title: Killed but metabolically active Bacillus anthracis vaccines induce broad and protective immunity against anthrax.
abstract: Bacillus anthracis is the causative agent of anthrax. We have developed a novel whole-bacterial-cell anthrax vaccine utilizing B. anthracis that is killed but metabolically active (KBMA). Vaccine strains that are asporogenic and nucleotide excision repair deficient were engineered by deleting the spoIIE and uvrAB genes, rendering B. anthracis extremely sensitive to photochemical inactivation with S-59 psoralen and UV light. We also introduced point mutations into the lef and cya genes, which allowed inactive but immunogenic toxins to be produced. Photochemically inactivated vaccine strains maintained a high degree of metabolic activity and secreted protective antigen (PA), lethal factor, and edema factor. KBMA B. anthracis vaccines were avirulent in mice and induced less injection site inflammation than recombinant PA adsorbed to aluminum hydroxide gel. KBMA B. anthracis-vaccinated animals produced antibodies against numerous anthrax antigens, including high levels of anti-PA and toxin-neutralizing antibodies. Vaccination with KBMA B. anthracis fully protected mice against challenge with lethal doses of toxinogenic unencapsulated Sterne 7702 spores and rabbits against challenge with lethal pneumonic doses of fully virulent Ames strain spores. Guinea pigs vaccinated with KBMA B. anthracis were partially protected against lethal Ames spore challenge, which was comparable to vaccination with the licensed vaccine anthrax vaccine adsorbed. These data demonstrate that KBMA anthrax vaccines are well tolerated and elicit potent protective immune responses. The use of KBMA vaccines may be broadly applicable to bacterial pathogens, especially those for which the correlates of protective immunity are unknown.
authors.affiliation: Anza Therapeutics Incorporated, Concord, California 94520, USA. jskoble@yahoo.com
authors.forename: Justin
authors.initials: J
authors.lastname: Skoble
authors.forename: John W
authors.initials: JW
authors.lastname: Beaber
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lovchik
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Sower
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Luckett
authors.forename: Johnny W
authors.initials: JW
authors.lastname: Peterson
authors.forename: Richard
authors.initials: R
authors.lastname: Calendar
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Portnoy
authors.forename: C Rick
authors.initials: CR
authors.lastname: Lyons
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
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*; D000942:Antigens, Bacterial / Q000276:immunology; D001408:Bacillus anthracis / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity / Q000528:radiation effects; D005260:Female; D011564:Furocoumarins; D006168:Guinea Pigs; D007109:Immunity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D011817:Rabbits; D013171:Spores, Bacterial / Q000235:genetics; D014466:Ultraviolet Rays; D014611:Vaccination; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014774:Virulence
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D011564:Furocoumarins; D015164:Vaccines, Inactivated; C118577:amotosalen