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Title: Novel antiviral therapeutics to control foot-and-mouth disease

Author
item DIAS, CAMILA - Oak Ridge Institute For Science And Education (ORISE)
item MORAES, MAURO - University Of Connecticut
item WEISS, MARCELO - Oak Ridge Institute For Science And Education (ORISE)
item Diaz San Segundo, Fayna
item PEREZ-MARTIN, EVA - Oak Ridge Institute For Science And Education (ORISE)
item SALAZAR, ANDRES - Oncovir, Inc
item De Los Santos, Teresa
item Grubman, Marvin

Submitted to: Journal of Interferon and Cytokine Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/28/2012
Publication Date: 8/27/2012
Citation: Dias, C.C., Moraes, M.P., Weiss, M., Diaz San Segundo, F.C., Perez-Martin, E., Salazar, A.M., De Los Santos, T.B., Grubman, M.J. 2012. Novel antiviral therapeutics to control foot-and-mouth disease. Journal of Interferon and Cytokine Research. 32(10):462-473.

Interpretive Summary: Foot-and-mouth disease virus (FMDV) is an antigenically variable virus consisting of 7 serotypes and multiple subtypes within each serotype, and it 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 they do not induce protection prior to about 7 days post vaccination. In the event of an FMD outbreak in a disease-free country such as the U.S., it is necessary to induce immediate protection in order to limit or inhibit disease spread prior to induction of vaccine induced immunity. We have previously shown that in cell culture all 7 serotypes of FMDV are inhibited by type I interferon. Furthermore, we have constructed an adenovirus vector containing the gene for type I interferon (Ad5-pIFN alpha) and demonstrated that swine inoculated with this vector are protected from viral infection when challenged, by intradermal inoculation, 1 day later with FMDV serotypes A24, O1 Manisa, or Asia-1. We also demonstrated that Ad5-pIFN alpha protects against infection in swine that are challenged by direct contact to infected animals, which is a natural route of FMDV transmission. In this study we examined the potential of other inducers of the innate response to rapidly protect swine. We found that poly ICLC, a synthetic double-stranded RNA, given alone or in combination with Ad5-pIFN alpha can protect swine challenged one day after administration against infection with FMDV. Furthermore, the combination treatment induces a broader array of innate responses. These results suggest that a combination of poly ICLC and IFN plus FMD vaccine may represent a more economical approach to provide rapid and long-lasting protection to animals against FMD in an emergency outbreak situation.

Technical Abstract: Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals. Vaccines require approximately 7 days to induce protection, thus prior to this time vaccinated animals are still susceptible to the disease. Our group has previously shown that swine inoculated with 1x10^11 focus forming units (FFU) of a replication-defective human adenovirus containing the gene for porcine interferon alpha (Adt-pIFN alpha) are sterilely protected from FMDV serotypes A24, O1 Manisa or Asia 1 when the animals are challenged 1 day post administration and protection can last for 3-5 days. Poly ICLC is a synthetic double stranded RNA that is a viral mimic and activates multiple innate immune pathways through interaction with TLR-3 and MDA-5. It is a potent inducer of IFNs. In this study, we initially examined the effect of poly IC and IFN-alpha on FMDV replication and gene induction in cell culture. Poly ICLC alone or combined with Adt-pIFN alpha was then evaluated for its therapeutic efficacy in swine against intradermal challenge with FMDV A24, 1 day post treatment. Groups of swine were subcutaneously inoculated with poly ICLC alone (4 or 8 mg) or in combination with different doses of Adt-pIFN alpha (2.5x10^9, 1x10^9 or 2.5x10^8 FFU). While different degrees of protection were achieved in all the treated animals, a dose of 8 mg of poly ICLC alone or combined with 1x10^9 FFU of Adt-pIFN alpha was sufficient to sterilely protect swine when challenged 24 h later with FMDV A24. IFN stimulated gene (ISG) expression in peripheral blood mononuclear cells at 1 day post treatment was broader and higher in protected animals than in non-protected animals. These data indicate that poly ICLC is a potent stimulator of IFN and ISGs in swine and at an adequate dose is sufficient to induce complete protection against FMD.