Anthrax vaccination strategies.
TL;DR: This review seeks to summarize work that has been done to build on the current PA-based vaccine methodology and to evaluate the search for future anthrax prophylaxis strategies.
About: This article is published in Molecular Aspects of Medicine.The article was published on 2009-12-01 and is currently open access. It has received 64 citations till now. The article focuses on the topics: Anthrax vaccines & Bacillus anthracis.
Citations
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TL;DR: Although anthrax is acknowledged as a toxinogenic disease, additional factors, other than the bacterial toxin, may be involved in the virulence of B. anthracis and may be needed for the long‐lasting protection conferred by PA immunization.
Abstract: The lethal anthrax disease is caused by spores of the gram-positive Bacillus anthracis, a member of the cereus group of bacilli. Although the disease is very rare in the Western world, development of anthrax countermeasures gains increasing attention due to the potential use of B. anthracis spores as a bio-terror weapon. Protective antigen (PA), the non-toxic subunit of the bacterial secreted exotoxin, fulfills the role of recognizing a specific receptor and mediating the entry of the toxin into the host target cells. PA elicits a protective immune response and represents the basis for all current anthrax vaccines. Anti-PA neutralizing antibodies are useful correlates for protection and for vaccine efficacy evaluation. Post exposure anti-toxemic and anti-bacteremic prophylactic treatment of anthrax requires prolonged antibiotic administration. Shorter efficient postexposure treatments may require active or passive immunization, in addition to antibiotics. Although anthrax is acknowledged as a toxinogenic disease, additional factors, other than the bacterial toxin, may be involved in the virulence of B. anthracis and may be needed for the long-lasting protection conferred by PA immunization. The search for such novel factors is the focus of several high throughput genomic and proteomic studies that are already leading to identification of novel targets for therapeutics, for vaccine candidates, as well as biomarkers for detection and diagnosis.
78 citations
Cites background from "Anthrax vaccination strategies."
...Some humanized forms of anti-PA antibodies for passive immunization are reportedly in very advanced stages of development and pharmaceutical licensure (47, 77, 100, 101)....
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...The main problems associated with the PA formulations approved for human vaccination relate to the requirement for repetitive administrations for attaining effective protection (47, 48)....
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TL;DR: A molecular model for the spore surface is presented and it is proposed how this surface can act as a semipermeable barrier and a matrix for binding of molecules involved in defense, germination control, and other interactions of the spores with the environment.
Abstract: Bacteria of the Bacillus cereus family form highly resistant spores, which in the case of the pathogen B. anthracis act as the agents of infection. The outermost layer, the exosporium, enveloping spores of the B. cereus family as well as a number of Clostridia, plays roles in spore adhesion, dissemination, targeting, and germination control. We have analyzed two naturally crystalline layers associated with the exosporium, one representing the “basal” layer to which the outermost spore layer (“hairy nap”) is attached, and the other likely representing a subsurface (“parasporal”) layer. We have used electron cryomicroscopy at a resolution of 0.8–0.6 nm and circular dichroism spectroscopic measurements to reveal a highly α-helical structure for both layers. The helices are assembled into 2D arrays of “cups” or “crowns.” High-resolution atomic force microscopy of the outermost layer showed that the open ends of these cups face the external environment and the highly immunogenic collagen-like fibrils of the hairy nap (BclA) are attached to this surface. Based on our findings, we present a molecular model for the spore surface and propose how this surface can act as a semipermeable barrier and a matrix for binding of molecules involved in defense, germination control, and other interactions of the spore with the environment.
76 citations
Cites background from "Anthrax vaccination strategies."
...Proteins of the exosporium are likely to have intimate interactions with the environment and are also potential candidates for vaccines and ligands for spore detection (10, 11)....
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TL;DR: A review of the current literature indicates that elements from each of these three structures, as well as membrane components, have been studied, and focuses on well-studied polymers or proteins.
72 citations
TL;DR: To investigate the cell entry and intracellular trafficking of anthrax oedema factor (EF) and lethal factor (LF), they were C‐terminally fused to the enhanced green fluorescent protein (EGFP) and monomeric Cherry (mCherry) fluorescent proteins.
