IAI Accepts, published online ahead of print on 11 August 2008

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Infect. Immun. doi:10.1128/IAI.00581-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Nasal IL-12 DNA Vaccine Co-Expressing Yersinia pestis F1-V Fusion Protein Confers Protection against Pneumonic Plague

Hitoki Yamanaka, Teri Hoyt, Xinghong Yang, Sarah Golden, Catharine M. Bosio, Kathryn Crist, Todd Becker, Massimo Maddaloni, and David W. Pascual^*

Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717; Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80521

^* To whom correspondence should be addressed. Email: dpascual{at}montana.edu.

Previous studies have shown that mucosal application of IL-12 can stimulate elevated secretory IgA (S-IgA) responses. Since possible exposure to plague is via Yersinia pestis- laden aerosols that results in pneumonic plague, arming both the mucosal and systemic immune systems may offer an added benefit for protective immunity. Two bicistronic plasmids were constructed that encoded the protective plague epitopes, capsular (F1) antigen and virulence antigen (V-Ag) as a F1-V fusion protein, but differed in the amounts of IL-12 produced. When applied nasally, serum IgG and mucosal IgA anti-F1- and anti-V-Ag titers were detectable beginning at wk 6 after three weekly doses, and recombinant F1-Ag boosts were required to elevate the F1-Ag-specific antibody (Ab) titers. Following pneumonic challenge, the best efficacy was obtained in mice primed with IL-12(Low)/F1-V vaccine with 80% survival when compared to mice immunized with IL-12(Low)/F1, IL-12(Low)/V, or IL-12(Low) vector DNA vaccines. Improved expression of IL-12 resulted in lost efficacy when using the IL-12(High)/F1-V DNA vaccine. Despite differences in the amount of IL-12 produced by the two F1-V DNA vaccines, Ab responses and Th cell responses to F1 and V-Ags were similar. These results show that IL-12 can be used as a molecular adjuvant to enhance protective immunity against pneumonic plague, but in a dose-dependent fashion.

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