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

Peterson, Johnny W.; Comer, Jason E.; Baze, Wallace B.; Noffsinger, David M.; Wenglikowski, Autumn; Walberg, Kristin G.; Hardcastle, Jason; Pawlik, Jennifer; Bush, Kathryn; Taormina, Joanna; Moen, Scott T.; Thomas, John; Chatuev, B. M.; Sower, Laurie; Chopra, Ashok K.; Stanberry, Lawrence R.; Sawada, Ritsuko; Scholz, Wolfgang; Sircar, J. C.

doi:10.1128/iai.00352-07

Cited by 57 publications

(57 citation statements)

References 30 publications

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“…More importantly, in few studies where post-challenge bacteremia has been evaluated in vaccinated NHP or rabbits, the detection of vegetative bacteria in the blood has been infrequent and rare. 9,21,22 The very limited initial vegetative growth we observed with bioluminescence in the NALT of mice vaccinated with the three vaccines is consistent with the trace levels of LF we detected in rabbits vaccinated with Wyeth/IL-15/PA or AVA/Biothrax (see Table 1). It is likely that in these vaccinated rabbits, just as in vaccinated mice, some minimal initial vegetative growth of B. anthracis would have occurred with the release of some trace amounts of exotoxins that we were able to capture with our ultra sensitive LF detection assay, although the bacillary biomass of this limited growth was not only insufficient to trigger a pyrogenic response, but was also rapidly cleared without any evidence of detectable bacteremia in these rabbits.…”

Section: Resultssupporting

confidence: 71%

Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection

Merkel

Perera

Lee

et al. 2013

Human Vaccines & Immunotherapeutics

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Section: Resultssupporting

confidence: 71%

Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection

Merkel

Perera

Lee

et al. 2013

Human Vaccines & Immunotherapeutics

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“…Thus, we hypothesize that the production of both toxins enabled the WT organisms to effectively overcome host defenses, first in the LALN and then systemically, while host defenses were able to slow the proliferation and subsequent spread of organisms producing only one toxin, and effectively prevent systemic spread of organisms that lacked both toxins or a capsule. Such a function of toxin(s) may also help explain the protective effect of passive treatment with anti-PA MAbs in preventing widespread dissemination in infected animals (51,57). Interestingly, the postmortem organ histopathology following an i.v.…”

Section: Discussionmentioning

confidence: 99%

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

et al. 2012

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ABSTRACTThe development of therapeutics against biothreats requires that we understand the pathogenesis of the disease in relevant animal models. The rabbit model of inhalational anthrax is an important tool in the assessment of potential therapeutics againstBacillus anthracis. We investigated the roles ofB. anthraciscapsule and toxins in the pathogenesis of inhalational anthrax in rabbits by comparing infection with the Ames strain versus isogenic mutants with deletions of the genes for the capsule operon (capBCADE), lethal factor (lef), edema factor (cya), or protective antigen (pagA). The absence of capsule or protective antigen (PA) resulted in complete avirulence, while the presence of either edema toxin or lethal toxin plus capsule resulted in lethality. The absence of toxin did not influence the ability ofB. anthracisto traffic to draining lymph nodes, but systemic dissemination required the presence of at least one of the toxins. Histopathology studies demonstrated minimal differences among lethal wild-type and single toxin mutant strains. When rabbits were coinfected with the Ames strain and the PA− mutant strain, the toxin produced by the Ames strain was not able to promote dissemination of the PA− mutant, suggesting that toxigenic action occurs in close proximity to secreting bacteria. Taken together, these findings suggest that a major role for toxins in the pathogenesis of anthrax is to enable the organism to overcome innate host effector mechanisms locally and that much of the damage during the later stages of infection is due to the interactions of the host with the massive bacterial burden.

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“…The titers of individual aliquots were determined by serial dilution and plating on BHI agar. Ames spores for challenge experiments were produced as described previously (41).…”

Section: Methodsmentioning

confidence: 99%

Killed but Metabolically Active Bacillus anthracis Vaccines Induce Broad and Protective Immunity against Anthrax

et al. 2009

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Bacillus anthracis is the causative agent of anthrax. We have developed a novel whole-bacterial-cell anthrax vaccine utilizing B. anthracis that is killed but metabolically active (KBMA). Vaccine strains that are asporogenic and nucleotide excision repair deficient were engineered by deleting the spoIIE and uvrAB genes, rendering B. anthracis extremely sensitive to photochemical inactivation with S-59 psoralen and UV light. We also introduced point mutations into the lef and cya genes, which allowed inactive but immunogenic toxins to be produced. Photochemically inactivated vaccine strains maintained a high degree of metabolic activity and secreted protective antigen (PA), lethal factor, and edema factor. KBMA B. anthracis vaccines were avirulent in mice and induced less injection site inflammation than recombinant PA adsorbed to aluminum hydroxide gel. KBMA B. anthracis-vaccinated animals produced antibodies against numerous anthrax antigens, including high levels of anti-PA and toxin-neutralizing antibodies. Vaccination with KBMA B. anthracis fully protected mice against challenge with lethal doses of toxinogenic unencapsulated Sterne 7702 spores and rabbits against challenge with lethal pneumonic doses of fully virulent Ames strain spores. Guinea pigs vaccinated with KBMA B. anthracis were partially protected against lethal Ames spore challenge, which was comparable to vaccination with the licensed vaccine anthrax vaccine adsorbed. These data demonstrate that KBMA anthrax vaccines are well tolerated and elicit potent protective immune responses. The use of KBMA vaccines may be broadly applicable to bacterial pathogens, especially those for which the correlates of protective immunity are unknown.

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

Cited by 57 publications

References 30 publications

Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection

Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

Killed but Metabolically Active Bacillus anthracis Vaccines Induce Broad and Protective Immunity against Anthrax

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