Abstract: To investigate the cell entry and intracellular trafficking of anthrax oedema factor (EF) and lethal factor (LF), they were C-terminally fused to the enhanced green fluorescent protein (EGFP) and monomeric Cherry (mCherry) fluorescent proteins. Both chimeras bound to the surface of BHK cells treated with protective antigen (PA) in a patchy mode. Binding was followed by rapid internalization, and the two anthrax factors were found to traffic along the same endocytic route and with identical kinetics, indicating that their intracellular path is essentially dictated by PA. Colocalization studies indicated that anthrax toxins enter caveolin-1 containing compartments and then endosomes marked by phoshatidylinositol 3-phoshate and Rab5, but not by early endosome antigen 1 and transferrin. After 40 min, both EF and LF chimeras were observed to localize within late compartments. Eventually, LF and EF appeared in the cytosol with a time-course consistent with translocation from late endosomes. Only the EGFP derivatives reached the cytosol because they are translocated by the PA channel, while the mCherry derivatives are not. This difference is attributed to a higher resistance of mCherry to unfolding. After translocation, LF disperses in the cytosol, while EF localizes on the cytosolic face of late endosomes.
56 citations
Cites background from "Anthrax vaccination strategies."
...anthracis infection in several animal species, including humans (Cybulski et al., 2009)....
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...These two toxins share the same B binding component, a protein of 83 kDa, named protective antigen (PA) from the fact that it is an immunogen that provides effective protection against B. anthracis infection in several animal species, including humans (Cybulski et al., 2009)....
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TL;DR: The anthrax letters crisis, following the discovery of a major bacterial warfare program in the USSR and the realization that Irak had been on the verge of using anthrax as a weapon during the first Gulf war, had the consequence of putting anthrax back on the agenda of scientists.
55 citations
References
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TL;DR: Clinical presentation and course of cases of bioterrorism-related inhalational anthrax, in the District of Columbia, Florida, New Jersey, and New York, are described; survival of patients was markedly higher than previously reported.
Abstract: From October 4 to November 2, 2001, the first 10 confirmed cases of inhalational anthrax caused by intentional release of Bacillus anthracis were identified in the United States. Epidemiologic investigation indicated that the outbreak, in the District of Columbia, Florida, New Jersey, and New York, resulted from intentional delivery of B. anthracis spores through mailed letters or packages. We describe the clinical presentation and course of these cases of bioterrorism-related inhalational anthrax. The median age of patients was 56 years (range 43 to 73 years), 70% were male, and except for one, all were known or believed to have processed, handled, or received letters containing B. anthracis spores. The median incubation period from the time of exposure to onset of symptoms, when known (n=6), was 4 days (range 4 to 6 days). Symptoms at initial presentation included fever or chills (n=10), sweats (n=7), fatigue or malaise (n=10), minimal or nonproductive cough (n=9), dyspnea (n=8), and nausea or vomiting (n=9). The median white blood cell count was 9.8 X 10(3)/mm(3) (range 7.5 to 13.3), often with increased neutrophils and band forms. Nine patients had elevated serum transaminase levels, and six were hypoxic. All 10 patients had abnormal chest X-rays; abnormalities included infiltrates (n=7), pleural effusion (n=8), and mediastinal widening (seven patients). Computed tomography of the chest was performed on eight patients, and mediastinal lymphadenopathy was present in seven. With multidrug antibiotic regimens and supportive care, survival of patients (60%) was markedly higher (<15%) than previously reported.
928 citations
"Anthrax vaccination strategies." refers background in this paper
...In the post-Cold War world this remains a concern, but following the attacks conducted through the US postal system in 2001 (Jernigan et al., 2001; Jernigan et al., 2002) this scenario has been eclipsed by the worry that anthrax spores might be used against the general population....
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TL;DR: A national investigation was initiated to identify additional cases and determine possible exposures to Bacillus anthracis, and 22 cases of anthrax were identified; 5 of the inhalational cases were fatal.
