title: Anthrax protective antigen delivered by Salmonella enterica serovar Typhi Ty21a protects mice from a lethal anthrax spore challenge.
abstract: 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.
authors.affiliation: Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. manuel.osorio@fda.hhs.gov
authors.forename: Manuel
authors.initials: M
authors.lastname: Osorio
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wu
authors.forename: Sunil
authors.initials: S
authors.lastname: Singh
authors.forename: Tod J
authors.initials: TJ
authors.lastname: Merkel
authors.forename: Siba
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Milan S
authors.initials: MS
authors.lastname: Blake
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Kopecko
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D000907:Antibodies, Bacterial / Q000097:blood*; D000918:Antibody Specificity; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D006460:Hemolysin Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D010957:Plasmids / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012485:Salmonella typhi / Q000235:genetics*; D013171:Spores, Bacterial / Q000472:pathogenicity*
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin