Location: Foreign Animal Disease Research
Project Number: 1940-32000-048-00-D
Project Type: Appropriated
Start Date: Dec 23, 2006
End Date: Dec 22, 2011
The objectives of this project are: 1. Develop improved vaccine platforms and delivery systems for controlling foot-and-mouth disease. Improved FMD vaccine platforms and delivery systems can be developed to allow stronger, more rapid induction of protective immunity and differentiation of vaccinated from infected animals making vaccines more effective in outbreak control strategies. 2. Determine the mechanism of early immune enhancement against foot and-mouth disease. Innate responses mediate the rapid induction of protective responses by biotherapeutics and vaccines under development at PIADC. Understanding and manipulating these responses will result in novel methods to control FMDV. 3. Determine mechanism of FMDV interference with host immune response. Identifying the mechanisms that FMDV has evolved to counteract both the innate and adaptive immune responses will allow development of more effective disease control strategies.
1- Improved vaccine platforms delivery systems for controlling foot-and-mouth disease. This will be accomplished by three approaches; a- construction of Adenovirus vectors with increased antigen expression by adding regions coding for FMDV non-structural proteins; b- examining different routes of administration of AD5 vectors,; and c- alter FMDV capsid structures to either generate more acid stable products, or capsids capable of broadening the immune response to different FMD serotypes. 2- Mechanisms of early immune enhancement against FMDV. This will be accomplished by two approaches; a- induction of antiviral response by IFN alpha, beta and gamma either alone or in combination; and b- induction of innate immune responses by TLR agonists either alone or in combination with vaccines. 3- Determine mechanisms of FMDV interference with the host response. This will be accomplished by studying the molecular mechanism of interference of innate responses and adaptive by different FMDV proteins, utilizing FMDV mutants for specific viral regions such as the leader-pro. Effects of FMDV infection on the initiation of adaptive immune responses will be determined by analyzing the function of pDC, MoDC, and NK cells from the blood following acute infection and test them for expression of proinflammatory cytokines, anti-inflammatory cytokines and production of suppressors of cytokine secretion. Inhibition of the induction of a CTL response to FMDV in infected animals will be determined by analyzing MHC bound peptides through mass spectroscopy. Once the T cell epitope of the virus has been identified, we will prepare a panel of MHC tetramers that will allow us to track the expansion of FMDV reactive T cells, which will determine the level of cellular immunity in infected and vaccinated animals.