scholarly journals Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 773 ◽  
Author(s):  
William S. Lawrence ◽  
Jennifer E. Peel ◽  
Satheesh K. Sivasubramani ◽  
Wallace B. Baze ◽  
Elbert B. Whorton ◽  
...  
Keyword(s):  
Protective Antigen ◽  
Protective Efficacy ◽  
Bacterial Load ◽  
Lethal Dose ◽  
Rabbit Model ◽  
Negative Control ◽  
Adult Rabbit ◽  
Microscopic Evaluation ◽  
Inhalation Anthrax ◽  
Anthrax Infection

The use of antibiotics is a vital means of treating infections caused by the bacteria Bacillus (B.) anthracis. Importantly, with the potential future use of multidrug-resistant strains of B. anthracis as bioweapons, new antibiotics are needed as alternative therapeutics. In this blinded study, we assessed the protective efficacy of teixobactin, a recently discovered antibiotic, against inhalation anthrax infection in the adult rabbit model. New Zealand White rabbits were infected with a lethal dose of B. anthracis Ames spores via the inhalation route, and blood samples were collected at various times to assess antigenemia, bacteremia, tissue bacterial load, and antibody production. Treatments were administered upon detection of B. anthracis protective antigen in the animals’ sera. For comparison, a fully protective dose of levofloxacin was used as a positive control. Rabbits treated with teixobactin showed 100% survival following infection, and the bacteremia was completely resolved by 24–48 h post-treatment. In addition, the bacterial/spore loads in tissues of the animals treated with teixobactin were either zero or dramatically less relative to that of the negative control animals. Moreover, microscopic evaluation of the tissues revealed decreased pathology following treatment with teixobactin. Overall, these results show that teixobactin was protective against inhalation anthrax infection in the rabbit model, and they indicate the potential of teixobactin as a therapeutic for the disease.

scholarly journals A Recombinant Carboxy-Terminal Domain of the Protective Antigen of Bacillus anthracis Protects Mice against Anthrax Infection

2002 ◽  
Vol 70 (3) ◽  
pp. 1653-1656 ◽  
Author(s):  
Helen C. Flick-Smith ◽  
Nicola J. Walker ◽  
Paula Gibson ◽  
Helen Bullifent ◽  
Sarah Hayward ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Fusion Proteins ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Anthrax Infection ◽  
Carboxy Terminal ◽  
Domain 4

ABSTRACT The immunogenicity and protective efficacy of overlapping regions of the protective antigen (PA) polypeptide, cloned and expressed as glutathione S-transferase fusion proteins, have been assessed. Results show that protection can be attributed to individual domains and imply that it is domain 4 which contains the dominant protective epitopes of PA.

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 Establishment of a New Zealand White Rabbit Model for Lethal Toxin (LT) Challenge and Efficacy of Monoclonal Antibody 5E11 in the LT-Challenged Rabbit Model

Toxins ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 289 ◽  
Author(s):  
Duanyang Zhang ◽  
Weicen Liu ◽  
Zhonghua Wen ◽  
Bing Li ◽  
Shuling Liu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Lethal Toxin ◽  
Anthrax Spores ◽  
Level 3 ◽  
Anthrax Protective Antigen ◽  
Biosafety Level

Anthrax caused by Bacillus anthracis is a lethal infectious disease, especially when inhaled, and the mortality rate approaches 100% without treatment. The anthrax antitoxin monoclonal antibody (MAb) 5E11 is a humanized antibody that targets the anthrax protective antigen (PA). The efficacy of 5E11 needs proper animal models. However, anthrax spores are extremely dangerous, so experiments must be conducted under Biosafety Level 3 conditions. Considering the critical effects of lethal toxin (LT) on hosts during infection, we report the establishment of a LT-challenged rabbit model, which caused 100% mortality with a dose of 2 mg PA + 1 mg LF, while a 4 mg PA + 2 mg LF challenge could limit death to within three days. Then, we evaluated 5E11 efficacy against LT. A prophylactic study showed that the i.v. administration of 40 mg/kg 5E11 four days before lethal dose LT challenge could lead to 100% survival. In therapeutic studies, the i.v. administration of 40 mg/kg 5E11 10 min after lethal dose LT challenge could provide complete protection. Overall, we developed a new LT-challenged rabbit model, and our results indicate that 5E11 shows potential for the clinical application in anthrax treatment.

