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Title: Delivery of a Foot-and-Mouth Disease Virus Empty Capsid Subunit Antigen with Nonstructural Protein 2B Improves Protection of Swine

Author
item PENA, LINDOMAR - USDA, ORISE FELLOW
item Moraes, Mauro
item Koster, Marla
item BURRAGE, THOMAS - DHS S&T PIADC
item Pacheco Tobin, Juan
item DIAZ SAN-SEGUNDO, FAYNA - USDA, ORISE FELLOW
item Grubman, Marvin

Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/11/2008
Publication Date: 8/30/2008
Citation: Pena, L., Moraes, M., Koster, M.J., Burrage, T., Pacheco Tobin, J., Diaz San-Segundo, F., Grubman, M.J. 2008. Delivery of a Foot-and-Mouth Disease Virus Empty Capsid Subunit Antigen with Nonstructural Protein 2B Improves Protection of Swine. Vaccine. 26:5689-5699.

Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals. Vaccines produced by chemical inactivation of virus are available, but there are concerns about their safety and about the ability to serologically distinguish vaccinated animals from infected animals. A possible alternative approach to develop safe, effective FMD vaccines is to produce viral subunit vaccines which do not contain infectious FMDV and lack the genetic information for a number of viral nonstructural proteins. We have used a replication-defective human adenovirus to deliver this vaccine (Ad5-FMDV). Thus, production of this vaccine does not require expensive high-containment manufacturing facilities, can be made in the U.S., which currently prohibits work with infectious FMDV on the mainland, and animals inoculated with this marker vaccine can readily be differentiated from infected animals using diagnostic assays employing the viral nonstructural proteins not present in the vaccine. Previous work in our laboratory has demonstrated that this Ad5-FMD vaccine can protect both swine and bovines after one inoculation. However, relatively large amounts of the vaccine are required. In this manuscript we have attempted to improve the protective efficacy of the Ad5-FMD vaccine by examining the potential favorable effect of the FMDV nonstructural proteins 2B and 2C when included as part of the Ad5-FMD vaccine. Swine were inoculated with both the original Ad5-FMD vaccine and Ad5-FMD vaccines containing 2B or 2BC and were challenged with FMDV 21 days later. The group inoculated with the vaccine containing the 2B coding region had enhanced protection as compared to the groups inoculated with the other Ad5-FMD vaccines. These results suggest that the 2B protein can enhance the potency and efficacy of the Ad5-FMD vaccine.

Technical Abstract: We have previously demonstrated that a replication-defective human adenovirus serotype 5 (Ad5) vector carrying the capsid (P1-2A) and 3C protease coding regions as well as a portion of the 2B coding region of foot-and-mouth disease virus (FMDV) (Ad5-A24) protects cattle and swine from direct inoculation challenge with virulent FMDV. However, relatively large amounts of Ad5 are required to induce protection. To attempt to develop more efficacious vaccines we have included coding regions from additional FMDV nonstructural (NS) proteins in our construct, while maintaining their DIVA (differentiation of infected from vaccinated animals) status. The proteins selected, 2B and 2C, are involved in rearranging membranes in infected cells resulting in the proliferation of cytoplasmic vesicles which subsequently serve as the sites of virus replication. Furthermore, we placed these FMDV constructs under the control of an altered cytomegalovirus (CMV) promoter (Ad5-CI). Addition of full-length 2B (Ad5-CI-A24-2B) resulted in a significant increase in the number of vesicles in infected cells as compared to cells infected with the original vector which contained only a portion of the 2B coding region or the new vector containing 2BC (Ad5-CI-A24-2BC). Swine inoculated with Ad5-CI-A24-2B developed an enhanced FMDV-specific neutralizing antibody and IgM response as compared to animals inoculated with the original vector. Furthermore, upon challenge these animals showed no clinical signs of disease or virus shedding, while the group inoculated with the Ad5-A24 or Ad5-CI-A24-2BC had a more delayed antibody response after vaccination and developed clinical disease that was less severe than the control group. In a second experiment we compared our original adenovirus vector, Ad5-A24, with a new vector containing the altered CMV promoter (Ad5-CI-A24) and found that the new vector had no effect on vaccine potency and efficacy. However, in this experiment all three animals vaccinated with Ad5-CI-A24-2B developed clinical disease. One animal in this group had no detectable FMDV-specific neutralizing antibody response at the time of challenge and had significant clinical disease, while the other two animals in this group, which were exposed to this animal for the duration of the experiment, had delayed and less severe disease as compared to animals in the other vaccinated groups. The combined results suggest that incorporation of the complete coding region of 2B into our subunit vaccine enhances its potency and protective efficacy.