title: Next-Generation Bacillus anthracis Live Attenuated Spore Vaccine Based on the htrA(-) (High Temperature Requirement A) Sterne Strain.
abstract: Anthrax is a lethal disease caused by the gram-positive spore-producing bacterium Bacillus anthracis. Live attenuated vaccines, such as the nonencapsulated Sterne strain, do not meet the safety standards mandated for human use in the Western world and are approved for veterinary purposes only. Here we demonstrate that disrupting the htrA gene, encoding the chaperone/protease HtrA (High Temperature Requirement A), in the virulent Bacillus anthracis Vollum strain results in significant virulence attenuation in guinea pigs, rabbits and mice, underlying the universality of the attenuated phenotype associated with htrA knockout. Accordingly, htrA disruption was implemented for the development of a Sterne-derived safe live vaccine compatible with human use. The novel B. anthracis SterneΔhtrA strain secretes functional anthrax toxins but is 10-10(4)-fold less virulent than the Sterne vaccine strain depending on animal model (mice, guinea pigs, or rabbits). In spite of this attenuation, double or even single immunization with SterneΔhtrA spores elicits immune responses which target toxaemia and bacteremia resulting in protection from subcutaneous or respiratory lethal challenge with a virulent strain in guinea pigs and rabbits. The efficacy of the immune-protective response in guinea pigs was maintained for at least 50 weeks after a single immunization.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Theodor
authors.initials: T
authors.lastname: Chitlaru
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Ma'ayan
authors.initials: M
authors.lastname: Israeli
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Bar-Haim
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Elia
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Shahar
authors.initials: S
authors.lastname: Rotem
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Ehrlich
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Cohen
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
authors.forename: Avigdor
authors.initials: A
authors.lastname: Shafferman
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D022122:Anthrax Vaccines; D000942:Antigens, Bacterial / Q000096:biosynthesis; D001408:Bacillus anthracis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology*; D001427:Bacterial Toxins / Q000096:biosynthesis; D004195:Disease Models, Animal; D023061:Gene Order; D056426:Genetic Loci; D006168:Guinea Pigs; D006801:Humans; D007114:Immunization; D051379:Mice; D010641:Phenotype; D011817:Rabbits; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000235:genetics* / Q000276:immunology*; D013171:Spores, Bacterial; D014613:Vaccines, Attenuated; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D022122:Anthrax Vaccines; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D014613:Vaccines, Attenuated; D037521:Virulence Factors; C030325:anthrax toxin; D012697:Serine Endopeptidases; C545478:htrA protein, Bacillus anthracis