title: A synthetic peptide vaccine directed against the 2ß2-2ß3 loop of domain 2 of protective antigen protects rabbits from inhalation anthrax.
abstract: The current vaccines for anthrax in the United States and United Kingdom are efficacious in the two most accepted animal models of inhalation anthrax, nonhuman primates and rabbits, but require extensive immunization protocols. We previously demonstrated that a linear determinant in domain 2 of Bacillus anthracis protective Ag (PA) is a potentially important target for an epitope-specific vaccine for anthrax, as Abs specific for this site, referred to as the loop-neutralizing determinant (LND), neutralize lethal toxin in vitro, yet are virtually absent in PA-immunized rabbits. In this study, we evaluated the immunogenicity and protective efficacy in rabbits of multiple antigenic peptides (MAPs) consisting of aa 304-319 from the LND of PA colinearly synthesized at the C terminus (T-B MAP) or N terminus (B-T MAP) with a heterologous T cell epitope from Plasmodium falciparum. Immunogenicity studies demonstrated that both MAPs elicited toxin-neutralizing Ab in rabbits. To evaluate the MAPs as potential anthrax vaccines, we immunized groups of rabbits (n = 7) with each MAP in Freund's adjuvant and then exposed all rabbits to a 200-LD(50) challenge with aerosolized spores of B. anthracis Ames strain. All seven rabbits immunized with the B-T MAP and 89% (six of seven) of rabbits immunized with the T-B MAP survived the spore challenge. Corollary studies with reference sera from human vaccinees immunized with rPA or anthrax vaccine absorbed and nonhuman primates immunized with PA revealed no detectable Ab with specificity for the LND. We conclude that a synthetic peptide vaccine targeting the LND would be a potentially efficacious vaccine for anthrax.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA. joscher@umich.edu
authors.forename: Jon
authors.initials: J
authors.lastname: Oscherwitz
authors.forename: Fen
authors.initials: F
authors.lastname: Yu
authors.forename: Kemp B
authors.initials: KB
authors.lastname: Cease
mesh_terms: D000280:Administration, Inhalation; D000595:Amino Acid Sequence; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology* / Q000472:pathogenicity; D002460:Cell Line; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000276:immunology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000276:immunology; D011817:Rabbits; D013171:Spores, Bacterial / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D022122:Anthrax Vaccines; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan