scholarly journals Characterization of a Therapeutic Model of Inhalational Anthrax Using an Increase in Body Temperature in New Zealand White Rabbits as a Trigger for Treatment

2012 ◽  
Vol 19 (9) ◽  
pp. 1517-1525 ◽  
Author(s):  
Jason E. Comer ◽  
Bryan D. Ray ◽  
Lisa N. Henning ◽  
Gregory V. Stark ◽  
Roy E. Barnewall ◽  
...  
Keyword(s):  
New Zealand ◽  
Body Temperature ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Content Type ◽  
Time To Death ◽  
Reactive Protein ◽  
Potential Efficacy ◽  
New Zealand White Rabbits ◽  
Therapeutic Model

ABSTRACTThe development of an appropriate animal therapeutic model is essential to assess the potential efficacy of therapeutics for use in the event of aBacillus anthracisexposure. We conducted a natural history study that showed New Zealand White rabbits exhibited a significant increase in body temperature (SIBT), changes in hematologic parameters, and increases in C-reactive protein and succumbed to disease with an average time to death of approximately 73 h following aerosol challenge withB. anthracisAmes spores. The SIBT was used as a trigger to treat with a fully human monoclonal antibody directed at protective antigen (PA). Ninety percent (9/10) of the treated rabbits survived the lethal inhalational challenge ofB. anthracis. Further characterization investigated the protective window of opportunity for anti-PA antibody administration up to 12 h post-onset of SIBT. Eighty-three percent (5/6) of the rabbits treated at SIBT and 100% (6/6) of those treated at 6 h after SIBT survived challenge. Only 67% (4/6) of the rabbits treated at 12 h after SIBT survived. The increase in body temperature corresponded with both bacteremia and antigenemia (PA in the blood), indicating that SIBT is a suitable trigger to initiate treatment in a therapeutic model of inhalational anthrax.

Fetal and maternal temperatures in rabbits

1965 ◽  
Vol 20 (4) ◽  
pp. 737-741 ◽  
Author(s):  
Frederick M. Hart ◽  
J. Job Faber
Keyword(s):  
New Zealand ◽  
Body Temperature ◽  
Heat Loss ◽  
Abdominal Cavity ◽  
Dorsal Surface ◽  
Ventral Surface ◽  
Sodium Pentobarbital ◽  
Deep Body Temperature ◽  
New Zealand White Rabbits ◽  
Deep Body

The differences between fetal deep body temperature and maternal aortic temperature were measured in 10 New Zealand white rabbits of 22—29 days gestation with thermocouples thrust into the fetuses immediately after the animals had been killed by a warmed overdose of sodium pentobarbital. Fetal temperatures exceeded maternal temperatures by —2.51 + 0.099.X °C, where X is the gestational age in days. There is 95% confidence that fetal temperatures exceeded maternal temperature by at least 0.25 °C at a fetal age of 29 days. Permanently implanted thermocouples in six nonpregnant rabbits showed that the ventral surface of the abdominal cavity is colder than the aorta, and that the dorsal surface is slightly warmer. Fetal heat loss is partly via the umbilical circulation and partly via the fetal body surface. tissue temperatures in rabbits; fetal heat loss Submitted on September 28, 1964

scholarly journals Bacillus anthracis Protective Antigen Kinetics in Inhalation Spore-Challenged Untreated or Levofloxacin/ Raxibacumab-Treated New Zealand White Rabbits

Toxins ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 120-138 ◽  
Author(s):  
Alfred Corey ◽  
Thi-Sau Migone ◽  
Sally Bolmer ◽  
Michele Fiscella ◽  
Chris Ward ◽  
...  
Keyword(s):  
New Zealand ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
New Zealand White Rabbits

scholarly journals Effect of Anthrax Immune Globulin on Response to BioThrax (Anthrax Vaccine Adsorbed) in New Zealand White Rabbits

2013 ◽  
Vol 57 (11) ◽  
pp. 5693-5696 ◽  
Author(s):  
Nina V. Malkevich ◽  
Subhendu Basu ◽  
Thomas L. Rudge ◽  
Kristin H. Clement ◽  
Ajoy C. Chakrabarti ◽  
...  
Keyword(s):  
Immune Response ◽  
New Zealand ◽  
Immune Globulin ◽  
Neutralizing Antibodies ◽  
Protective Antigen ◽  
Anthrax Vaccine ◽  
New Zealand White Rabbits ◽  
Anthrax Toxins

