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Study of a Synthetic Porcine Reproductive and Respiratory Syndrome Virus Strain as a Vaccine Candidate
Porcine reproductive and respiratory syndrome virus (PRRSV), causing reproductive failure in sows and pneumonia in growing pigs, continues to be a severe enemy of the global pig industry. Current PRRSV vaccines are ineffective at providing adequate levels of protection against heterologous PRRSV strains, presumably because PRRSV strains circulating in the field are genetically divergent from the vaccine strains. In addition, most PRRSV strains are shown to be a suppressor of the type I IFNs response, the down-regulation of which appears to interfere with host protective immunity. PRRSV-CON containing a consensus genome sequence of PRRSV-2 was generated to overcome the genetic diversity of PRRSV and it was found to confer optimal levels of heterologous protection. Moreover, we found that PRRSV-CON has a unique phenotype of inducing type I IFNs instead of suppressing these cytokines like most of the wide type PRRSV strains do. We hypothesize that a candidate PRRSV vaccine based on PRRSV-CON could provide broad cross-protection against heterologous PRRSV strains, and its ability of inducing type I IFNs contributes to the overall levels of heterologous protection. The gain- and loss-of-function studies revealed that the 3.3 kb genomic region of PRRSV-CON encoding viral proteins nsp1α, nsp1β and the N-terminus of nsp2 was correlated to its IFN-inducing phenotype. Through an immunization/challenge experiment in a young pig model using the immunizing antigens PRRSV-CON at passage 1 (designated as CON-P1) and its mutant CON/FL12D that is devoid of the type I IFN-inducing phenotype, immunization with CON-P1 carrying the phenotype of inducing type I IFN response confers significantly higher levels of heterologous protection than CON/FL12D does. This suggests that the virus’ capability of type I IFN induction may contribute to protective immunity against heterologous PRRSV strain. We successfully reduced the virulence of CON-P1 by continually passaging this virus in MARC-145 cells. When experimentally inoculated into pigs, PRRSV-CON at passage 90 (designated as CON-P90) conferred comparable levels of protection against heterologous PRRSV strain as its parental strain CON-P1, indicating that CON-P90 can serve as an excellent candidate for developing a modified live vaccine. In summary, the results obtained in this dissertation provide useful and novel information for designing more effective PRRSV vaccines with improved levels of protection against heterologous PRRSV strains.
Sun, Haiyan, "Study of a Synthetic Porcine Reproductive and Respiratory Syndrome Virus Strain as a Vaccine Candidate" (2017). ETD collection for University of Nebraska - Lincoln. AAI10683682.