Abstract

In the aftermath of the attacks of September 11 and the anthrax scare, we have a heightened awareness of US vulnerability to bioterrorism. One of the most feared infectious agents is variola virus, the causative agent of smallpox. Various strains of vaccinia virus (VV) are highly effective in preventing this disease, but have definite rates of complications. Severe illness or death is rare in people with normal immune responses, but considerably more common in individuals with cell-mediated immune defects. The number of individuals that are at risk from this normally innocuous vaccine has greatly increased with the spread of the human immunodeficiency virus (HIV), and it now becomes important to improve the efficacy and safety of this vaccine. We have worked extensively with VV as a recombinant vaccine for a number of diseases; our rinderpest vaccine was described as one of two outstanding rVVs in a leading journal (G. Ada, Nature 349:369, 1991). We have also developed strategies for attenuating VV while enhancing efficacy, with one of the most effective being the incorporation of the interferon-gamma (IFN-gamma) gene. We have shown that expression of IFN-gamma leads to a TH1 immune response essential against viral infection with no deleterious effects. We have also studied the effects of inactivating VV immunomodulating genes such as B8R, B13R, and B22R that are virulence factors in VV. Based on our past experience, we propose developing a safer and more efficacious vaccine for smallpox based on the New York City Board of Health (Wyeth) strain of VV that is currently used in the US. We will delete the B8R gene and insertionally inactivate the TK virulence gene with the human IFN-gamma gene to increase attenuation of the virus and the protective cell-mediated immune responses. This recombinant VV will be compared to the parental vaccine in both normal and simian immunodeficiency virus-infected macaques (used as a model for HIV-infected humans) to assess efficacy and safety for normal and immunodeficient individuals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054951-03
Application #
6847411
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Challberg, Mark D
Project Start
2003-09-30
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2005
Total Cost
$466,212
Indirect Cost

  Institution

Name
University of California Davis
Department
Biochemistry
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618

  Publications

Verardi, Paulo H; Legrand, Fatema A; Chan, Kenneth S et al. (2014) IL-18 expression results in a recombinant vaccinia virus that is highly attenuated and immunogenic. J Interferon Cytokine Res 34:169-78
Holechek, Susan A; Denzler, Karen L; Heck, Michael C et al. (2013) Use of a recombinant vaccinia virus expressing interferon gamma for post-exposure protection against vaccinia and ectromelia viruses. PLoS One 8:e77879
Yilma, Tilahun; Verardi, Paulo; Jones, Leslie (2010) Development of safe and efficacious viral vaccines for animals. Crit Rev Immunol 30:223-37
Lin, Fan-ching; Peng, Yue; Jones, Leslie A et al. (2009) Incorporation of CD40 ligand into the envelope of pseudotyped single-cycle Simian immunodeficiency viruses enhances immunogenicity. J Virol 83:1216-27
Peng, Yue; Lin, Fan-ching; Verardi, Paulo H et al. (2009) Lower levels of gamma interferon expressed by a pseudotyped single-cycle simian immunodeficiency virus enhance immunogenicity in rats. J Virol 83:1592-601
Peng, Yue; Lin, Fan-ching; Verardi, Paulo H et al. (2007) Pseudotyped single-cycle simian immunodeficiency viruses expressing gamma interferon augment T-cell priming responses in vitro. J Virol 81:2187-95
Legrand, Fatema A; Verardi, Paulo H; Chan, Kenneth S et al. (2005) Vaccinia viruses with a serpin gene deletion and expressing IFN-gamma induce potent immune responses without detectable replication in vivo. Proc Natl Acad Sci U S A 102:2940-5
Chan, Kenneth S; Verardi, Paulo H; Legrand, Fatema A et al. (2005) Nef from pathogenic simian immunodeficiency virus is a negative factor for vaccinia virus. Proc Natl Acad Sci U S A 102:8734-9
Legrand, Fatema A; Verardi, Paulo H; Jones, Leslie A et al. (2004) Induction of potent humoral and cell-mediated immune responses by attenuated vaccinia virus vectors with deleted serpin genes. J Virol 78:2770-9