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Author Getachew, Rebecca
Title Disabling the C12L and B8R genes of vaccinia virus synergistically enhances safety and efficacy of the vaccine
book jacket
Descript 110 p
Note Source: Dissertation Abstracts International, Volume: 73-03, Section: B, page: 1421
Adviser: Tilahun Yilma
Thesis (Ph.D.)--University of California, Davis, 2011
One of the most feared infectious agents is variola virus, the causative agent of smallpox. The vaccine for smallpox, vaccinia virus (VACV), is highly effective, but severe illness and even death has been observed in individuals with immune defects. The population at risk from this normally innocuous vaccine has greatly increased with the spread of human immunodeficiency virus and the increase in the number of individuals who are on immunosuppressive drugs. Thus, further improvement of the safety of the vaccine is necessary
Various attenuated replication competent and defective VACV based vaccines have been developed. Although the pre-clinical and clinical data of many of these vaccines are promising, the efficacies, particularly the replication defective, are still in question. In this study, we develop attenuated replication competent recombinants that are based on the vaccine approved Wyeth strain (WY) of VACV. The virus encodes various immunomodulating genes that interfere with the host response to infection. In order to attenuate and enhance immune response to VACV, we inactivated two genes that encode secreted proteins that directly and indirectly inhibit the host's IFN-gamma response. The C12L and B8R genes encode homologs of an IL-18 binding protein and an IFN-gamma receptor respectively. The C12 protein acts an IL-18 antagonist; it binds to the IL-18 cytokine and prevents its activities one of which is to induce IFN-gamma. The B8 protein binds directly to IFN-gamma and hinders its antiviral and immune-modulating functions. To evaluate the effects of these genes on the immune responses and virulence of VACV, single (vYDelta2C12L and vYDeltaB8R) and double (vYDelta2C12LB8R) deleted recombinants (rVACVs) were generated. Inactivation of these genes enhanced in-vitro IFN-gamma expression and function
The relative virulence of the rVACVs was assessed in-vivo using immunodeficient mice. The rVACV with both genes deleted (vYDelta2C12LB8R) was found to be the most attenuated followed by vYDelta2C12L and vYDeltaB8R respectively. Cell-mediated immune (CMI) responses induced by vaccination with the rVACVs were also assessed in normal mice. vYDelta2C12LB8R and vYDeltaB8R induced comparable CMI responses to the parental WY despite the attenuation of the rVACVs however, vYDelta2C12L induced lower virus specific CD8+T-cell responses. In addition, inactivation of the genes did not alter humoral responses induced by the rVACVs. The responses induced by all of the rVACVs protected normal mice from severe weight loss when challenged with the virulent WR strain of VACV. Mice vaccinated with vYDelta2C12LB8R or WY had the least weight loss followed by the mice that received vYDeltaB8R and vYDelta2C12L, respectively. Although vYDelta2C12LB8R is the most attenuated rVACV, it was found to induce the most protective responses suggesting deletion of both genes had a synergistic effect on the immune responses, possibly due to enhanced expression and function of IFN-gamma
School code: 0029
Host Item Dissertation Abstracts International 73-03B
Subject Biology, Virology
Health Sciences, Immunology
0720
0982
Alt Author University of California, Davis. Immunology
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