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Infection and Immunity, April 2009, p. 1475-1482, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00828-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Anthrax Protective Antigen Delivered by Salmonella enterica Serovar Typhi Ty21a Protects Mice from a Lethal Anthrax Spore Challenge{triangledown} ,{dagger}

Manuel Osorio,1* Yanping Wu,1,{ddagger} Sunil Singh,1 Tod J. Merkel,2 Siba Bhattacharyya,1 Milan S. Blake,3 and Dennis J. Kopecko1

Laboratory of Enteric and Sexually Transmitted Diseases,1 Laboratory of Respiratory and Special Pathogens,2 Laboratory of Bacterial Polysaccharides, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland3

Received 3 July 2008/ Returned for modification 30 September 2008/ Accepted 18 January 2009

Bacillus anthracis, the etiological agent of anthrax disease, is a proven weapon of bioterrorism. Currently, the only licensed vaccine against anthrax in the United States is AVA Biothrax, which, although efficacious, suffers from several limitations. This vaccine requires six injectable doses over 18 months to stimulate protective immunity, requires a cold chain for storage, and in many cases has been associated with adverse effects. In this study, we modified the B. anthracis protective antigen (PA) gene for optimal expression and stability, linked it to an inducible promoter for maximal expression in the host, and fused it to the secretion signal of the Escherichia coli alpha-hemolysin protein (HlyA) on a low-copy-number plasmid. This plasmid was introduced into the licensed typhoid vaccine strain, Salmonella enterica serovar Typhi strain Ty21a, and was found to be genetically stable. Immunization of mice with three vaccine doses elicited a strong PA-specific serum immunoglobulin G response with a geometric mean titer of 30,000 (range, 5,800 to 157,000) and lethal-toxin-neutralizing titers greater than 16,000. Vaccinated mice demonstrated 100% protection against a lethal intranasal challenge with aerosolized spores of B. anthracis 7702. The ultimate goal is a temperature-stable, safe, oral human vaccine against anthrax infection that can be self-administered in a few doses over a short period of time.

* Corresponding author. Mailing address: 29 Lincoln Dr., Building 29, Room 431, Bethesda, MD 20892. Phone: (301) 435-4458. Fax: (301) 480-5527. E-mail: manuel.osorio{at}fda.hhs.gov

{triangledown} Published ahead of print on 29 January 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: S. R. Blanke

{ddagger} Present address: National Institutes of Child Health and Human Development, NIH, Bethesda, MD.

Infection and Immunity, April 2009, p. 1475-1482, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00828-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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