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Title: Simultaneous deletion of the 9GL and UK genes from the African swine fever virus Georgia 2007 isolate results in virus attenuation and may be a potential virus vaccine strain

Author
item O'DONNELL, VIVIAN - University Of Connecticut
item RISATTI, GUILLERMO - University Of Connecticut
item Holinka-Patterson, Lauren
item Krug, Peter
item CARLSON, JOLENE - Kansas State University
item VELAZQUEZ-SALINAS, LAURO - Oak Ridge Institute For Science And Education (ORISE)
item AZZINARO, PAUL - Oak Ridge Institute For Science And Education (ORISE)
item Gladue, Douglas
item Borca, Manuel

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/18/2016
Publication Date: 1/10/2017
Citation: O'Donnell, V., Risatti, G.R., Holinka-Patterson, L.G., Krug, P.W., Carlson, J., Velazquez-Salinas, L., Azzinaro, P., Gladue, D.P., Borca, M.V. 2017. Simultaneous deletion of the 9GL and UK genes from the African swine fever virus Georgia 2007 isolate results in virus attenuation and may be a potential virus vaccine strain. Journal of Virology. 91(1):e01760-16.

Interpretive Summary: Interpretative Abstract African swine fever virus (ASFV) causes a highly contagious and often lethal viral disease of domestic pigs that could have significant economic consequences for the swine industry if introduced in the United States. Currently, there is no licensed commercial vaccine to control of African Swine Fever (ASF). Researchers at USDA-RS showed that removal of certain individual genes from ASFV results in attenuation and the virus does no longer cause disease in animals. This approach was used successfully to produce experimental live attenuated vaccines against different strains of ASFV that induced solid protection against challenge with the deadly parental viruses when used in low doses. However, at higher doses these viruses could cause disease or even death and therefore were not suitable vaccines. In the current a novel virus lacking multiple genes was derived from the highly virulent ASFV Georgia 2007 and administered s a vaccine. This novel virus didi not induce disease in swine even if administered at relatively high doses, and importantly, animals were protected against disease as early as 14 days post-inoculation when challenged with a lethal dose of the parental Georgia 2007 virus. This is the first rationally designed experimental ASFV vaccine that protects against the highly virulent ASFV Georgia 2007 isolate as soon as 2 weeks post-vaccination.

Technical Abstract: African Swine Fever Virus (ASFV) is the etiological agent of a contagious and often lethal viral disease of domestic pigs that has significant economic consequences for the swine industry. The control of African Swine Fever (ASF) has been hampered by the unavailability of vaccines. Successful experimental vaccines have been derived from naturally occurring, cell culture-adapted, or genetically modified live attenuated ASFV. Recombinant viruses harboring engineered deletions of specific virulence-associated genes induce solid protection against challenge with parental viruses. Deletion of the 9GL, B119L, gene in highly virulent ASFVs Malawi Lil-20/1, Mal, and Pretoriuskop/96/4, Delta 9GL viruses, resulted in complete protection when challenged with parental isolates. When similar deletions were created within the ASFV Georgia 2007, ASFV-G, genome, attenuation was achieved but the protective and lethal doses were too similar. To enhance attenuation of ASFV-G, we deleted another gene, UK, DP96R, which was previously shown to be involved in attenuation of the ASFV E70 isolate. Here we report the construction of a double gene deletion recombinant virus, ASFV-G-Delta9GL/DeltaUK, derived from the highly virulent ASFV Georgia 2007 isolate. ASFV-G-Delta9GL/DeltaUK administered intramuscularly (IM) to swine does not induce disease even if administered at relatively high doses, 106 HAD50. Importantly, animals infected with 104 HAD50 of ASFV-G-Delta9GL/DeltaUK were protected against clinical disease as early as 14 days post-inoculation when challenged with ASFV-G. Presence of protection correlates with appearance of serum anti-ASFV antibodies but not with virus specific circulating ASFV-specific INF-' producing cells. ASFV-G-Delta9GL/DeltaUK is the first rationally designed experimental ASFV vaccine that protects against the highly virulent ASFV Georgia 2007 isolate as soon as two weeks post-vaccination.