title: Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease.
abstract: Bacillus anthracis is a sporulating Gram-positive bacterium that is the causative agent of anthrax and a potential weapon of bioterrorism. The U.S.-licensed anthrax vaccine is made from an incompletely characterized culture supernatant of a nonencapsulated, toxigenic strain (anthrax vaccine absorbed [AVA]) whose primary protective component is thought to be protective antigen (PA). AVA is effective in protecting animals and elicits toxin-neutralizing antibodies in humans, but enthusiasm is dampened by its undefined composition, multishot regimen, recommended boosters, and potential for adverse reactions. Improving next-generation anthrax vaccines is important to safeguard citizens and the military. Here, we report that vaccination with recombinant forms of a conserved domain (near-iron transporter [NEAT]), common in Gram-positive pathogens, elicits protection in a murine model of B. anthracis infection. Protection was observed with both Freund's and alum adjuvants, given subcutaneously and intramuscularly, respectively, with a mixed composite of NEATs. Protection correlated with an antibody response against the NEAT domains and a decrease in the numbers of bacteria in major organs. Anti-NEAT antibodies promote opsonophagocytosis of bacilli by alveolar macrophages. To guide the development of inactive and safe NEAT antigens, we also report the crystal structure of one of the NEAT domains (Hal) and identify critical residues mediating its heme-binding and acquisition activity. These results indicate that we should consider NEAT proteins in the development of an improved antianthrax vaccine.
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Balderas
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Chinh T Q
authors.initials: CT
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Austen
authors.initials: A
authors.lastname: Terwilliger
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Keitel
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California, USA.
authors.forename: Angelina
authors.initials: A
authors.lastname: Iniguez
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Torres
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California, USA.
authors.forename: Frederico
authors.initials: F
authors.lastname: Palacios
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California, USA.|Department of Pharmaceutical Sciences, University of California at Irvine, Irvine, California, USA.
authors.forename: Celia W
authors.initials: CW
authors.lastname: Goulding
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA maresso@bcm.edu.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Maresso
mesh_terms: D000818:Animals; D000881:Anthrax / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000097:blood; D001408:Bacillus anthracis; D001426:Bacterial Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D007273:Injections, Intramuscular; D051379:Mice; D008958:Models, Molecular; D010586:Phagocytes; D011487:Protein Conformation
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins