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United States Department of Agriculture

Agricultural Research Service

Research Project: FOOT-AND-MOUTH DISEASE VIRUS (FMDV) COUNTERMEASURES DISCOVERY

Location: Foreign Animal Disease Research

2008 Annual Report


1a.Objectives (from AD-416)
1. Develop improved vaccine platforms and delivery systems to control FMD. 2. Determine the mechanism of early immune enhancement against FMDV.


1b.Approach (from AD-416)
1. Development of improved FMD vaccines will be accomplished by: a.) focus on development of improved adenovirus-vectored FMDV vaccine platform and its routes of inoculation. b.) focus on the construction and testing of leader-deleted FMDV with a negative marker as an inactivated vaccine platform. c.) focus on the construction of T cell independent antigens as a vaccine platform. 2. Mechanisms of immune enhancement against FMD will be explored by characterization of: a.) induction of antiviral response by IFN alpha, beta and gamma and combinations of them. b.) induction of innate immune responses by TLR agonists utilized alone or as adjuvants in combination with vaccines.


3.Progress Report
In FY 2008 we are continuing to pursue the development of improved FMD vaccine platforms and delivery systems. We have constructed a second generation Ad5-A24 vector containing the viral nonstructural protein 2B and this vector induces an enhanced immune response and protective immunity in swine. Based on previous work demonstrating that an inactivated leader deleted FMDV vaccine can protect swine, we have added markers to this vaccine candidate and demonstrated protection of cattle. We have planned and will soon be testing an alternate vaccine delivery system that more efficiently infects dendritic cells, the major antigen presenting cell, using our Ad5-A24 vaccine vector system. We continue to examine, at the molecular level, the mechanism of interferon-induced protection. We have already demonstrated that individual or combinations of interferons induce an accumulation of dendritic cells in the skin and an upregulation of various chemokines that are involved in attracting immune cells to the site of infection. The progress of this project relates to the component 1: Biodefense Research, Problem Statement 1A: Foreign Animal Diseases of the National Program in Animal Health, within the NP 103 Action Plan.


4.Accomplishments
1. Leader-deleted Foot-and-Mouth Disease Virus (FMDV) as an inactivated vaccine or cattle

The current Foot-and-Mouth (FMD) vaccine has a number of drawbacks including the need to grow large amounts of infectious FMDV for vaccine production and the inability to distinguish vaccinated from infected animals. We previously produced a safer attenuated leader-deleted virus and demonstrated its utility as a vaccine. We now removed a critical region from this virus and showed that we can serologically distinguish vaccinated from infected animals. The progress of this project relates to component 1: Biodefense Research, Problem Statement 1A: Foreign Animal Diseases of the National Program in Animal Health, within the NP 103 Action Plan.

2. Protection of swine with interferon (IFN) alpha and gamma

To control Foot-and-Mouth Disease (FMD) outbreaks it is necessary to rapidly inhibit virus replication. The traditional inactivated FMD vaccine requires approximately 7 days to induce protection. We previously demonstrated that IFN alpha alone can rapidly protect swine from Foot-and-Mouth Disease Virus (FMDV) challenge, but this approach was not completely successful in cattle. To improve FMDV control measures we found that a combination of IFN alpha and gamma, at lower doses than each alone, can rapidly protect swine. The progress of this project relates to component 1: Biodefense Research, Problem Statement 1A: Foreign Animal Diseases of the National Program in Animal Health, within the NP 103 Action Plan.

3. Ad5-A24 vaccine containing nonstructural protein 2B has improved efficacy in swine

The dose of the Ad5-A24 vaccine required to protect swine and cattle is high. To attempt to improve the potency and efficacy of this vaccine candidate we included the nonstructural protein 2B. Swine inoculated with this vaccine had a more rapid neutralizing antibody response and enhanced protection as compared to animals inoculated with the vaccine lacking 2B. The progress of this project relates to component 1: Biodefense Research, Problem Statement 1A: Foreign Animal Diseases of the National Program in Animal Health, within the NP 103 Action Plan.

4. Induction of rapid immune responses in swine inoculated with toll-like receptor (TLR) agonists

To control Foot-and-Mouth Disease (FMD) outbreaks it is necessary to rapidly inhibit virus replication. The inactivated FMD vaccine requires approximately 7 days to induce protection. Activation of TLRs can induce a rapid immune response. We showed that inoculation of swine with TLR 7/8 agonists activated natural killer (NK) cells which resulted in more rapid clearance of virus from infected animals potentially preventing virus spread. The progress of this project relates to component 1: Biodefense Research, Problem Statement 1A: Foreign Animal Diseases of the National Program in Animal Health, within the NP 103 Action Plan

5. Toll-like receptor (TLR) agonists as adjuvants for inactivated Foot-and-Mouth Disease (FMD) vaccine

The inactivated FMD vaccine only induces protection for a short period of time. The TLR 9 agonist, cytosine phosphate guanosine (CpG), has been shown to enhance the efficacy of vaccines. In a collaborative international study we vaccinated swine with the inactivated FMD vaccine in the presence or absence of CpG. Animals inoculated with vaccine and CpG showed no enhanced protection as compared to animals given only vaccine. The progress of this project relates to component 1: Biodefense Research, Problem Statement 1A: Foreign Animal Diseases of the National Program in Animal Health, within the NP 103 Action Plan.


6.Technology Transfer

Number of Active CRADAs1
Number of Non-Peer Reviewed Presentations and Proceedings10

Review Publications
Grubman, M.J., Moraes, M., Diaz-San Segundo, F., Pena, L., De Los Santos, T. 2008. Evading the Host Immune Response: How Foot-and-Mouth Disease Virus Has Become an Effective Pathogen. Federation of European Microbiological Societies Microbiology Letters. 53:8-17.

De Los Santos, T., Diaz-San Segundo, F., Grubman, M.J. 2007. Degradation of Nuclear Factor Kappa B During Foot-and-Mouth Disease Virus Infection. Journal of Virology. 81(23):12803-12815.

Nfon, C., Ferman Ii, G.S., Toka, F., Golde, W.T. 2008. Interferon Alpha Production by Circulating Dendritic Cells is Inhibited During Acute Infection with Foot-and-Mouth Disease Virus (FMDV). Viral Immunology. 21:68-77.

Last Modified: 9/10/2014
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