title: Development of an inhalational Bacillus anthracis exposure therapeutic model in cynomolgus macaques.
abstract: Appropriate animal models are required to test medical countermeasures to bioterrorist threats. To that end, we characterized a nonhuman primate (NHP) inhalational anthrax therapeutic model for use in testing anthrax therapeutic medical countermeasures according to the U.S. Food and Drug Administration Animal Rule. A clinical profile was recorded for each NHP exposed to a lethal dose of Bacillus anthracis Ames spores. Specific diagnostic parameters were detected relatively early in disease progression, i.e., by blood culture (∼37 h postchallenge) and the presence of circulating protective antigen (PA) detected by electrochemiluminescence (ECL) ∼38 h postchallenge, whereas nonspecific clinical signs of disease, i.e., changes in body temperature, hematologic parameters (ca. 52 to 66 h), and clinical observations, were delayed. To determine whether the presentation of antigenemia (PA in the blood) was an appropriate trigger for therapeutic intervention, a monoclonal antibody specific for PA was administered to 12 additional animals after the circulating levels of PA were detected by ECL. Seventy-five percent of the monoclonal antibody-treated animals survived compared to 17% of the untreated controls, suggesting that intervention at the onset of antigenemia is an appropriate treatment trigger for this model. Moreover, the onset of antigenemia correlated with bacteremia, and NHPs were treated in a therapeutic manner. Interestingly, brain lesions were observed by histopathology in the treated nonsurviving animals, whereas this observation was absent from 90% of the nonsurviving untreated animals. Our results support the use of the cynomolgus macaque as an appropriate therapeutic animal model for assessing the efficacy of medical countermeasures developed against anthrax when administered after a confirmation of infection.
authors.affiliation: Battelle, Columbus, Ohio, USA. henningl@battelle.org
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Henning
authors.forename: Jason E
authors.initials: JE
authors.lastname: Comer
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Stark
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Ray
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Tordoff
authors.forename: Katherine A B
authors.initials: KA
authors.lastname: Knostman
authors.forename: Gabriel T
authors.initials: GT
authors.lastname: Meister
mesh_terms: D000818:Animals; D000881:Anthrax / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy*; D000907:Antibodies, Bacterial / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000942:Antigens, Bacterial / Q000097:blood; D001427:Bacterial Toxins / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D019983:Guideline Adherence; D008252:Macaca fascicularis; D008297:Male; D018419:Primate Diseases / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy*; D012141:Respiratory Tract Infections / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy*; D016019:Survival Analysis; D013997:Time Factors; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D015415:Biomarkers; C030325:anthrax toxin