CVI Accepts, published online ahead of print on 5 November 2008

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Clin. Vaccine Immunol. doi:10.1128/CVI.00333-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Fusion Protein, Flagellin/F1/V, is an Effective Plague Vaccine in Mice and Two Species of Nonhuman Primates

Steven B. Mizel^*, Aaron H. Graff, Nammalwar Sriranganathan, Sean Ervin, Cynthia J. Lees, Mark O. Lively, Roy R. Hantgan, Michael J. Thomas, James Wood, and Brian Bell

Department of Microbiology and Immunology, Department of Pediatrics, Section on Comparative Medicine, and Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157; Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061; and Walter Reed Army Institute of Research Bioproduction Facility, Silver Spring, MD 20910

^* To whom correspondence should be addressed. Email: smizel{at}wfubmc.edu.

A number of studies have clearly demonstrated that flagellin is a potent adjuvant that promotes robust immune responses when given with a protein antigen. In view of the potential biological and practical benefits of a recombinant protein vaccine composed of a single fusion protein containing flagellin and antigen, we have evaluated the efficacy of a fusion protein composed of flagellin and two protective antigens of Yersinia pestis (F1 and V) in eliciting protection against respiratory challenge with Y. pestis. Flagellin/F1/V was produced and purified in high yield under Good Manufacturing Practices conditions. The fusion protein retains full toll-like receptor 5 (TLR5) stimulating activity in vitro. Using a prime/boost immunization protocol, we found that flagellin/F1/V elicits robust antigen-specific humoral immunity in mice and two species of nonhuman primates. Immune mice are fully protected against intra-nasal challenge with 150 mean tolerated doses of Y. pestis CO92. In immune mice, the bacteria are completely cleared within 3 days after challenge. Flagellin/F1/V exhibits full stability for at least 297 days at 4°C and at least 168 days at 25°C. Between 29 and 84 days at 37°C, the protein exhibits a loss of biological activity that appears to be associated with a substantial change in protein diameter, possibly due to oligomerization. Based on our results we believe that flagellin/F1/V is an outstanding candidate for evaluation in humans.

This article has been cited by other articles:

• Bates, J. T., Uematsu, S., Akira, S., Mizel, S. B. (2009). Direct Stimulation of tlr5+/+ CD11c+ Cells Is Necessary for the Adjuvant Activity of Flagellin. J. Immunol. 182: 7539-7547 [Abstract] [Full Text]  
• Weimer, E. T., Lu, H., Kock, N. D., Wozniak, D. J., Mizel, S. B. (2009). A Fusion Protein Vaccine Containing OprF Epitope 8, OprI, and Type A and B Flagellins Promotes Enhanced Clearance of Nonmucoid Pseudomonas aeruginosa. Infect. Immun. 77: 2356-2366 [Abstract] [Full Text]