the most economically significant disease of swine worldwide for the last 25 years. The annual worldwide impact is estimated at over $1 billion. Only a few countries with a representative population remain PRRS-free; the rest of the world is positive and suffers continual reinfections. A recent survey of UK vets estimated the prevalence of PRRS at approximately 50% of all sows and piglets. Improved antiviral therapies for PRRS are necessary.
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Keywords: arterivirus, PRRSV, swine, pig, vaccine, frameshift, antivirals
Potential improvements to the safety and/or efficacy characteristics of live PRRS vaccine such as quicker onset of immunity, broader cross-protection against virulent genetically diverse subtypes, reduced viral shedding to non-vaccinates and reduced persistence in vaccinated animals.
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Luris reference numberINV-003.029
International Patent Published 23 Jan 2014 under WO 2014/015116A2 assigned under collaboration agreement to University of Cambridge, GB, South Dakota State University, US, University of Cork, IE, and Leiden University Medical Center, NL.