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INVESTIGATOR: Ramamoorthy, S.; Webb, BR, TH.; Pillatzki, AN, .

PERFORMING INSTITUTION:
NORTH DAKOTA STATE UNIV
FARGO, NORTH DAKOTA 58105

INTEGRATING VACCINE EFFICACY AND SAFETY BY DIRECTED SUICIDAL REPLICATION

NON-TECHNICAL SUMMARY: Porcine reproductive and respiratory disease syndrome virus (PRRSV) and porcine circovirus type 3 (PCV3) are economically important swine viruses which cause reproductive failure and respiratory disease. While vaccines against PCV3 are yet to be developed, it is known that attenuated vaccines against PRRSV are more effective than inactivated vaccines. However, attenuated PRRSV vaccines and live vaccines in general are associated with the risk of reversion to virulence and recombination with field strains. Hence, the primary goal of this project is to develop a rapid-attenuation method targeting enhanced vaccine safety while retaining or improving vaccine efficacy. The proposed method involves harnessing the natural property of rapid mutation in viruses to induce suicidal replication of the vaccine construct in the host. The primary objectives of the project are therefore to develop directed suicidal vaccines against PRRSV and PCV3, and test the efficacy and safety of the test vaccines in a dual PCV3 and PRRSV coinfection model. In addition, the data generated is expected to contribute to the current understanding pathogenesis in PCV3 and PRRSV coinfections. The expected project outputs include the development of improved, safe and effective vaccines against PCV3 and PRRSV.

OBJECTIVES: Porcine productive and respiratory disease syndrome virus (PRRSV) continues to remain the leading cause of economic losses to the pork industry for over 30 years, and PRRS is characterized by severe respiratory distress and reproductive failure in breeding animals Despite significant investment, efficacy and safety of current PRRSV vaccines remain questionable. While modified live vaccines (MLVs) against PRRSV are generally the most effective, they are associated with significant safety concerns such as recombination with field strains and reversion to virulence. The primary goal of this project is to develop a novel method to improve the safety of live attenuated vaccines. The targeted approach will harness the naturally high mutation rates of viruses such as PRRSV to direct the suicidal replication of the modified live vaccine and result in effective immunity and rapid clearance from the host to integrate vaccine safety and efficacy. Porcine circovirus type 3 (PCV3) is a recently discovered virus which also causes reproductive failure, respiratory illness and the porcine dermatitis and nephropathy syndrome. PCV3 and PRRSV are frequently co-detected in reproductive failure, underscoring the urgent need to better understand and prevent PCV3, especially in the context of coinfections. Vaccines against PCV3 are not yet available. Although porcine circoviruses are DNA viruses, their mutation rates are similar to that of RNA viruses. Given the similarities in the clinical manifestations of PCV3 and PRRSV, the other goals of the project are to develop a PCV3 and PRRSV dual infection model and apply the directed suicidal vaccine approach to develop modified live vaccines against both PCV3 and PRRSV, and assess protection against both viral infections using the dual infection model.The objectives of the project are to:Aim 1 - To develop and test a DS-PRRSV MLV To test the hypothesis that a DS-PRRSV-MLV will elicit superior efficacy and safety compared to a commercial PRRSV MLV, the DS-PRRSV-MLV candidate developed by us will be tested in a piglet vaccination and heterologous PRRSV challenge model.Aim 2 - To develop and test a DS-PCV3-MLV vaccine against singular PCV3 challenge and dual PCV3 and PRRSV challenge. Objective 2.1 To optimize singular and dual PCV3 and PCV3 and PRRSV swine infection models respectively. To test the hypothesis that dual infection of weanling piglets with recombinant PCV3 and PRRSV will result in exacerbation of clinical signs, swine will be infected with either PCV3 alone or with PCV3 and PRRSV, and clinical and immunological parameters evaluated.?Objective 2.2. To develop and test the safety and efficacy of a DS-PCV3-MLV against single and dual PCV3 and PRRSV challenge. To test the hypothesis that the DS-PCV3-MLV can protect against PCV3 and also mitigate the effects of PRRSV in coinfections, the DS-PCV3-MLV will be tested by vaccination of piglets and challenge with PCV3 alone or PCV3+PRRSV.