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Title: Immunization of bighorn sheep against mannheimia haemolytica with a bovine herpesvirus 1-vectored vaccine

Author
item BATRA, SAI - Washington State University
item SHANTHALINGAM, SUDARVILI - Washington State University
item DONOFRIO, GAETANO - University Of Parma
item HALDORSON, GARY - Washington State University
item CHOWDHURY, SHAFIQUL - Louisiana State University
item White, Stephen
item SRIKUMARAN, SUBRAMANIAM - Washington State University

Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2017
Publication Date: 3/14/2017
Citation: Batra, S.A., Shanthalingam, S., Donofrio, G., Haldorson, G.J., Chowdhury, S., White, S.N., Srikumaran, S. 2017. Immunization of bighorn sheep against mannheimia haemolytica with a bovine herpesvirus 1-vectored vaccine. Vaccine. 35(12):1630-1636.

Interpretive Summary: Pneumonia has significantly contributed to decline of the North American bighorn sheep (BHS) population, and outbreaks in BHS herds can incur mortalities up to 90%. Mannheimia haemolytica is a very important pathogen of BHS pneumonia, consistently causing 100% mortality under experimental conditions. Previous work indicated that a vaccine containing leukotoxin and surface antigens of M. haemolytica induced 100% protection in BHS, but required multiple booster doses. BHS can be vaccinated when handled to introduce them to a new area, but administration of booster doses is virtually impossible. We tested use of a viral vector to see if it might enable single vaccine administration with continuing immune exposure and stronger immune responses using the same antigens. We tested a BHV-1 viral vector which did infect bighorn sheep and was shed after initial infection. The virus became latent as is common for herpesviruses, but could be reactivated by dexamethasone treatment. Once M. haemolytica antigens from earlier studies were added to the viral vector, the vaccine successfully induced antibody responses in many BHS. Nonetheless, the vaccine did not protect BHS from M. haemolytica challenge. These data indicate that BHV-1 is a suitable viral vector for BHS immunization, but additional experiments will be required to produce a more efficacious vaccine.

Technical Abstract: Pneumonia has significantly contributed to the drastic decline of bighorn sheep (BHS, Ovis canadensis) population in North America. Pneumonia outbreaks in BHS herds can incur mortalities up to 90%. Transplantation of healthy BHS into habitats that suffered pneumonia outbreaks has failed to restore BHS numbers. Mannheimia haemolytica is a very important pathogen of BHS pneumonia, consistently causing 100% mortality under experimental conditions. Leukotoxin is the critical virulence factor of M. haemolytica. In a ‘proof of concept’ study, a vaccine containing leukotoxin and surface antigens of M. haemolytica induced 100% protection in BHS, but required multiple booster doses. BHS can be vaccinated at the time of transplantation. Administration of booster doses, however, is impossible. Bovine herpesvirus-1 (BHV-1) is an ideal vector for BHS because of its large genome, and ability to undergo latency with subsequent reactivation which obviates the need for booster administration. The objective of this study was to evaluate a BHV-1-vectored vaccine encoding M. haemolytica immunogens. Prior to vaccine development, we determined the permissiveness of BHS for BHV-1 infection. BHS inoculated with wild-type BHV-1 shed the virus following infection. The lytic phase of infection was superseded by latency. Treatment of latently-infected BHS with dexamethasone reactivated the virus. A recombinant BHV-1-vectored vaccine encoding a leukotoxin-neutralizing epitope and immuno-dominant epitopes of the outer membrane protein PlpE was developed by replacing the viral glycoprotein C gene with a leukotoxin-plpE chimera gene. Four of six BHS vaccinated with the recombinant virus had significantly higher leukotoxin-neutralizing antibodies at day 21 post-vaccination, while two of six BHS had significantly higher surface antigen antibodies at day 17 post-vaccination. These antibodies, however, were inadequate for protection of BHS from M. haemolytica challenge. These data indicate that BHV-1 is a suitable vector for the immunization of BHS. Additional experimentation with the chimeric insert could result in a more efficacious vaccine.