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Infection and Immunity, April 2009, p. 1649-1663, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00530-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Killed but Metabolically Active Bacillus anthracis Vaccines Induce Broad and Protective Immunity against Anthrax{triangledown}

Justin Skoble,1* John W. Beaber,2,{dagger} Yi Gao,3 Julie A. Lovchik,4 Laurie E. Sower,5 Weiqun Liu,1 William Luckett,1 Johnny W. Peterson,5 Richard Calendar,2 Daniel A. Portnoy,2,6 C. Rick Lyons,4 and Thomas W. Dubensky Jr.1

Anza Therapeutics Incorporated, Concord, California 94520,1 Department of Molecular and Cell Biology, University of California, Berkeley, California 94720,2 Cerus Corporation, Concord, California 94520,3 Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131,4 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555,5 School of Public Health, University of California, Berkeley, California 947206

Received 30 April 2008/ Returned for modification 11 June 2008/ Accepted 12 January 2009

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.

* Corresponding author. Present address: 2423 Roosevelt Avenue, Berkeley, CA 94703. Phone: (510) 847-0261. Fax: (510) 643-6334. E-mail: jskoble{at}yahoo.com

{triangledown} Published ahead of print on 21 January 2009.

Editor: S. R. Blanke

{dagger} Present address: Xoma LLC, 2910 Seventh Street, Berkeley, CA 94710.

Infection and Immunity, April 2009, p. 1649-1663, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00530-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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