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ARS Home » Northeast Area » Orient Point, New York » Plum Island Animal Disease Center » Foreign Animal Disease Research » Research » Research Project #431980

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

Location: Foreign Animal Disease Research

Project Number: 8064-32000-061-00-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-protective immunity against multiple FMDV subtypes, and are capable of preventing infection and controlling/abrogating persistent infections. 1.1) Development of novel FMD vaccine platforms. 1.1.1) Development of marker FMDV LL3B3D vaccines against relevant outbreak strains. 1.1.2) Development of improved second-generation Ad5-FMD vaccines. 1.1.3) Discovery of modified live attenuated FMDV vaccine candidates (MLAV). 1.1.4) Discovery of cross-protective vaccines against multiple FMDV subtypes. 1.2) Development of novel biotherapeutics to prevent or control FMD prior to vaccine-induced protection. 1.2.1) Discovery/development of novel biotherapeutics with increased potency and extended systemic half-life. 1.2.2) Evaluation of combined delivery of biotherapeutics and vaccine in swine and cattle. 1.3) Evaluation of vaccine-induced immunity and FMDV carrier state. 1.3.1) Characterization of host immunity associated with novel vaccines against FMDV. 1.3.2) 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) Elucidation of host-pathogen interactions of FMDV in acute and persistent infections. The information derived will be used to devise effective anti-viral intervention strategies. 2.1) Determine the molecular basis for FMDV-host interactions that impact virulence. 2.1.1) Examination of virus factors contributing to FMDV virulence. 2.1.2) Examination of host factors contributing to FMDV virulence. 2.2) Identification of molecular mechanisms associated with the establishment of FMDV persistence. 2.2.1) Determination of host and/or other non-FMDV factors causing or associated with clearance of FMDV from bovine nasopharyngeal tissue. 2.2.2) Investigation of within-host FMDV genomic evolution to characterize site-specific mutational pressure, genomic variation, and potential adaptation to the host. 2.3) Determination of the immune mechanisms affecting protective immunity against FMDV. 2.3.1) Analysis of CD4 helper T-cell response to FMDV vaccination. 2.3.2) Analysis of the CD8 cytotoxic T-cell response to FMDV vaccination. 2.3.3) Analysis of B-cell responses to FMDV in peripheral blood and lymphoid tissue. 3) Understanding the ecology of FMDV in endemic regions, determining drivers of transmission and maintenance in endemic settings, and characterizing risk factors driving FMDV emergence and spread. 3.1) Characterize the ecology of FMDV in endemic regions in Asia and Africa, including determining the factors driving viral transmission and maintenance. 3.2) Characterize factors driving FMDV emergence and spread of novel FMDV strains in endemic settings. 3.3) 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 the development of novel FMD vaccine platforms: including of marker FMDV-LL3B3D vaccines against relevant outbreak strains, second–generation Ad5-FMD vaccines, the discovery of modified live-attenuated FMDV vaccine candidates, and the discovery of cross-protective vaccines against multiple subtypes. Novel biotherapeutics to prevent or control FMD prior to vaccine-induced protection will be based on the discovery/development of novel biotherapeutics with increased potency and extended systemic half-life. An evaluation of combined delivery of biotherapeutics and vaccine in swine and cattle will be conducted. To evaluate vaccine-induced immunity and FMDV carrier state the host immunity associated with novel vaccines against FMDV will be characterized. Novel vaccines will be evaluated for their ability to prevent the FMD carrier state in cattle and assess the host response associated with the carrier divergence. 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. The molecular mechanisms associated with the establishment of FMDV persistence will be identified through the determination of host and/or other non-FMDV factors causing or associated with clearance of FMDV from bovine nasopharyngeal tissue. 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.