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 Immunogenicity and Protective Efficacy of a Non-Living Anthrax Vaccine versus a Live Spore Vaccine with Simultaneous Penicillin-G Treatment in Cattle

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 595
Author(s):  
Solomon Jauro ◽  
Okechukwu C. Ndumnego ◽  
Charlotte Ellis ◽  
Angela Buys ◽  
Wolfgang Beyer ◽  
...  
Keyword(s):  
Protective Antigen ◽  
Protective Efficacy ◽  
Lethal Dose ◽  
Passive Immunization ◽  
Penicillin G ◽  
Passive Immunisation ◽  
Protective Capacity ◽  
Anthrax Vaccine ◽  
Recombinant Protective Antigen

Sterne live spore vaccine (SLSV) is the current veterinary anthrax vaccine of choice. Unlike the non-living anthrax vaccine (NLAV) prototype, SLSV is incompatible with concurrent antibiotics use in an anthrax outbreak scenario. The NLAV candidates used in this study include a crude recombinant protective antigen (CrPA) and a purified recombinant protective antigen (PrPA) complemented by formalin-inactivated spores and Emulsigen-D®/Alhydrogel® adjuvants. Cattle were vaccinated twice (week 0 and 3) with NLAVs plus penicillin-G (Pen-G) treatment and compared to cattle vaccinated twice with SLSV alone and with Pen-G treatment. The immunogenicity was assessed using ELISA against rPA and FIS, toxin neutralisation assay (TNA) and opsonophagocytic assay. The protection was evaluated using an in vivo passive immunisation mouse model. The anti-rPA IgG titres for NLAVs plus Pen-G and SLSV without Pen-G treatment showed a significant increase, whereas the titres for SLSV plus Pen-G were insignificant compared to pre-vaccination values. A similar trend was measured for IgM, IgG1, and IgG2 and TNA titres (NT50) showed similar trends to anti-rPA titres across all vaccine groups. The anti-FIS IgG and IgM titres increased significantly for all vaccination groups at week 3 and 5 when compared to week 0. The spore opsonising capacity increased significantly in the NLAV vaccinated groups including Pen-G treatment and the SLSV without Pen-G but much less in the SLSV group with Pen-G treatment. Passive immunization of A/J mice challenged with a lethal dose of 34F2 spores indicated significant protective capacity of antibodies raised in the SLSV and the PrPA + FIS + adjuvants vaccinated and Pen-G treated groups but not for the NLAV with the CrPA + FIS + adjuvants and the SLSV vaccinated and Pen-G treated group. Our findings indicate that the PrPA + FIS + Emulsigen-D®/Alhydrogel® vaccine candidate may provide the same level of antibody responses and protective capacity as the SLSV. Advantageously, it can be used concurrently with Penicillin-G in an outbreak situation and as prophylactic treatment in feedlots and valuable breeding stocks.

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 Human Monoclonal Anti-Protective Antigen Antibody Completely Protects Rabbits and Is Synergistic with Ciprofloxacin in Protecting Mice and Guinea Pigs against Inhalation Anthrax

2006 ◽  
Vol 74 (2) ◽  
pp. 1016-1024 ◽  
Author(s):  
Johnny W. Peterson ◽  
Jason E. Comer ◽  
David M. Noffsinger ◽  
Autumn Wenglikowski ◽  
Kristin G. Walberg ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Treatment Strategies ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Treatment ◽  
Inhalation Anthrax ◽  
Anthrax Infection ◽  
Anthrax Spores ◽  
Species Specific

