scholarly journals Development of an Inhalational Bacillus anthracis Exposure Therapeutic Model in Cynomolgus Macaques

2012 ◽  
Vol 19 (11) ◽  
pp. 1765-1775 ◽  
Author(s):  
Lisa N. Henning ◽  
Jason E. Comer ◽  
Gregory V. Stark ◽  
Bryan D. Ray ◽  
Kevin P. Tordoff ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Cynomolgus Macaque ◽  
Content Type ◽  
Clinical Observations ◽  
Medical Countermeasures ◽  
Therapeutic Model

ABSTRACTAppropriate 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 ofBacillus anthracisAmes 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.

scholarly journals Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Lisa N. Henning ◽  
Sarah Carpenter ◽  
Gregory V. Stark ◽  
Natalya V. Serbina
Keyword(s):  
Monoclonal Antibody ◽  
New Zealand ◽  
Bacillus Anthracis ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Survival Rates ◽  
Anamnestic Response ◽  
Content Type ◽  
Treatment Regimens

ABSTRACT The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response.

scholarly journals Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy

2015 ◽  
Vol 22 (9) ◽  
pp. 1070-1078 ◽  
Author(s):  
Patricia Fellows ◽  
Jessica Price ◽  
Shannon Martin ◽  
Karen Metcalfe ◽  
Robert Krile ◽  
...  
Keyword(s):  
Lethal Dose ◽  
Clinical Signs ◽  
Cynomolgus Macaque ◽  
Vaccine Dose ◽  
Dose Schedule ◽  
Dependent Manner ◽  
Pneumonic Plague ◽  
Content Type ◽  
Antibody Titers ◽  
Time To Onset

ABSTRACTThe efficacy of a recombinant plague vaccine (rF1V) was evaluated in cynomolgus macaques (CMs) to establish the relationship among vaccine doses, antibody titers, and survival following an aerosol challenge with a lethal dose ofYersinia pestisstrain Colorado 92. CMs were vaccinated with a range of rF1V doses on a three-dose schedule (days 0, 56, and 121) to provide a range of survival outcomes. The humoral immune response following vaccination was evaluated with anti-rF1, anti-rV, and anti-rF1V bridge enzyme-linked immunosorbent assays (ELISAs). Animals were challenged via aerosol exposure on day 149. Vaccine doses and antibody responses were each significantly associated with the probability of CM survival (P< 0.0001). Vaccination also decreased signs of pneumonic plague in a dose-dependent manner. There were statistically significant correlations between the vaccine dose and the time to onset of fever (P< 0.0001), the time from onset of fever to death (P< 0.0001), the time to onset of elevated respiratory rate (P= 0.0003), and the time to onset of decreased activity (P= 0.0251) postinfection in animals exhibiting these clinical signs. Delays in the onset of these clinical signs of disease were associated with larger doses of rF1V. Immunization with ≥12 μg of rF1V resulted in 100% CM survival. Since both the vaccine dose and anti-rF1V antibody titers correlate with survival, rF1V bridge ELISA titers can be used as a correlate of protection.

scholarly journals A High-Affinity Monoclonal Antibody to Anthrax Protective Antigen Passively Protects Rabbits before and after Aerosolized Bacillus anthracis Spore Challenge

2005 ◽  
Vol 73 (2) ◽  
pp. 795-802 ◽  
Author(s):  
Nehal Mohamed ◽  
Michelle Clagett ◽  
Juan Li ◽  
Steven Jones ◽  
Steven Pincus ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Cell Binding ◽  
Anthrax Spore ◽  
Before And After ◽  
Anthrax Infection ◽  
Anthrax Protective Antigen ◽  
Binding Component

ABSTRACT We have developed a therapeutic for the treatment of anthrax using an affinity-enhanced monoclonal antibody (ETI-204) to protective antigen (PA), which is the central cell-binding component of the anthrax exotoxins. ETI-204 administered preexposure by a single intravenous injection of a dose of between 2.5 and 10 mg per animal significantly protected rabbits from a lethal aerosolized anthrax spore challenge (∼60 to 450 times the 50% lethal dose of Bacillus anthracis Ames). Against a similar challenge, ETI-204 administered intramuscularly at a 20-mg dose per animal completely protected rabbits from death (100% survival). In the postexposure setting, intravenous administration of ETI-204 provided protection 24 h (8 of 10) and 36 h (5 of 10) after spore challenge. Administration at 48 h postchallenge, when 3 of 10 animals had already succumbed to anthrax infection, resulted in the survival of 3 of 7 animals (43%) for the duration of the study (28 days). Importantly, surviving ETI-204-treated animals were free of bacteremia by day 10 and remained so until the end of the studies. Only 11 of 51 ETI-204-treated rabbits had positive lung cultures at the end of the studies. Also, rabbits that were protected from inhalational anthrax by administration of ETI-204 developed significant titers of PA-specific antibodies. Presently, the sole therapeutic regimen available to treat infection by inhalation of B. anthracis spores is a 60-day course of antibiotics that is effective only if administered prior to or shortly after exposure. Based upon results reported here, ETI-204 is an effective therapy for prevention and treatment of inhalational anthrax.

