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Clinical and Vaccine Immunology, July 2008, p. 1115-1123, Vol. 15, No. 7
1071-412X/08/$08.00+0     doi:10.1128/CVI.00015-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Immunogenicity of Bacillus anthracis Protective Antigen Domains and Efficacy of Elicited Antibody Responses Depend on Host Genetic Background

Department of Microbiology and Immunology,¹ Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461²

Received 9 January 2008/ Returned for modification 19 February 2008/ Accepted 1 May 2008

Neutralizing antibodies to Bacillus anthracis protective antigen (PA), a component of anthrax toxin, mediate protection against anthrax. PA is antigenically complex and can elicit protective and nonprotective antibodies. Furthermore, vaccinated individuals demonstrate considerable variability in their antibody responses to PA. To explore the relationship between PA structure and antigenicity, we produced Escherichia coli strains expressing full-length PA (PA1-4), domains 2 to 4 (PA2-4), domain 1, (PA1), and domain 4 (PA4) and evaluated the immunogenicities and protective efficacies of the protein fractions in four mouse strains (strains A/J, BALB/c, C57BL/6, and Swiss Webster). Immunization with PA1-4 resulted in significantly higher lethal toxin-neutralizing antibody titers than immunization with any recombinant protein (rPA) fraction of PA. The magnitude and neutralizing capacity of the antibody response to full-length PA and its fragments varied depending on the mouse strain. We found no correlation between the antibody titer and the neutralizing antibody titer for A/J and Swiss Webster mice. In C57BL/6 mice, antibody titers and neutralization capacity correlated for two of four rPA domain proteins tested, while BALB/c mice displayed a similar correlation with only one rPA. By correlating the reactivity of immune sera with solvent-exposed linear peptide segments of PA, we tentatively assign the presence of four new linear B-cell epitopes in PA amino acids 121 to 150, 143 to 158, 339 to 359, and 421 to 440. We conclude that the genetic background of the host determines the relative efficacy of the antitoxin response. The results suggest that the variability observed in vaccination studies with PA-derived vaccines is a result of host heterogeneity and implies a need to develop other antigens as vaccine candidates.

Published ahead of print on 14 May 2008.