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Journal of Virology, August 2007, p. 8774-8783, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00538-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Development of Smallpox Vaccine Candidates with Integrated Interleukin-15 That Demonstrate Superior Immunogenicity, Efficacy, and Safety in Mice

Liyanage P. Perera,^1* Thomas A. Waldmann,¹ Joseph D. Mosca,² Nicole Baldwin,³ Jay A. Berzofsky,⁴ and Sang-Kon Oh^4,

Metabolism Branch,¹ Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1374,⁴ JDM Technologies Inc., Ellicott City, Maryland 21042,² Baylor Institute for Immunology Research, Baylor University Medical Center at Dallas, 3434 Live Oak Street, Dallas, Texas 75204³

Received 14 March 2007/ Accepted 30 May 2007

The potential use of variola virus, the etiological agent of smallpox, as a bioterror agent has heightened the interest in the reinitiation of smallpox vaccination. However, the currently licensed Dryvax vaccine, despite its documented efficacy in eradicating smallpox, is not optimal for the vaccination of contemporary populations with large numbers of individuals with immunodeficiencies because of severe adverse effects that can occur in such individuals. Therefore, the development of safer smallpox vaccines that can match the immunogenicity and efficacy of Dryvax for the vaccination of contemporary populations remains a priority. Using the Wyeth strain of vaccinia virus derived from the Dryvax vaccine, we generated a recombinant Wyeth interleukin-15 (IL-15) with integrated IL-15, a cytokine with potent immunostimulatory functions. The integration of IL-15 into the Wyeth strain resulted in a >1,000-fold reduction in lethality of vaccinated athymic nude mice and induced severalfold-higher cellular and humoral immune responses in wild-type mice that persisted longer than those induced by the parental Wyeth strain. The superior efficacy of Wyeth IL-15 was further demonstrated by the ability of vaccinated mice to fully survive a lethal intranasal challenge of virulent vaccinia virus even 10 months after vaccination, whereas all mice vaccinated with parental Wyeth strain succumbed. By integrating IL-15 into modified vaccinia virus Ankara (MVA), a virus currently under consideration as a substitute for the Dryvax vaccine, we developed a second vaccine candidate (MVA IL-15) with greater immunogenicity and efficacy than Dryvax. Thus, Wyeth IL-15 and MVA IL-15 viruses hold promise as more-efficacious and safe alternatives to the Dryvax vaccine.

Published ahead of print on 6 June 2007.

Current address: Baylor Institute for Immunology Research, Baylor University Medical Center at Dallas, 3434 Live Oak Street, Dallas, TX 75204.

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