ABSTRACT Prevention of inhalation anthrax requires early and extended antibiotic therapy, and therefore, alternative treatment strategies are needed. We investigated whether a human monoclonal antibody (AVP-21D9) to protective antigen (PA) would protect mice, guinea pigs, and rabbits against anthrax. Control animals challenged with Bacillus anthracis Ames spores by the intranasal route died within 3 to 7 days. AVP-21D9 alone provided minimal protection against anthrax in the murine model, but its efficacy was notably better in guinea pigs. When Swiss-Webster mice, challenged with five 50% lethal doses (LD50s) of anthrax spores, were given a single 16.7-mg/kg of body weight AVP-21D9 antibody dose combined with ciprofloxacin (30 mg/kg/day for 6 days) 24 h after challenge, 100% of the mice were protected for more than 30 days, while ciprofloxacin or AVP-21D9 alone showed minimal protection. Similarly, when AVP-21D9 antibody (10 to 50 mg/kg) was combined with a low, nonprotective dose of ciprofloxacin (3.7 mg/kg/day) and administered to guinea pigs for 6 days, synergistic protection against anthrax was observed. In contrast, a single dose of AVP-21D9 antibody (1, 5, 10, or 20 mg/kg) but not 0.2 mg/kg alone completely protected rabbits against challenge with 100 LD50s of B. anthracis Ames spores, and 100% of the rabbits survived rechallenge. Further, administration of AVP-21D9 (10 mg/kg) to rabbits at 0, 6, and 12 h after challenge with anthrax spores resulted in 100% survival; however, delay of antibody treatment by 24 and 48 h reduced survival to 80% and 60%, respectively. Serological analysis of sera from various surviving animals 30 days postprimary infection showed development of a species-specific PA enzyme-linked immunosorbent assay antibody titer that correlated with protection against reinfection. Taken together, the effectiveness of human anti-PA antibody alone or in combination with low ciprofloxacin levels may provide the basis for an improved strategy for prophylaxis or treatment following inhalation anthrax infection.

scholarly journals Mucosal or Parenteral Administration of Microsphere-Associated Bacillus anthracis Protective Antigen Protects against Anthrax Infection in Mice

2002 ◽  
Vol 70 (4) ◽  
pp. 2022-2028 ◽  
Author(s):  
Helen C. Flick-Smith ◽  
Jim E. Eyles ◽  
Richard Hebdon ◽  
Emma L. Waters ◽  
Richard J. Beedham ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Dose Schedule ◽  
Mucosal Immune Response ◽  
Parenteral Administration ◽  
Routes Of Administration ◽  
Anthrax Infection ◽  
Anthrax Vaccines ◽  
Lethal Doses

ABSTRACT Existing licensed anthrax vaccines are administered parenterally and require multiple doses to induce protective immunity. This requires trained personnel and is not the optimum route for stimulating a mucosal immune response. Microencapsulation of vaccine antigens offers a number of advantages over traditional vaccine formulations, including stability without refrigeration and the potential for utilizing less invasive routes of administration. Recombinant protective antigen (rPA), the dominant antigen for protection against anthrax infection, was encapsulated in poly-l-lactide 100-kDa microspheres. Alternatively, rPA was loosely attached to the surfaces of microspheres by lyophilization. All of the microspheric formulations were administered to A/J mice with a two-dose schedule by either the intramuscular route, the intranasal route, or a combination of these two routes, and immunogenicity and protective efficacy were assessed. An intramuscular priming immunization followed by either an intramuscular or intranasal boost gave optimum anti-rPA immunoglobulin G titers. Despite differences in rPA-specific antibody titers, all immunized mice survived an injected challenge consisting of 103 median lethal doses of Bacillus anthracis STI spores. Immunization with microencapsulated and microsphere-associated formulations of rPA also protected against aerosol challenge with 30 median lethal doses of STI spores. These results show that rPA can be encapsulated and surface bound to polymeric microspheres without impairing its immunogenicity and also that mucosal or parenteral administration of microspheric formulations of rPA efficiently protects mice against both injected and aerosol challenges with B. anthracis spores. Microspheric formulations of rPA could represent the next generation of anthrax vaccines, which could require fewer doses because they are more potent, are less reactogenic than currently available human anthrax vaccines, and could be self-administered without injection.

