Submitted to: Veterinary Immunology and Immunopathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/24/2004
Publication Date: 11/1/2004
Citation: Meier, W., Husmann, R., Calzada-Nova, G., Schnitzlein, W.M., Lunney, J.K., Zuckermann, F. 2004. In vivo modulation of the prrs virus vaccine-induced immune responses of swine toward a THL phenotype. Veterinary Immunology and Immunopathology. 102:299-314. Interpretive Summary: Porcine reproductive and respiratory syndrome (PRRS) is an economically important disease of swine characterized by abortion, stillbirth and weak-born pigs. In its non-reproductive form, this syndrome affects younger pigs more severely than older animals, producing reduced growth and pneumonia that can be made more severe by co-infection with other pathogens. Because of its economic impact major efforts have addressed the development of vaccines, but they are only partially effective in providing pigs protection against PRRSV infection. Attenuated, modified live virus (MLV) vaccines provide immunized pigs protection from subsequent challenge with the homologous PRRSV strain; however, the overall protective immunity provided by MLV to swine in commercial settings is generally inadequate. One characteristic of PRRSV infection, that probably contributes to the retarded development of a specific cell-mediated immune response, is the lack of induced interferon-alpha (IFNA) production. Usually, virus-infected cells secrete type I IFN (IFNA, IFNB) and the released cytokine interacts with a subset of naïve T cells to promote their conversion into virus-specific IFN-gamma (IFNG) secreting cells (SC). Alternatively, for viruses that are poor inducers of type I IFN, the development of a Th1, IFNG dominated response can be generated by a pathway that utilizes interleukin-12 (IL12). Based on this, the present studies were undertaken to determine if the antiviral adaptive immunity induced by vaccination with PRRS MLV could be modified simply by the co-administration of rIL12 protein directly, or of porcine IFNA or IL12 indirectly via plasmids expressing these cytokines. Our results showed that all three adjuvants positively influenced the intensity and rate of development of the virus-specific IFNG response, with IFNA giving a significantly higher and longer lasting increase in IFNG SC than IL12 or MLV alone. No significant changes in anti-viral antibody or serum neutralizing activity, nor protection against challenge infection, were found. There was however an improvement in weight gain after viral challenge with IFNA adjuvant. Additionally, the effect of stimulation with a known IFNA inducer, namely double-stranded RNA, was examined and shown to increase IFNG SC. We propose that the strong humoral immunity bias of the host response to PRRSV is mostly responsible for the difficulties in the development of a vaccine deemed effective in the field. Although our use of porcine cytokines, especially IFNA, as adjuvant did not radically affect PRRSV's inherent ability to promote this type of polarized immunity, a positive impact on the transition of T lymphocytes to IFNG SC was noticed. The limited up-regulation of cellular IFNG responses indicates that more substantial innate immune stimulants will be required to immunomodulate the immune response to PRRSV and overcome the tendency of PRRSV not to elicit this type of Th1 response.
Technical Abstract: Immunization of pigs with a modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine initially elicits a weak interferon-gamma (IFNG) response. To improve the immune response, an adjuvant consisting of plasmid encoding either porcine interleukin (IL)-12 or IFN-alpha (IFNA) was co-administered during vaccination. In the presence of the adjuvant, at least a three-fold increase in the primary virus-specific IFNG response was observed. While this enhancement was only transient (one week) when the IL-12 expressing plasmid was used, the effect was not only still apparent at six weeks after vaccination in the presence of the IFNA expressing plasmid but even after challenge with a virulent genetically divergent PRRSV. In contrast, no effect of the adjuvant on the production of anti-virus antibodies was noticed throughout the study. Despite the apparent augmentation of a T helper 1 (Th1) type response by the inclusion of IFNA or IL-12 during vaccination, this modulation only slightly and transiently improved the clinical outcome and did not necessarily correlate with a reduction in viremia. Since a similar increase in the degree of the IFNG response to the PRRSV vaccine could be achieved by substituting polyinosinic-polycytidylic acid in lieu of either cytokine, exposure to PRRSV in the presence of a variety of Th1 polarizing molecules can positively influence the development of the cell-mediated immune response of swine to this pathogen. Conceivably, such intervention could be applied to improve the formulation of anti-PRRSV vaccines.