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Title: Venezuelan Equine Encephalitis Virus replicon particles can induce rapid protection against Foot-and-Mouth Disease Virus

Author
item Diaz San Segundo, Fayna
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 PEREZ-MARTIN, EVA - Oak Ridge Institute For Science And Education (ORISE)
item OWENS, GARY - Alphavax, Inc
item CUSTER, MAX - Alphavax, Inc
item KAMRUD, KURT - Alphavax, Inc
item De Los Santos, Teresa
item Grubman, Marvin

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2013
Publication Date: 3/6/2013
Citation: Diaz San Segundo, F.C., Dias, C.C., Moraes, M.P., Weiss, M., Perez-Martin, E., Owens, G., Custer, M., Kamrud, K., De Los Santos, T.B., Grubman, M.J. 2013. Venezuelan Equine Encephalitis Virus replicon particles can induce rapid protection against Foot-and-Mouth Disease Virus. Journal of Virology. 87(10):5447-5460. DOI: 10.1128/JVI.03462-12.

Interpretive Summary: Foot-and-Mouth Disease Virus (FMDV) is a variable virus consisting of 7 serotypes and multiple subtypes each requiring a separate vaccine to achieve protection. 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. Production of interferons (IFNs) is the first host response to viral infection and it can rapidly control pathogen replication. We have previously constructed an adenovirus vector containing the gene for porcine type I IFN (Ad5-poIFNalpha) and demonstrated that swine inoculated with this vector are protected when challenged 1 day later with FMDV serotypes A24, O1 Manisa, or Asia-1. However, a relatively high dose of Ad5-poIFNalpha vector is required to induce protection. In this study we examined the potential of another rapid inducer of the host protective response. Venezuelan Equine Encephalitis Virus (VEE) replicon particles (VRPs) can induce a rapid protective response in cell culture and can protect mice against VEE and influenza virus infection. We found VRPs rapidly inhibit FMDV replication in cell culture. Furthermore, in an FMDV mouse model VRP pretreatment resulted in survival of all mice after challenge, while all nontreated mice died. These results suggest that it would be worthwhile to test the efficacy of VRP-poIFNalpha and VRP-bovine IFNalpha in naturally susceptible animals.

Technical Abstract: We have previously shown that swine pretreated with a replication-defective human adenovirus vector (Ad5) containing the porcine type I interferon gene (poIFN-alpha/Beta) are sterilely protected when challenged one day later with Foot-and-Mouth Disease Virus (FMDV), but the dose required is relatively high. Venezuelan Equine Encephalitis (VEE) virus empty replicon particles (VRPs) can induce rapid protection of mice against homologous VEE virus challenge and in some cases heterologous virus challenge. As an alternative approach to induce rapid protection against FMDV we have examined the ability of VRPs containing either the gene for green fluorescent protein (VRP-GFP) or poIFN-alpha (VRP-poIFNalpha) to block FMDV replication in vitro and in vivo. Pretreatment of swine or bovine cell lines with either VRP significantly inhibited subsequent infection with FMDV as early as 6 h after treatment and for at least 120 h post treatment. Furthermore, mice pretreated with either 10^7 or 10^8 infectious units (IU) of VRP-GFP and challenged with a lethal dose of FMDV 24 h later were protected from death. Protection was induced as early as 6 h after treatment and lasted at least for 48 h in mice inoculated with 10^8 IU VRP-GFP and correlated with induction of an antiviral response and production of IFN-alpha. By 6 h after treatment a number of genes were induced and the number of genes and the level of induction increased at 24 h. Moreover, the chemokine IP-10, which is induced by IFN-alpha and VRP-GFP, is involved in protection against FMDV since only 30 percent of IP-10 knockout mice treated with IFN-alpha are protected against FMDV challenge, while 100 percent of IFN-alpha treated wild-type mice are protected.