In vitro and in vivo Assessment of Silver Nanoparticles Against Clostridium botulinum Type A Botulinum

2019 ◽  
Vol 16 (1) ◽  
pp. 113-119 ◽  
Author(s):  
Mohammad Aminianfar ◽  
Siavash Parvardeh ◽  
Mohsen Soleimani
Keyword(s):  
Silver Nanoparticles ◽  
Botulinum Toxin ◽  
Clostridium Botulinum ◽  
Lethal Dose ◽  
Type A ◽  
Positive Control ◽  
Negative Control ◽  
Laboratory Animals ◽  
Control Group ◽  
Nano Silver

Background: Clostridium botulinum causes botulism, a serious paralytic illness that results from the ingestion of a botulinum toxin. Because silver nanoparticle products exhibit strong antimicrobial activity, applications for silver nanoparticles in healthcare have expanded. Therefore, the objective of the current study was to assess a therapeutic strategy for the treatment of botulism toxicity using silver nanoparticles. Methods: A preliminary test was conducted using doses that produce illness in laboratory animals to determine the absolute lethal dose (LD100) of botulinum toxin type A (BoNT/A) in mice. Next, the test animals were divided into six groups containing six mice each. Groups I, II and III were the negative control (botulinum toxin only), positive control-1 (nano-silver only) and positive control-2 (no treatment), respectively. The remaining groups were allocated to the toxin that was supplemented with three nano-silver treatments. Results: The mortality rates of mice caused by BoNT/A significantly reduced in the treatment groups with different doses and injection intervals of nano-silver when compared to the negative control group. BoNT/A toxicity induced by intraperitoneal injection of the toxin of Clostridium botulinum causes rapid death while when coupled with nano-osilver results in delayed death in mice. Conclusion: These results, while open to future improvement, represent a preliminary step towards the satisfactory control of BoNT/A with the use of silver nanoparticles for human protection against this bioterrorism threat. Further study in this area can elucidate the underlying mechanism for detoxifying BoNT/A by silver nanoparticles.

scholarly journals β-elemene alleviates airway stenosis via the ILK/Akt pathway modulated by MIR143HG sponging miR-1275

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Guoying Zhang ◽  
Cheng Xue ◽  
Yiming Zeng
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Model ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Akt Pathway ◽  
Loss Of Function ◽  
Airway Stenosis

Abstract Background We have previously found that β-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis. This study aimed to elucidate the underlying mechanism and protective efficacy of β-elemene in vitro and in vivo. Methods Microarray and bioinformatic analysis were used to identify altered pathways related to cell viability in a β-elemene-treated primary cell model and to construct a β-elemene-altered ceRNA network modulating the target pathway. Loss of function and gain of function approaches were performed to examine the role of the ceRNA axis in β-elemene's regulation of the target pathway and cell viability. Additionally, in a β-elemene-treated rabbit model of airway stenosis, endoscopic and histological examinations were used to evaluate its therapeutic efficacy and further verify its mechanism of action. Results The hyperactive ILK/Akt pathway and dysregulated LncRNA-MIR143HG, which acted as a miR-1275 ceRNA to modulate ILK expression, were suppressed in β-elemene-treated airway granulation fibroblasts; β-elemene suppressed the ILK/Akt pathway via the MIR143HG/miR-1275/ILK axis. Additionally, the cell cycle and apoptotic phenotypes of granulation fibroblasts were altered, consistent with ILK/Akt pathway activity. In vivo application of β-elemene attenuated airway granulation hyperplasia and alleviated scar stricture, and histological detections suggested that β-elemene's effects on the MIR143HG/miR-1275/ILK axis and ILK/Akt pathway were in line with in vitro findings. Conclusions MIR143HG and ILK may act as ceRNA to sponge miR-1275. The MIR143HG/miR-1275/ILK axis mediates β-elemene-induced cell cycle arrest and apoptosis of airway granulation fibroblasts by modulating the ILK/Akt pathway, thereby inhibiting airway granulation proliferation and ultimately alleviating airway stenosis.

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