Location:
Project Number: 8064-32000-061-000-D
Project Type: In-House Appropriated
Start Date: Oct 11, 2016
End Date: Oct 10, 2021
Objective:
1) Development of intervention strategies to control and eradicate FMDV including vaccines and biotherapeutics/adjuvants that rapidly induce long lasting and cross-protectiveimmunity against multiple FMDV subtypes, and are capable of preventing infection and controlling/abrogating persistent infections, developing vaccine formulations and delivery targeting the mucosal immune responses. Development of novel FMD vaccine platforms. Development of marker FMDV LL3B3D vaccines against relevant outbreak strains. Development of improved second-generation Ad5-FMD vaccines. Discovery of modified live attenuated FMDV vaccine candidates (MLAV). Discovery of cross-protective vaccines against multiple FMDV subtypes, and develop vaccine formulations. Development of novel biotherapeutics to prevent or control FMD prior to vaccine-induced protection. Discovery/development of novel biotherapeutics with increased potency and extended systemic half-life. Evaluation of combined delivery of biotherapeutics and vaccine in swine and cattle. Evaluation of vaccine-induced immunity and FMDV carrier state. Characterization of host immunity associated with novel vaccines against FMDV. Evaluation of novel vaccines for ability to prevent the FMD carrier state in cattle and assess the host response associated with the carrier divergence.
2) . Elucidate the host-pathogen interactions of FMDV, including identifying viral determinants of FMDV that control virulence in susceptible hosts, determining virus/host interactions at the primary sites of infection in ruminants and pigs with focus on factors defining tropism and early host responses, and determining characteristics and mechanisms of FMDV within-hot evolution over distinct phases of infection. Determine the molecular basis for FMDV-host interactions that impact virulence. Examination of virus factors contributing to FMDV virulence. Examination of host factors contributing to FMDV virulence. Identification of molecular mechanisms associated with the establishment of FMDV persistence. Determination of host and/or other non-FMDV factors causing or associated with clearance of FMDV from bovine nasopharyngeal tissue. Investigation of within-host FMDV genomic evolution to characterize sitespecific mutational pressure, genomic variation, and potential adaptation to the host. Determination of the immune mechanisms affecting protective immunity against FMDV. Analysis of CD4 helper T-cell response to FMDV vaccination. Analysis of CD8 cytotoxic T-cell response to FMDV vaccination. Analysis of B-cell responses to FMDV in peripheral blood and lymphoid tissue.
3) Understanding ecology of FMDV in endemic regions, determining drivers of transmission and maintenance in endemic settings, characterizing risk factors driving FMDV emergence and spread. Characterize the ecology of FMDV in endemic regions in Asia and Africa, including determining the factors driving viral transmission and maintenance. Characterize factors driving FMDV emergence and spread of novel FMDV strains in endemic settings. Role of Asian buffalo in maintenance and transmission of FMDV in endemic settings.
Approach:
1. The development of intervention strategies to control and eradicate FMDV will be achieved through research on novel FMD vaccine platforms including of marker modified live-attenuated FMDV vaccine candidates (e.g. FMDV-LL3B3D), second–generation Ad5-FMD vaccines, and cross-protective vaccines against multiple subtypes. Additionally, combinations of vaccine and biotherapeutics / and or adjuvants will be investigated as a way to induce mucosal immunity necessary not only to prevent disease but also to decrease persistent infection. These vaccine/ adjuvant formulations will be tested using alternate routes such as transdermal and by direct mucosal delivery.
2. The host-pathogen interactions of FMDV will be determined through: the identification of viral determinants of FMDV that control virulence in susceptible hosts, determining virus/host interactions associated with the FMDV life cycle, and determining the mechanisms of protective immunity to FMDV. The molecular basis for FMDV-host interactions that impact virulence and their specific contributions to virulence will be determined. In addition, the interactions of the virus with specific tissues at the primary infection sites will be studied by characterizing infected tissues at the cellular and subcellular level as well as utilizing transcriptomic analyses with micro arrays and next generation RNAseq. Bioinformatic analyses will be extensively applied in order to understand species specific factors mediating the establishment and maintenance of persistent infections. The within-host FMDV genomic evolution will be characterized through an examination of site-specific mutational pressure, genomic variation and potential adaption to the host. The immune mechanisms affecting protective immunity against FMDV will be determined through the analysis of CD4 helper and CD8 cytotoxic T cell responses to FMDV vaccination and B-cell responses to FMDV in peripheral blood and lymphoid tissue.
3. The characterization of the ecology of FMDV in endemic regions, including determining drivers of FMDV transmission and maintenance in endemic regions, characterizing factors driving FMDV emergence and spread, and the characterization of the role of the Asian buffalo in the transmission and maintenance of FMDV in the context of tolerance to infection will be analyzed. Efforts will focus on the characterization of the ecology of FMDV in endemic regions in Asia and Africa, including determining the factors driving viral transmission and maintenance. Factors driving FMDV emergence and spread of novel FMDV strains in endemic settings will be characterized. The role of Asian buffalo in maintenance and transmission of FMDV in endemic settings will be assessed.