ABSTRACTDevelopment of anthrax countermeasures that may be used concomitantly in a postexposure setting requires an understanding of the interaction between these products. Anthrax immune globulin intravenous (AIGIV) is a candidate immunotherapeutic that contains neutralizing antibodies against protective antigen (PA), a component of anthrax toxins. We evaluated the interaction between AIGIV and BioThrax (anthrax vaccine adsorbed) in rabbits. While pharmacokinetics of AIGIV were not altered by vaccination, the vaccine-induced immune response was abrogated in AIGIV-treated animals.

scholarly journals Mouse Monoclonal Antibodies to Anthrax Edema Factor Protect against Infection

2011 ◽  
Vol 79 (11) ◽  
pp. 4609-4616 ◽  
Author(s):  
Clinton E. Leysath ◽  
Kuang-Hua Chen ◽  
Mahtab Moayeri ◽  
Devorah Crown ◽  
Rasem Fattah ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Essential Element ◽  
Content Type ◽  
Time To Death ◽  
Edema Factor ◽  
Edema Toxin

ABSTRACTBacillus anthracisis the causative agent of anthrax, and the tripartite anthrax toxin is an essential element of its pathogenesis. Edema factor (EF), a potent adenylyl cyclase, is one of the toxin components. In this work, anti-EF monoclonal antibodies (MAb) were produced following immunization of mice, and four of the antibodies were fully characterized. MAb 3F2 has an affinity of 388 pM, was most effective for EF detection, and appears to be the first antibody reported to neutralize EF by binding to the catalytic CBdomain. MAb 7F10 shows potent neutralization of edema toxin activityin vitroandin vivo; it targets the N-terminal protective antigen binding domain. The four MAb react with three different domains of edema factor, and all were able to detect purified edema factor in Western blot analysis. None of the four MAb cross-reacted with the lethal factor toxin component. Three of the four MAb protected mice in both a systemic edema toxin challenge model and a subcutaneous spore-induced foreleg edema model. A combination of three of the MAb also significantly delayed the time to death in a third subcutaneous spore challenge model. This appears to be the first direct evidence that monoclonal antibody-mediated neutralization of EF alone is sufficient to delay anthrax disease progression.

scholarly journals Delineating Surface Epitopes of Lyme Disease Pathogen Targeted by Highly Protective Antibodies of New Zealand White Rabbits

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Artem S. Rogovskyy ◽  
Salvador Eugenio C. Caoili ◽  
Yurij Ionov ◽  
Helen Piontkivska ◽  
Pavel Skums ◽  
...  
Keyword(s):  
New Zealand ◽  
Lyme Disease ◽  
Protective Efficacy ◽  
Empirical Studies ◽  
Surface Expression ◽  
The United States ◽  
Mammalian Host ◽  
Content Type ◽  
Random Peptide ◽  
New Zealand White Rabbits

ABSTRACTLyme disease (LD), the most prevalent vector-borne illness in the United States and Europe, is caused byBorreliella burgdorferi. No vaccine is available for humans. Dogmatically,B. burgdorferican establish a persistent infection in the mammalian host (e.g., mice) due to a surface antigen, VlsE. This antigenically variable protein allows the spirochete to continually evade borreliacidal antibodies. However, our recent study has shown that theB. burgdorferispirochete is effectively cleared by anti-B. burgdorferiantibodies of New Zealand White rabbits, despite the surface expression of VlsE. Besides homologous protection, the rabbit antibodies also cross-protect against heterologousB. burgdorferispirochetes and significantly reduce the pathology of LD arthritis in persistently infected mice. Thus, this finding that NZW rabbits develop a unique repertoire of very potent antibodies targeting the protective surface epitopes, despite abundant VlsE, prompted us to identify the specificities of the protective rabbit antibodies and their respective targets. By applying subtractive reverse vaccinology, which involved the use of random peptide phage display libraries coupled with next-generation sequencing and our computational algorithms, repertoires of nonprotective (early) and protective (late) rabbit antibodies were identified and directly compared. Consequently, putative surface epitopes that are unique to the protective rabbit sera were mapped. Importantly, the relevance of newly identified protection-associated epitopes for their surface exposure has been strongly supported by prior empirical studies. This study is significant because it now allows us to systematically test the putative epitopes for their protective efficacy with an ultimate goal of selecting the most efficacious targets for development of a long-awaited LD vaccine.

