title: A Refined Guinea Pig Model of Foot-and-Mouth Disease Virus Infection for Assessing the Efficacy of Antiviral Compounds.
abstract: An antiviral containment strategy for foot-and-mouth disease (FMD) outbreaks could support or replace current contingency plans in case of an outbreak in Europe and could spare many healthy animals from being pre-emptively culled. Recently, substantial progress has been made towards the development of small molecule drugs that inhibit FMD virus (FMDV) replication in vitro. For the initial in vivo evaluation of antiviral lead molecules, a refined FMDV-infection model in guinea pigs (GP) is herewith described. This GP model was validated by demonstrating the antiviral effect of T-1105 (an influenza virus inhibitor with reported activity against FMDV). Sixteen animals were orally administered with T-1105 twice daily (400 mg/kg/day) for five consecutive days and inoculated intraplantarly with 100 GPID50 of the GP-adapted FMDV strain O1 Manisa 1 h after the first administration. The efficacy of T-1105 was compared with that of prophylactic vaccination with a highly potent double-oil emulsion-inactivated O1 Manisa vaccine. Ten animals received a single, full (2 ml) cattle vaccine dose and were inoculated 3 weeks later. Fourteen T-1105-treated and all vaccinated GP were completely protected from generalization of vesicular lesions. At 2 dpi, viral RNA was detected in serum of 9/16 T-1105-treated and of 6/10 vaccinated animals. At 4 dpi, viral RNA was detected in serum, organs and oral swabs of half of the T-1105-treated animals and only in the serum of 1/10 of the vaccinated animals. Mean viral RNA levels in serum and organs of T-1105-treated and vaccinated animals were reduced compared to untreated controls (P < 0.01). T-1105 conferred a substantial clinical and virological protection against infection with O1 Manisa, similar to the protection afforded by vaccination. These results validate the suitability of the enhanced GP model for the purpose of initial evaluation of inhibitors of FMDV replication and illustrate the potential of selective inhibitors of viral replication to control FMD outbreaks.
authors.affiliation: Unit of Vesicular and Exotic Diseases, OD Viral Diseases, CODA-CERVA, Veterinary and Agrochemical Research Centre, Brussel, Belgium.
authors.forename: A R
authors.initials: AR
authors.lastname: De Vleeschauwer
authors.affiliation: Unit of Vesicular and Exotic Diseases, OD Viral Diseases, CODA-CERVA, Veterinary and Agrochemical Research Centre, Brussel, Belgium.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lefebvre
authors.affiliation: Unit of Vesicular and Exotic Diseases, OD Viral Diseases, CODA-CERVA, Veterinary and Agrochemical Research Centre, Brussel, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Willems
authors.affiliation: MSD Animal Health, Intervet International GmbH, Köln, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Paul
authors.affiliation: Aratana Therapeutics NV, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Billiet
authors.affiliation: Aratana Therapeutics NV, Leuven, Belgium.
authors.forename: L E
authors.initials: LE
authors.lastname: Murao
authors.affiliation: Aratana Therapeutics NV, Leuven, Belgium.|Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Aratana Therapeutics NV, Leuven, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Goris
authors.affiliation: Unit of Vesicular and Exotic Diseases, OD Viral Diseases, CODA-CERVA, Veterinary and Agrochemical Research Centre, Brussel, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: De Clercq
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005060:Europe; D005536:Foot-and-Mouth Disease / Q000188:drug therapy* / Q000517:prevention & control; D029544:Foot-and-Mouth Disease Virus / Q000302:isolation & purification; D006168:Guinea Pigs; D011719:Pyrazines / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D014611:Vaccination / Q000662:veterinary; D014765:Viral Vaccines / Q000008:administration & dosage
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D011719:Pyrazines; D012367:RNA, Viral; C541937:T 1105; D014765:Viral Vaccines
keywords: 3-oxo-3,4-dihydro-2-pyrazinecarboxamide derivative T-1105; animal welfare; antiviral drug; biosecurity; foot-and-mouth disease virus; guinea pig; proof-of-concept