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Journal of Virology, March 2004, p. 2770-2779, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2770-2779.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Induction of Potent Humoral and Cell-Mediated Immune Responses by Attenuated Vaccinia Virus Vectors with Deleted Serpin Genes

Fatema A. Legrand, Paulo H. Verardi, Leslie A. Jones, Kenneth S. Chan, Yue Peng, and Tilahun D. Yilma*

International Laboratory of Molecular Biology for Tropical Disease Agents, Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California 95616

Received 28 August 2003/ Accepted 18 November 2003

Vaccinia virus (VV) has been effectively utilized as a live vaccine against smallpox as well as a vector for vaccine development and immunotherapy. Increasingly there is a need for a new generation of highly attenuated and efficacious VV vaccines, especially in light of the AIDS pandemic and the threat of global bioterrorism. We therefore developed recombinant VV (rVV) vaccines that are significantly attenuated and yet elicit potent humoral and cell-mediated immune responses. B13R (SPI-2) and B22R (SPI-1) are two VV immunomodulating genes with sequence homology to serine protease inhibitors (serpins) that possess antiapoptotic and anti-inflammatory properties. We constructed and characterized rVVs that have the B13R or B22R gene insertionally inactivated (v{Delta}B13R and v{Delta}B22R) and coexpress the vesicular stomatitis virus glycoprotein (v50{Delta}B13R and v50{Delta}B22R). Virulence studies with immunocompromised BALB/cBy nude mice indicated that B13R or B22R gene deletion decreases viral replication and significantly extends time of survival. Viral pathogenesis studies in immunocompetent CB6F1 mice further demonstrated that B13R or B22R gene inactivation diminishes VV virulence, as measured by decreased levels of weight loss and limited viral spread. Finally, rVVs with B13R and B22R deleted elicited potent humoral, T-helper, and cytotoxic T-cell immune responses, revealing that the observed attenuation did not reduce immunogenicity. Therefore, inactivation of immunomodulating genes such as B13R or B22R represents a general method for enhancing the safety of rVV vaccines while maintaining a high level of immunogenicity. Such rVVs could serve as effective vectors for vaccine development and immunotherapy.

* Corresponding author. Mailing address: International Laboratory of Molecular Biology for Tropical Disease Agents, University of California, Davis, CA 95616. Phone: (530) 752-8306. Fax: (530) 752-1354. E-mail: tdyilma{at}ucdavis.edu.

Journal of Virology, March 2004, p. 2770-2779, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2770-2779.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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