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Research Project: Intervention Strategies to Support the Global Control and Eradication of Foot-and-Mouth Disease Virus (FMDV)

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Title: Use of Protein Pegylation to prolong the antiviral effect of IFN against FMDV

Author
item Diaz San Segundo, Fayna
item MEDINA, GISSELLE - University Of Kansas
item MOGULOTHU, AISHWARYA - University Of Connecticut
item Azzinaro, Paul
item ATTREED, SARAH - Oak Ridge Institute For Science And Education (ORISE)
item Gutkoska, Joseph
item LOMBARDI, KIMBERLY - Elanco Animal Health, Inc
item SHIELDS, JACOB - Elanco Animal Health, Inc
item HUDOCK, TERESA - Elanco Animal Health, Inc
item De Los Santos, Teresa

Submitted to: Frontiers in Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/9/2021
Publication Date: 5/5/2021
Citation: Diaz San Segundo, F.C., Medina, G.N., Mogulothu, A., Azzinaro, P.A., Attreed, S.E., Gutkoska, J.R., Lombardi, K.R., Shields, J., Hudock, T.A., De Los Santos, T.B. 2021. Use of Protein Pegylation to prolong the antiviral effect of IFN against FMDV. Frontiers in Microbiology. https://doi.org/10.3389/fmicb.2021.668890.
DOI: https://doi.org/10.3389/fmicb.2021.668890

Interpretive Summary: Foot and mouth disease (FMD) vaccines require 5-7 days to induce protection. We have previously demonstrated that pigs treated subcutaneously of intramuscullarly with a adenovirus vector that delivers porcine interferon alpha (Ad5-poIFNalpha) could be protected against FMD for about 3 days after inoculation. Here we demonstrate that protection against FMD can be extended to 5 days by substituting Ad5-poIFN alpha with pegylated IFN, alpha a chemically modified version of IFN. Our results highlight the potential of using pegylated IFN in combination with vaccines to fully protect pigs against FMD soon after treatment.

Technical Abstract: Interferons (IFNs) are considered the first line of defense against viral diseases. Due to their ability to modulate immune responses, they have become an attractive therapeutic option to control virus infections. In fact, similar to many other viruses, foot-and-mouth disease virus (FMDV), the most contagious pathogen of cloven-hoofed animals, is highly sensitive to the action of IFNs. Previous studies have demonstrated that type I, II and III IFNs, expressed using a replication defective human adenovirus 5 (Ad5) vector, can effectively block FMDV replication in vitro and can protect animals when challenged one day after Ad5-IFN treatment, in some cases providing sterile immunity. Rapidly spreading FMD is currently controlled by the use of vaccination, although development of a protective adaptive immune response takes 5 to 7 days. Therefore, an optimal strategy to control FMD outbreaks is to block virus replication and spread through sustained IFN activity while the vaccine-stimulated adaptive immune response is developed. However, because of challenges with protein half-life in vivo, such an approach has not yet been developed in the context of FMD. One strategy to chemically improve drug pharmacodynamics is the use of pegylation. In this proof-of-concept study, we demonstrate that pegylated recombinant porcine (po)IFNa displays strong and long-lasting antiviral activity against FMDV in vitro and in vivo, completely protecting swine against FMD for at least 5 after a single dose. These results highlight the potential of this biotherapeutics to use in combination with vaccines to fully control FMD in the field.