Enhanced Safety and Efficacy of Recombinant Vaccines

NON-TECHNICAL SUMMARY: Development of safe and effective recombinant vaccines for livestock will increase the ability to control diseases while enabling differentiation of vaccinated and infected animals. The long-term objective of this proposal is to increase the safety and efficacy of live recombinant vaccines for use in control of veterinary diseases. <P>
APPROACH: We plan to develop recombinant vaccinia virus vaccines that are safer and more effective as vaccines for livestock. Using vesicular stomatitis virus as a model we plan to develop rVVs that express cytokines and immunogenic heterologous proteins in rVVs that have had immunomodulating genes removed to enhance immune responses in vaccinated animals. These vaccines will enhance protection of animals from disease and enable the detection of vaccinated vs naturally infected livestock.
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PROGRESS: 2002/10 TO 2007/09 <BR>
OUTPUTS: This is a continuation of work we have been pursuing to increase the safety and efficacy of live attenuated recombinant vaccines. The objectives of this research are to investigate the effects on safety and efficacy of recombinant vaccinia viruses with immunomodulating genes deleted and expressing cytokine genes. Results from this research has been disseminated via presentation of the data in scientific meetings and publication in scientific journals. <BR>PARTICIPANTS: Dr. Tilahun Yilma, VM:ILMB, UC Davis. Principal investigator. Dr. Paulo Verardi, VM:ILMB, UC Davis, co-investigator, design strategies for constructing recombinant viruses, train and supervise graduate students, postdocs, and technicians. Dr. Leslie Jones, VM:ILMB, UC Davis, co-investigator, design animal studies, immune assays, train and supervise graduate students, postdocs, and technicians. Dr. James Papin, postdoc, constructed the rift valley fever recombinant vaccines, Fatema LeGrand, Graduate student, constructed recombinant vaccinia viruses and conducted animal research, Kenneth Chan, graduate student, assisted in the assessment of immune responses to vaccination, Yue Peng, graduate student, helped with the immunological assays, Shirley Leung, VM:ILMB, UC Davis, laboratory supervisor train and supervise graduate students, postdocs, technicians, and lab assistants in lab safety. Ensure lab equipment maintenance, supplies, and compliance with university regulations. Patricia Weber, Technician, constructed recombinant vaccinia viruses with inducible promoters, Sandy Yan, VM:ILMB, UC Davis, laboratory technician. This project provided training for graduate students and postdoctoral scholars. <BR>TARGET AUDIENCES: Individuals and organizations interested in the development of safe and effective vaccines for the control of livestock diseases. <P>
IMPACT: 2002/10 TO 2007/09<BR>
We have demonstrated the adjuvant effect and attenuating effects of interferon-gamma for animal vaccines using vesicular stomatitis virus as a modelƒ|ƒnƒnWe have also demonstrated that the immunomodulating vaccinia virus genes such as the interferon-gamma receptor homolog (B8R) and two serpin gene homologs (B13R and B22R) are virulence factors for the virus. Deletions of these genes decrease virulence of the virus without decreasing the immune responses. Similarly, inactivation of these genes and co-expression of interferon-gamma resulted extremely attenuated vaccinia viruses that still replicate well in vitro and induce excellent immune responses without detectable replication in vivo. We have cloned the murine cytokine, interleukin-18 (IL 18) gene and have inserted it into the B13R and B22R targeting vectors. Also called interferon gamma inducing factor, IL 18 is a potent inducer of interferon gamma and granulocyte/macrophage colony stimulating factor (GM CSF) production in T cells from T cells and natural killer cells and also decreases the levels of interleukin 10. We have demonstrated that expression of IL-18 attenuates vaccinia virus replication in immunodeficient mice (nude and SCID) although not completely, like interferon-gamma. Mice vaccinated with recombinant vaccinia viruses expressing interferon-gamma had no detectable virus replication but had equivalent cell-mediated and humoral immune responses. Vaccination with recombinant vaccinia virus expressing IL-18 resulted in low-level detectable replication of the virus in tissues and enhanced, albeit not significantly, immune responses to vaccination. Experiments in mice without a functional interferon-gamma gene demonstrated that the attenuating effect of IL-18 was dependent on the expression of interferon-gamma. We are currently testing the immunogenicity of a new recombinant vaccinia virus vaccine for rift valley fever virus in mice. These vaccines express the rift valley fever virus surface glycoproteins (G1 and G2) with or without human interferon-gamma to increase safety for vaccinating personnel and animal handlers.