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Clinical and Vaccine Immunology, January 2009, p. 21-28, Vol. 16, No. 1
1071-412X/09/$08.00+0     doi:10.1128/CVI.00333-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Flagellin-F1-V Fusion Protein Is an Effective Plague Vaccine in Mice and Two Species of Nonhuman Primates{triangledown}

Steven B. Mizel,1* Aaron H. Graff,1 Nammalwar Sriranganathan,2 Sean Ervin,3 Cynthia J. Lees,4 Mark O. Lively,5 Roy R. Hantgan,5 Michael J. Thomas,5 James Wood,6 and Brian Bell6

Department of Microbiology and Immunology,1 Department of Pediatrics,3 Section on Comparative Medicine,4 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157,5 Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24061,2 Walter Reed Army Institute of Research Bioproduction Facility, Silver Spring, Maryland 209106

Received 8 September 2008/ Returned for modification 16 October 2008/ Accepted 21 October 2008

A number of studies have clearly demonstrated that flagellin is a potent adjuvant that promotes robust immune responses when it is 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-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 were fully protected against intranasal challenge with 150 mean tolerated doses of Y. pestis CO92. In immune mice, the bacteria were completely cleared within 3 days after challenge. Flagellin-F1-V exhibited full stability for at least 297 days at 4°C and at least 168 days at 25°C. At between 29 and 84 days at 37°C, the protein exhibited a loss of biological activity that appeared to be associated with a substantial change in protein diameter, possibly due to oligomerization. On the basis of our results, we believe that flagellin-F1-V is an outstanding candidate for evaluation in studies with humans.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1064. Phone: (336) 716-2216. Fax: (336) 716-9928. E-mail: smizel{at}wfubmc.edu

{triangledown} Published ahead of print on 5 November 2008.

Clinical and Vaccine Immunology, January 2009, p. 21-28, Vol. 16, No. 1
1071-412X/09/$08.00+0     doi:10.1128/CVI.00333-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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]  


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