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Infection and Immunity, May 2009, p. 2030-2035, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01254-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Frequency and Domain Specificity of Toxin-Neutralizing Paratopes in the Human Antibody Response to Anthrax Vaccine Adsorbed

Donald Reason,^1* Justine Liberato,¹ Jinying Sun,¹ Wendy Keitel,² and Jianhui Zhou¹

Children's Hospital Oakland Research Institute, Oakland, California,¹ Baylor College of Medicine, Departments of Molecular Virology, Microbiology and Medicine, Houston, Texas²

Received 13 October 2008/ Returned for modification 27 November 2008/ Accepted 28 January 2009

Protective antigen (PA) is the cell surface recognition unit of the binary anthrax toxin system and the primary immunogenic component in both the current and proposed "next-generation" anthrax vaccines. Several studies utilizing animal models have indicated that PA-specific antibodies, acquired by either active or passive immunization, are sufficient to protect against infection with Bacillus anthracis. To investigate the human antibody response to anthrax immunization, we have established a large panel of human PA-specific monoclonal antibodies derived from multiple individuals vaccinated with the currently approved anthrax vaccine BioThrax. We have determined that although these antibodies bind PA in standard binding assays such as enzyme-linked immunosorbent assay, Western blotting, capture assays, and dot blots, less than 25% are capable of neutralizing lethal toxin (LT) in vitro. Nonneutralizing antibodies also fail to neutralize toxin when present in combination with other nonneutralizing paratopes. Although neutralizing antibodies recognize determinants throughout the PA monomer, they are significantly less common among those paratopes that bind to the immunodominant amino-terminal portion of the molecule. These findings demonstrate that PA binding alone is not sufficient to neutralize LT and suggest that for an antibody to effectively block PA-mediated toxicity, it must bind to PA such that one of the requisite toxin functions is disrupted. A vaccine design strategy that directed a higher percentage of the antibody response toward neutralizing epitopes may result in a more efficacious vaccine for the prevention of anthrax infection.

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* Corresponding author. Mailing address: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609. Phone: (510) 450-7638. Fax: (510) 450-7910. E-mail: dreason{at}chori.org

Published ahead of print on 17 February 2009.

Editor: A. Camilli

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Infection and Immunity, May 2009, p. 2030-2035, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01254-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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