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Infection and Immunity, August 2009, p. 3380-3388, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00358-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Synthetic Peptide Vaccine Targeting a Cryptic Neutralizing Epitope in Domain 2 of Bacillus anthracis Protective Antigen{triangledown}

Jon Oscherwitz,1,2* Fen Yu,1 Jana L. Jacobs,1 Te-Hui Liu,3 Philip R. Johnson,3 and Kemp B. Cease1,2

Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105,1 Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, Michigan 48105,2 Joseph Stokes Jr. Research Institute, Children's Hospital of Philadelphia, Abramson Research Center, Room 1216B, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 191043

Received 27 March 2009/ Returned for modification 28 April 2009/ Accepted 27 May 2009

Current evidence suggests that protective antigen (PA)-based anthrax vaccines may elicit a narrow neutralizing antibody repertoire, and this may represent a vulnerability with PA-based vaccines. In an effort to identify neutralizing specificities which may complement those prevalent in PA antiserum, we evaluated whether sequences within the 2β2-2β3 loop of PA, which are apparent in the crystal structure of heptameric but not monomeric PA, might represent a target for an epitope-specific vaccine for anthrax and, further, whether antibodies to these sequences are induced in rabbits immunized with monomeric PA. We evaluated the immunogenicity in rabbits of a multiple antigenic peptide (MAP) displaying copies of amino acids (aa) 305 to 319 of this region. Overall, four out of six rabbits vaccinated with the MAP peptide in Freund's adjuvant developed high-titer, high-avidity antibody responses which cross-reacted with the immobilized peptide sequence comprising aa 305 to 319 and with PA, as determined by an enzyme-linked immunosorbent assay, and which displayed potent and durable neutralization of lethal toxin (LeTx) in vitro, with peak titers which were 452%, 100%, 67%, and 41% of the peak neutralization titers observed in positive-control rabbits immunized with PA. Importantly, analysis of sera from multiple cohorts of rabbits with high-titer immunity to PA demonstrated a virtual absence of this potent antibody specificity, and work by others suggests that this specificity may be present at only low levels in primate PA antiserum. These results highlight the potential importance of this immunologically cryptic neutralizing epitope from PA as a target for alternative and adjunctive vaccines for anthrax.

* Corresponding author. Mailing address: Ann Arbor Veterans Affairs Medical Center, Research Service 11R, 2215 Fuller Rd., Ann Arbor, MI 48105. Phone: (734) 845-5195. Fax: (734) 845-3246. E-mail: joscher{at}umich.edu

{triangledown} Published ahead of print on 1 June 2009.

Editor: R. P. Morrison

Infection and Immunity, August 2009, p. 3380-3388, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.00358-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Oscherwitz, J., Yu, F., Cease, K. B. (2009). A Heterologous Helper T-Cell Epitope Enhances the Immunogenicity of a Multiple-Antigenic-Peptide Vaccine Targeting the Cryptic Loop-Neutralizing Determinant of Bacillus anthracis Protective Antigen. Infect. Immun. 77: 5509-5518 [Abstract] [Full Text]  


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