|Diaz-san Segundo, Fayna|
|De Los Santos, Teresa|
Submitted to: Journal of Interferon and Cytokine Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2010
Publication Date: 2/12/2011
Citation: Dias, C.C., Moraes, M.P., Diaz-San Segundo, F., De Los Santos, T.B., Grubman, M.J. 2011. Porcine type I interferon rapidly protects swine against challenge with multiple serotypes of foot-and-mouth disease virus. Journal of Interferon and Cytokine Research. 31(2):227-236. 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 US, 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 sterilely protected when challenged, by intradermal inoculation, 1 day later with FMDV serotype A24. In this study, we have extended our experiments to FMDV serotypes O1 Manisa and Asia-1 and demonstrated that Ad5-pIFN alpha induces sterile protection against these FMDV serotypes. We also demonstrated that Ad5-pIFN alpha induces sterile protection in swine that are challenged by contact exposure to infected animals, which is the natural route of FMDV infection. Finally, we attempted to reduce the protective dose of Ad5-pIFN alpha and showed that intramuscular inoculation at 4 sites in the neck induced sterile protection at a 10-fold lower dose as compared to intramuscular inoculation at 1 site in the rear limb, our previous method of inoculation. These results demonstrate the utility of interferon pretreatment of swine as an approach to sterilely protect against FMD in an emergency outbreak situation, and suggest that a combination of interferon pretreatment and vaccination can induce both rapid and long-term protection.
Technical Abstract: Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals that rapidly replicates and spreads within infected animals and into the environment. Vaccines require approximately 7 days to induce protection, but prior to this time vaccinated animals are still susceptible to disease. We have previously demonstrated that intramuscular (IM) inoculation of a replication-defective human adenovirus type 5 (Ad5) vector containing the porcine interferon alpha gene (Ad5-pIFN alpha) can sterilely protect swine challenged one day later by intradermal (ID) inoculation with FMDV A24 Cruzeiro. To extend these studies, we have demonstrated the effectiveness of Ad5-pIFN alpha against other FMDV serotypes including O1 Manisa and Asia-1 in an ID challenge study, and against A24 Cruzeiro in a direct contact challenge model. We also show that an Ad5 vector containing the pIFN beta gene can sterilely protect swine against ID challenge with FMDV A24. Furthermore, we found that IM inoculation of a 10-fold lower dose of Ad5-pIFN alpha at 4 sites in the neck as compared to 1 site in the right hind limb can sterilely protect swine against ID challenge. These studies demonstrate the utility of Ad5 delivered type I IFN as a means to rapidly protect swine against FMD, and suggest that various modifications of this approach may enable this strategy to be successfully used in other FMD susceptible species.