Project Number: 3625-32000-088-00
Project Type: Appropriated

Start Date: Mar 20, 2007
End Date: Oct 19, 2011

Objective:
Obj. 1: Identify mechanisms of PRRS virus (PRRSV) pathogenesis to develop vaccination strategies to enhance or improve immunity against PRRSV. Sub-objective 1.2: Use reverse genetic technology to identify determinants of viral pathogenesis, immune evasion, and transmission. Sub-objective 1.3: Use reverse genetic technology to design live attenuated vaccine strains that provide broad protection against PRRSV infection and allow the differentiation of infected from vaccinated animals. Obj. 2: Identify mechanisms of SI virus (SIV) pathogenesis and develop vaccination strategies to enhance or provide broad cross-protection for circulating subtypes of SIV. Sub-objective 2.4: Characterize humoral and cell mediated immune responses elicited by influenza vaccines administered in the face of maternal antibodies. Sub-objective 2.5: Characterize heterologous protection provided by humoral and cell mediated immune responses elicited by influenza vaccines. Obj. 3: Identify the host-pathogen interactions and environmental factors that lead to PCVAD and discover effective measures to prevent, control, and eliminate this emerging disease from U.S. swine herds. Obj. 4: Develop methods of modulation of innate and adaptive immune responses to swine viral pathogens with an emphasis on modulating the effects of innate immunity on pathogenesis of viral diseases.

Approach:
For improved PRRSV control, identify strategies for improved immunoprophylaxis by testing vaccine strategies with recombinant adenoviruses expressing selected PRRS viral gene constructs to increase safety and efficacy of PRRS vaccines. For improved SIV control, identify mechanisms of SIV pathogenesis and develop vaccination strategies to enhance cross-protection for circulating subtypes of SIV. Investigate the role of avian polymerase genes in adaptation of novel reassortant SIVs to pigs. Study specific regions within identified genes that confer growth advantages. Maintain a contemporary repository for emerging SIV subtypes and genotypes and combine with novel vaccine approaches for improved SIV vaccines. Develop vaccine strategies that have broader subtype coverage through use of better cross-reacting isolates, novel combinations of adjuvants and/or cytokines, and different routes of vaccination. Specific aims: A) Genetic, antigenic and pathogenic characterization of novel isolates; B) Evaluation of new inactivated vaccines against current isolates; and C) Evaluation of genetically engineered, modified-live vaccines against current isolates. For improved control of PCV type 2, conduct research to identify mechanisms of PCV2 pathogenesis in PMWS and perform genetic analysis of the replication and virulence mechanisms of PCV2 to develop vaccination strategies against porcine circoviruses. Goal is to develop recombinant virus vaccines against PMWS by attenuation of the viral replication and virulence mechanisms; and develop and evaluate multiplex diagnostic assays to detect pathogens involved in PCVAD, determine the role of endemic and novel swine viruses in inducing PCVAD, and evaluate genetic and biological determinants that lead to PCVAD. Development of methods for modulation of innate and adaptive immune responses to swine viral pathogens will focus on modulating the effects of innate immunity on pathogenesis of viral diseases. Evaluate whether early serum IFN-gamma response is caused by the interaction of PRRSV structural proteins with components of the hosts' immune system. Ameliorate clinical disease through prophylactic or metaphylactic administration of granulocyte-colony stimulating factor in an attempt to reduce the severity or duration of viral pneumonia associated with PRRSV and SIV. Investigate the B cell response to these swine viruses with a focus on immunoglobulin class switch recombination and diversification of the VDJ repertoire. Changes in B cells correlate with the appearance of neutralizing antibody; understanding the virulence mechanisms contributing to the delayed development of neutralizing antibody against PRRSV may provide essential insights into improved control of PRRSV shedding in vaccinated and infected pigs. BSL-2: Recertified 6/11/10 #304, 6/17/10 #306, 8/27/10 #274, 8/1/10 #309, 8/28/10 #311, 9/22/10 #314, 9/21/10 #329, 10/17/10 #244. BSL-2/BSL-3: Recertified 8/21/10 #310; 10/17/10 #243, 11/10/10 #316, Certified 8/16/10 #334. BSL-1/BSL2: Cancelled 3/14/11 #332. BSL-3/BSL-AG: Certified 4/4/11 #342; Certified 2/14/11 #0003RA.