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 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 Efficacy of ETI-204 Monoclonal Antibody as an Adjunct Therapy in a New Zealand White Rabbit Partial Survival Model for Inhalational Anthrax

2015 ◽  
Vol 59 (4) ◽  
pp. 2206-2214 ◽  
Author(s):  
Bethany Biron ◽  
Katie Beck ◽  
David Dyer ◽  
Marc Mattix ◽  
Nancy Twenhafel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
New Zealand ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Adjunct Therapy ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Effective Therapeutic Strategy

ABSTRACTInhalational anthrax is characterized by extensive bacteremia and toxemia as well as nonspecific to mild flu-like symptoms, until the onset of hypotension, shock, and mortality. Without treatment, the mortality rate approaches 100%. Antibiotic treatment is not always effective, and alternative treatments are needed, such as monotherapy for antibiotic-resistant inhalational anthrax or as an adjunct therapy in combination with antibiotics. TheBacillus anthracisantitoxin monoclonal antibody (MAb) ETI-204 is a high-affinity chimeric deimmunized antibody which targets the anthrax toxin protective antigen (PA). In this study, a partial protection New Zealand White (NZW) rabbit model was used to evaluate the protective efficacy of the adjunct therapy with the MAb. Following detection of PA in the blood, NZW rabbits were administered either an antibiotic (doxycycline) alone or the antibiotic in conjunction with ETI-204. Survival was evaluated to compare the efficacy of the combination adjunct therapy with that of an antibiotic alone in treating inhalational anthrax. Overall, the results from this study indicate that a subtherapeutic regimen consisting of an antibiotic in combination with an anti-PA MAb results in increased survival compared to the antibiotic alone and would provide an effective therapeutic strategy against symptomatic anthrax in nonvaccinated individuals.

scholarly journals Recombinant Protective Antigen Anthrax Vaccine Improves Survival when Administered as a Postexposure Prophylaxis Countermeasure with Antibiotic in the New Zealand White Rabbit Model of Inhalation Anthrax

2012 ◽  
Vol 19 (8) ◽  
pp. 1158-1164 ◽  
Author(s):  
Elizabeth K. Leffel ◽  
James S. Bourdage ◽  
E. Diane Williamson ◽  
Matthew Duchars ◽  
Thomas R. Fuerst ◽  
...  
Keyword(s):  
Immune Response ◽  
New Zealand ◽  
Survival Rate ◽  
Protective Antigen ◽  
Zealand White Rabbit ◽  
Postexposure Prophylaxis ◽  
Content Type ◽  
New Zealand White Rabbit ◽  
Inhalation Anthrax ◽  
Recombinant Protective Antigen

ABSTRACTInhalation anthrax is a potentially lethal form of disease resulting from exposure to aerosolizedBacillus anthracisspores. Over the last decade, incidents spanning from the deliberate mailing ofB. anthracisspores to incidental exposures in users of illegal drugs have highlighted the importance of developing new medical countermeasures to protect people who have been exposed to “anthrax spores” and are at risk of developing disease. The New Zealand White rabbit (NZWR) is a well-characterized model that has a pathogenesis and clinical presentation similar to those seen in humans. This article reports how the NZWR model was adapted to evaluate postexposure prophylaxis using a recombinant protective antigen (rPA) vaccine in combination with an oral antibiotic, levofloxacin. NZWRs were exposed to multiples of the 50% lethal dose (LD50) ofB. anthracisspores and then vaccinated immediately (day 0) and again on day 7 postexposure. Levofloxacin was administered daily beginning at 6 to 12 h postexposure for 7 treatments. Rabbits were evaluated for clinical signs of disease, fever, bacteremia, immune response, and survival. A robust immune response (IgG anti-rPA and toxin-neutralizing antibodies) was observed in all vaccinated groups on days 10 to 12. Levofloxacin plus either 30 or 100 μg rPA vaccine resulted in a 100% survival rate (18 of 18 per group), and a vaccine dose as low as 10 μg rPA resulted in an 89% survival rate (16 of 18) when used in combination with levofloxacin. In NZWRs that received antibiotic alone, the survival rate was 56% (10 of 18). There was no adverse effect on the development of a specific IgG response to rPA in unchallenged NZWRs that received the combination treatment of vaccine plus antibiotic. This study demonstrated that an accelerated two-dose regimen of rPA vaccine coadministered on days 0 and 7 with 7 days of levofloxacin therapy results in a significantly greater survival rate than with antibiotic treatment alone. Combination of vaccine administration and antibiotic treatment may be an effective strategy for treating a population exposed to aerosolizedB. anthracisspores.

The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

1992 ◽  
Vol 76 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Stuart A. Grossman ◽  
Carla Reinhard ◽  
O. Michael Colvin ◽  
Mark Chasin ◽  
Robert Brundrett ◽  
...  
Keyword(s):  
New Zealand ◽  
Brain Tissue ◽  
Direct Injection ◽  
Normal Brain ◽  
Local Concentration ◽  
Content Type ◽  
Drug Concentrations ◽  
New Zealand White Rabbits ◽  
The Brain ◽  
Fine Print

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time. The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

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