scholarly journals The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Trudy H. Grossman ◽  
Michael S. Anderson ◽  
Lindsay Drabek ◽  
Melanie Gooldy ◽  
Henry S. Heine ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Day Treatment ◽  
Inhalation Exposure ◽  
Treated Group ◽  
Average Dose ◽  
Once Daily ◽  
Content Type ◽  
Cynomolgus Macaques ◽  
Observation Period

ABSTRACT The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

scholarly journals Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

2013 ◽  
Vol 81 (4) ◽  
pp. 1152-1163 ◽  
Author(s):  
Vladimir Savransky ◽  
Daniel C. Sanford ◽  
Emily Syar ◽  
Jamie L. Austin ◽  
Kevin P. Tordoff ◽  
...  
Keyword(s):  
Animal Model ◽  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Alternative Model ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Regional Lymph Nodes ◽  
Content Type ◽  
Ames Strain

ABSTRACTNonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of theBacillus anthracisAmes strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

scholarly journals Toxin-Deficient Mutants of Bacillus anthracis Are Lethal in a Murine Model for Pulmonary Anthrax

2006 ◽  
Vol 74 (11) ◽  
pp. 6067-6074 ◽  
Author(s):  
Sara Heninger ◽  
Melissa Drysdale ◽  
Julie Lovchik ◽  
Julie Hutt ◽  
Mary F. Lipscomb ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Murine Model ◽  
Parent Strain ◽  
Protective Antigen ◽  
Histopathological Examination ◽  
Lethal Factor ◽  
Lethal Dose ◽  
Etiologic Agent ◽  
Time To Death ◽  
Edema Factor

ABSTRACT Bacillus anthracis, the etiologic agent of anthrax, produces at least three primary virulence factors: lethal toxin, edema toxin, and a capsule. The capsule is absolutely required for dissemination and lethality in a murine model of inhalation anthrax, yet the roles for the toxins during infection are ill-defined. We show in a murine model that when spores of specific toxin-null mutants are introduced into the lung, dissemination and lethality are comparable to those of the parent strain. Mutants lacking one or more of the structural genes for the toxin proteins, i.e., protective antigen, lethal factor, and edema factor, disseminated from the lung to the spleen at rates similar to that of the virulent parental strain. The 50% lethal dose (LD50) and mean time to death (MTD) of the mutants did not differ significantly from those of the parent. The LD50s or MTDs were also unaffected relative to those of the parent strain when mice were inoculated intravenously with vegetative cells. Nonetheless, histopathological examination of tissues revealed subtle but distinct differences in infections by the parent compared to some toxin mutants, suggesting that the host response is affected by toxin proteins synthesized during infection.

scholarly journals A Mouse Model of Acinetobacter baumannii-Associated Pneumonia Using a Clinically Isolated Hypervirulent Strain

2013 ◽  
Vol 57 (8) ◽  
pp. 3601-3613 ◽  
Author(s):  
Greg Harris ◽  
Rhonda Kuo Lee ◽  
Christopher K. Lam ◽  
Gregory Kanzaki ◽  
Girishchandra B. Patel ◽  
...  
Keyword(s):  
Mouse Model ◽  
Acinetobacter Baumannii ◽  
Inflammatory Cell ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Body Weight Loss ◽  
Community Acquired Pneumonia ◽  
Content Type ◽  
Bacterial Replication ◽  
Formalin Fixed

ABSTRACTAcinetobacter baumanniiis an important emerging pathogen in health care-acquired infections and is responsible for severe nosocomial and community-acquired pneumonia. Currently available mouse models ofA. baumanniipneumonia show poor colonization with little to no extrapulmonary dissemination. Here, we describe a mouse model ofA. baumanniipneumonia using a clinical isolate (LAC-4 strain) that reliably reproduces the most relevant features of human pulmonaryA. baumanniiinfection and pathology. Using this model, we have shown that LAC-4 infection induced rapid bacterial replication in the lungs, significant extrapulmonary dissemination, and severe bacteremia by 24 h postintranasal inoculation. Infected mice showed severe bronchopneumonia and dilatation and inflammatory cell infiltration in the perivascular space. More significantly, 100% of C57BL/6 and BALB/c mice succumbed to 108CFU of LAC-4 inoculation within 48 h. When this model was used to assess the efficacy of antimicrobials, all mice treated with imipenem and tigecycline survived a lethal intranasal challenge, with minimal clinical signs and body weight loss. Moreover, intranasal immunization of mice with formalin-fixed LAC-4 protected 40% of mice from a lethal (100× 100% lethal dose) intraperitoneal challenge. Thus, this model offers a reproducible acute course ofA. baumanniipneumonia without requiring additional manipulation of host immune status, which will facilitate the development of therapeutic agents and vaccines againstA. baumanniipneumonia in humans.

