COUNTERMEASURES FOR FOOT-AND-MOUTH DISEASE UTILIZING DIAGNOSTICS, BIOTHERAPEUTICS, A NOVEL VACCINE PLATFORM AND IMPROVED CHALLENGE SYSTEMS
Location: Foreign Animal Disease Research
Project Number: 1940-32000-057-30
Start Date: May 24, 2011
End Date: Sep 30, 2014
Objective 1. Development of a rationally designed Foot-and-Mouth Disease (FMD) differentiation of infected from vaccinated animal (DIVA) bovine serological diagnostic assay to be used with next generation FMD vaccines in cattle.
Objective 2. Identify and evaluate different classes and subclasses of swine and cattle interferon induced in response to FMV infection and assess their potential use as biotherapeutitcs against FMDV. Specific objectives include; (A.) Identification of biotherapeutic candidates to control FMDV inclusive of adenovirus 5- vectored interferon (Ad5-IFN) administered in correlation with non-host pathogen associated molecular patterns (PAMPs) to provide a broader, enhanced and prolonged antiviral and protective response and, (B.) Conduct further studies of bovine interferon (IFNs) expressed in the Ad5 vector, which was previously developed by ARS, PIADC. Determine which IFNs are induced in response to infection at the primary sites of replication. This information will determine the top candidates for use as biotherapeutic agents.
Objective 3. Develop a vaccine platform for eliciting rapid serum and mucosal antibody responses to FMDV.
Objective 4. Development of improved challenge systems for FMD vaccine and biotherapeutics testing in cattle and swine. Novel challenge systems will be used to assess the animals’ ability to transmit FMDV in the pre-clinical phase of the disease.
1. A competitive ELISA (cELISA)will be developed by ARS, PIADC, that uses a FMDV 3ABC recombinant protein and a monoclonal antibody specific for an immunodominant B-cell epitope on the 3B protein that will be compatible with either next generation FMD molecular vaccines or current, high quality inactivated vaccines in which non-structural proteins (NSPs) have been removed. Collaborators from the Texas Veterinary Medical Diagnostic Laboratory (TVMDL) will provide monoclonal antibody and recombinant 3 ABC reagents for use in the cELISA development. The cELISA will then be evaluated in cooperation with USDA-APHIS for eventual use in the National Animal Health Laboratory Network. ARS, PIADC also will seek to engage a private manufacturer early in the research and development process of the cELISA to accelerate technology transfer for public use.
2. (A). Studies will be continued in swine utilizing the combination of Ad5-pIFN alpha and poly ICLC (PAMP) to test for broader and enhance antiviral response, examine alternative routes of inoculation to enhance efficacy, continue in vitro studies to examine the potency of polyIC and other PAMPs alone and in combination with INFs and conduct in vivo studies utilizing top candidates. Subsequent bovine studies will be preformed utilizing similar approach. (B.) To support use of Ad5-type I IFN-immunomodulator vectors as biotherapeutics against FMDV in cattle, studies will be conducted to develop methodologies to quantify and identify type I IFNs replication properties and understand their role in the immune response, identify immune-modulators that induce type I IFN and/or host response and develop new Ad5-type I IFN-immunomodulator vectors and test in cattle.
3. To develop a rapid acting vaccine platform, developed by collaborators from the University of Georgia School of Veterinary Medicine, studies will be conducted utilizing the dextran-FMDV vaccine to measure the immunogenicity kinetics in cattle. Develop tools to induce B cell to switch to immunoglobulin A (IgA) and IgG1secretion, in order to enhance the mucosal antibody response. This will be accomplished by expressing proteins in replication defective human adenovirus vector-5 (huAd5) in vitro. Further studies will be done in vivo to determine if Ad5 vectors can affect B cells in bovine. Identification of adjutants effecting B cell mechanisms of immunoglobulin switch and secretion will be conducted. The identified adjutants will be utilized in Ad5 FMDV vaccine trials.
4. Transmission studies will focus on the development, optimization and subsequent validation of direct inoculation of swine with FMDV via ornonasal deposition and comparison of the efficacy of intra-oral and intra-nasal routes with inoculation intradermally in heel bulb (IDHB). Swine and cattle cohabitation contact studies will be conducted utilizing swine previously infected with FMDV via oronasal and heel bulb inoculation methods to determine the potential of FMDV from donor pigs to cattle in the pre-clinical phase of infection.