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Title: Combination of Adt-O1MANISA AND Ad5-boIFN induces early protective immunity against foot-and-mouth diseases in cattle

Author
item DIAZ-SAN SEGUNDO, FAYNA - University Of Connecticut
item MONTIEL, NESTOR - Oak Ridge Institute For Science And Education (ORISE)
item STURZA, DIEGO - Oak Ridge Institute For Science And Education (ORISE)
item PEREZ-MARTIN, EVA - Oak Ridge Institute For Science And Education (ORISE)
item Hickman, Danielle
item RAMIREZ-MEDINA, ELIZABETH - Oak Ridge Institute For Science And Education (ORISE)
item Grubman, Marvin
item De Los Santos, Teresa

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/27/2016
Publication Date: 9/27/2016
Citation: Diaz-San Segundo, F., Montiel, N.A., Sturza, D.F., Perez-Martin, E., Hickman, D.M., Ramirez-Medina, E., Grubman, M.J., De Los Santos, T.B. 2016. Combination of Adt-O1MANISA AND Ad5-boIFN induces early protective immunity against foot-and-mouth diseases in cattle. Journal of Virology. 499:340-349.

Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes a fast spreading disease that affects farm animals resulting in economically and socially devastating consequences. Current strategy to control FMD in case of an outbreak includes vaccination. However, this strategy needs seven days to stop virus spread. Our group has demonstrated that type III interferon (IFN Lambda 3) can be used to rapidly control the disease in cattle, since this cytokine is a potent molecule to control several viral diseases by stimulating the innate immune response. Nevertheless, to ultimately control FMD it is necessary to stimulate both the innate and the adaptive immune response and therefore inducing an early and sustain protection against the virus. Our work demonstrates that cattle treated with a combination of an IFN based biotherapuetic (Ad5-boIFN Lambda 3) and Ad5-O1Manisa vaccine induces immediate protection against FMDV challenge. Interestingly, animals treated with the combination were completely protected despite the absence of detectable innate or humoral adaptive immune response in sera at the time of challenge. However, combination treatment induced a significant protective cellular immune response, indicating that the addition of Ad5-boIFN Lambda 3 to the Ad5-based-vaccine not only enhances early vaccine protection, but confirms the adjuvant effect of type III IFN with Ad5- vectored FMD vaccine in cattle.

Technical Abstract: Foot-and-mouth-disease (FMD) remains one of the most important economic concerns for the agricultural industry worldwide. Although vaccination with a commercially available inactivated whole virus formulation, or a recently developed replication-defective human adenovirus 5 vector-based subunit vaccine (Ad5-FMD) have proven effective countermeasures, they still require 5-7 days to induce complete protection. Due to the high replication rate of the FMD virus (FMDV), new control strategies that stimulate the rapid innate immune response are needed to control virus replication and onset of disease. We have previously described the use of bovine type III interferon (IFN) (i.e. IFN Lambda 3) as a potential biotherapeutic to protect cattle against FMDV. However, although boIFN Lambda 3 expressed from an Ad5 vector (Ad5-boIFN Lambda 3) was able to delay disease onset, some animals showed clinical signs late starting by 9 days after treatment. Therefore, we hypothesized that use of a combination of Ad5-boIFN Lambda 3 and Ad5-FMD vaccine could induce immediate as well as long-lasting protection of cattle against FMDV challenge. In order to prove our hypothesis, four groups of three steers each were vaccinated with an Ad5 vector expressing FMDV capsids of serotype O1Manisa (Adt-O1Manisa), Ad5-boIFN Lambda 3, the combination of both, or control PBS. All animals were challenged with FMDV O1Manisa at three days post immunization. Our results indicated that all animals treated with the combination of Ad5-FMD and Ad5-boIFN Lambda 3 were fully protected against FMD despite the absence of detectable neutralizing antibodies or antiviral activity in sera at the time of challenge. Furthermore, detection of a strong CD4+ and CD8+ IFN gamma systemic response suggested that boIFN Lambda 3 provided an adjuvant effect when used in combination with the Ad5-FMD vaccine.