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Infection and Immunity, October 2008, p. 4564-4573, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00581-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Nasal Interleukin-12 DNA Vaccine Coexpressing Yersinia pestis F1-V Fusion Protein Confers Protection against Pneumonic Plague

Hitoki Yamanaka,¹ Teri Hoyt,¹ Xinghong Yang,¹ Sarah Golden,¹ Catharine M. Bosio,^2, Kathryn Crist,¹ Todd Becker,¹ Massimo Maddaloni,¹ and David W. Pascual^1*

Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717,¹ Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80521²

Received 12 May 2008/ Returned for modification 18 June 2008/ Accepted 31 July 2008

Previous studies have shown that mucosal application of interleukin-12 (IL-12) can stimulate elevated secretory immunoglobulin A (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 antigen (F1-Ag) 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-Ag and anti-V-Ag titers were detectable beginning at week 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 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.

Published ahead of print on 11 August 2008.

Editor: R. P. Morrison

Present address: Immunity to Pulmonary Pathogens Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840.