scholarly journals Human Monoclonal Antibody AVP-21D9 to Protective Antigen Reduces Dissemination of the Bacillus anthracis Ames Strain from the Lungs in a Rabbit Model

2007 ◽  
Vol 75 (7) ◽  
pp. 3414-3424 ◽  
Author(s):  
Johnny W. Peterson ◽  
Jason E. Comer ◽  
Wallace B. Baze ◽  
David M. Noffsinger ◽  
Autumn Wenglikowski ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Rabbit Model ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Lethal Challenge ◽  
Tissue Sections ◽  
Inhalation Anthrax

ABSTRACT Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis disseminated to the bloodstream in some naïve animals as early as 24 h postchallenge and increased in frequency with time. AVP-21D9 significantly reduced the dissemination of the bacteria to the bloodstream and to various organs following infection. Examination of tissue sections from infected control animals, stained with hematoxylin-eosin and the Gram stain, showed edema and/or hemorrhage in the lungs and the presence of bacteria in mediastinal lymph nodes, with necrosis and inflammation. Tissue sections from infected rabbits dosed with AVP-21D9 appeared comparable to corresponding tissues from uninfected animals despite lethal challenge with B. anthracis Ames spores. Concomitant treatment with AVP-21D9 at the time of challenge conferred complete protection in the rabbit inhalation anthrax model. Early treatment increased the efficacy progressively and in a dose-dependent manner. Thus, AVP-21D9 could offer an adjunct or alternative clinical treatment regimen against inhalation anthrax.

scholarly journals Phase I Study Evaluating the Safety and Pharmacokinetics of MDX-1303, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

2011 ◽  
Vol 18 (12) ◽  
pp. 2136-2142 ◽  
Author(s):  
Valerie Riddle ◽  
Phillip Leese ◽  
Diann Blanset ◽  
Melany Adamcio ◽  
Matthew Meldorf ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase I ◽  
Bacillus Anthracis ◽  
Phase I Study ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Systemic Exposure ◽  
Healthy Human ◽  
Serious Adverse Events

ABSTRACTMDX-1303 (Valortim) is a fully human monoclonal antibody (hMAb) with a high affinity forBacillus anthracisprotective antigen (PA). MDX-1303 binds to PA and interferes with the activity of the anthrax toxin; it was selected based on its superior functional activity in the toxin neutralization activity (TNA) assay. MDX-1303 has demonstrated efficacy in the postexposure and therapeutic settings in New Zealand White rabbits, cynomolgus monkeys, and African green monkeys. This phase I study sought to characterize the safety, tolerability, immunogenicity, and pharmacokinetics (PK)/pharmacodynamics (PD) of MDX-1303 in healthy human subjects. Cohorts of 3 to 10 subjects were administered MDX-1303 as either a single intravenous (i.v.) dose at dose levels of 0.3, 1, 3, 10, and 20 mg/kg of body weight or as a single intramuscular (i.m.) dose at 100 mg. Forty-six subjects were enrolled, and 16 (35%) of these subjects experienced one or more grade 1 adverse events considered to be related to treatment with MDX-1303. There were no grade 2 to 4 adverse events or serious adverse events (SAEs) considered to be related to treatment. The mean half-life of MDX-1303 ranged from 22 to 33 days across the i.v. administration cohorts and was approximately 32 days following i.m. administration. Systemic exposure following 100-mg i.m. administration was within the range of exposure following 1-mg/kg i.v. administration with a relative bioavailability of approximately 65%. MDX-1303 was generally well tolerated, and no anti-MDX-1303 antibodies were detected following a single dose.

scholarly journals Efficient Neutralization of Antibody-Resistant Forms of Anthrax Toxin by a Soluble Receptor Decoy Inhibitor

2008 ◽  
Vol 53 (3) ◽  
pp. 1210-1212 ◽  
Author(s):  
Shilpi Sharma ◽  
Diane Thomas ◽  
John Marlett ◽  
Marianne Manchester ◽  
John A. T. Young
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Anthrax Toxin ◽  
Soluble Receptor ◽  
Antibody Neutralization

ABSTRACT A soluble receptor decoy inhibitor (RDI), comprised of the extracellular I domain of ANTXR2, is a candidate anthrax therapeutic. Here we show that RDI can effectively neutralize altered forms of the protective antigen toxin subunit that are resistant to 14B7 monoclonal antibody neutralization. These data highlight the potential of RDI to act as an adjunct to existing antibody-based therapies and indicate that inhibitors based on RDI might be useful as a stand-alone treatment against specifically engineered strains of Bacillus anthracis.

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