Vaccinia viruses with a serpin gene deletion and expressing IFN-gamma induce potent immune responses without detectable replication in vivo.
In a continuing effort to develop safe and efficacious vaccine and immunotherapeutic vectors, we constructed recombinant vaccinia virus (rVV) vaccines lacking either the B13R (SPI-2) or the B22R (SPI-1) immune-modulating gene and coexpressing IFN-gamma. B13R and B22R are nonessential VV immune-modulating genes that have antiapoptotic and antiinflammatory properties with sequence homology to serine protease inhibitors (serpins). IFN-gamma is a cytokine with potent immunoregulatory, antineoplastic, and antiviral properties. We observed that these rVVs with a deletion in a serpin gene and expressing IFN-gamma replicated to high titers in tissue culture yet were avirulent in both immunocompromised and immunocompetent mice with no detectable viral replication in these animals. A single immunization elicited potent humoral, T helper, and cytotoxic T cell immune responses in mice despite the absence of any detectable virus replication in vivo. IFN-gamma coexpression and the inactivation of one or more VV immune-modulating genes provide an optimized method for increasing the safety while maintaining the efficacy of rVV vaccines. This strategy provides a method for developing highly safe and efficacious vaccines for smallpox and other diseases and immunotherapeutic vectors.
Legrand
Fatema A
FA
International Laboratory of Molecular Biology for Tropical Disease Agents, Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Verardi
Paulo H
PH
Chan
Kenneth S
KS
Peng
Yue
Y
Jones
Leslie A
LA
Yilma
Tilahun D
TD
D000818:Animals; D005260:Female; D017353:Gene Deletion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D010455:Peptides / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000502:physiology*; D015843:Serpins / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence; D014779:Virus Replication
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D015843:Serpins; C086597:lambda Spi-1; D007371:Interferon-gamma