Abstract: In October 2001, the first inhalational anthrax case in the United States since 1976 was identified in a media company worker in Florida. A national investigation was initiated to identify additional cases and determine possible exposures to Bacillus anthracis. Surveillance was enhanced through health-care facilities, laboratories, and other means to identify cases, which were defined as clinically compatible illness with laboratory-confirmed B. anthracis infection. From October 4 to November 20, 2001, 22 cases of anthrax (11 inhalational, 11 cutaneous) were identified; 5 of the inhalational cases were fatal. Twenty (91%) case-patients were either mail handlers or were exposed to worksites where contaminated mail was processed or received. B. anthracis isolates from four powder-containing envelopes, 17 specimens from patients, and 106 environmental samples were indistinguishable by molecular subtyping. Illness and death occurred not only at targeted worksites, but also along the path of mail and in other settings. Continued vigilance for cases is needed among health-care providers and members of the public health and law enforcement communities.
634 citations
"Anthrax vaccination strategies." refers background in this paper
...In the post-Cold War world this remains a concern, but following the attacks conducted through the US postal system in 2001 (Jernigan et al., 2001; Jernigan et al., 2002) this scenario has been eclipsed by the worry that anthrax spores might be used against the general population....
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TL;DR: Protecting monkeys exposed to a lethal aerosol dose of Bacillus anthracis when the antibiotic was discontinued by combining postexposure antibiotic treatment with vaccination was provided.
Abstract: Inhalation anthrax is a rare disease that is almost invariably fatal. This study determined whether a prolonged course of postexposure antibiotics with or without vaccination would protect monkeys exposed to a lethal aerosol dose of Bacillus anthracis when the antibiotic was discontinued. Beginning 1 day after exposure, groups of 10 animals were given penicillin, ciprofloxacin, doxycycline, doxycycline plus vaccination, vaccination alone, or saline. Antibiotics were administered for 30 days and then discontinued. Vaccine was given on days 1 and 15. Two animals died of causes other than anthrax and were not included in the statistical analysis. Nine of 10 controls and 8 of 10 animals given only vaccine died. Each antibiotic regimen completely protected animals while on therapy and provided significant long-term protection upon discontinuance of the drug (penicillin, 7 of 10 survived, P < .02; ciprofloxacin, 8 of 9 survived, P < .002; doxycycline, 9 of 10 survived, P < .002; doxycycline plus vaccination, 9 of 9 survived, P < .0002). Protection against rechallenge was provided by combining postexposure antibiotic treatment with vaccination.
389 citations
"Anthrax vaccination strategies." refers background in this paper
...One approach involves the use of those same vaccines, which have been shown to improve the outcome of exposure in previously-unvaccinated individuals when combined with antibiotic therapy (Friedlander et al., 1993; Fowler et al., 2005; Peterson et al., 2006; Baccam and Boechler, 2007)....
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TL;DR: The results suggest that the three toxin components might act synergistically in vivo to cause lethality and edema formation.
Abstract: Three proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF; a calmodulin-dependent adenylate cyclase), compose the lethal (PA + LF) and edema (PA + EF) toxins secreted by Bacillus anthracis. Mutant strains, each deficient in the production of one toxin component, were constructed, and their virulence was then studied. A kanamycin resistance cassette was inserted in each cya (encoding EF) and lef (encoding LF) gene, and the constructs were separately introduced into B. anthracis Sterne on a mobilizable shuttle plasmid. An EF- strain and an LF- strain were then isolated after homologous recombination with the resident toxin-encoding plasmid, pXO1. Spores from these mutants and from a previously constructed PA- mutant were used to inoculate mice, and the lethality and local edema formation were monitored. LF- or PA- mutants were not lethal even at high inocula, whereas the EF- mutant induced lethal infections. This indicates that LF in combination with PA is a key virulence factor required for lethality. Skin edema formation was observed with the LF- mutant, which produces only the combination of PA and EF. However, EF- and LF- mutants were significantly less efficient at inducing, respectively, lethality and edema than was the parental Sterne strain. These results suggest that the three toxin components might act synergistically in vivo to cause lethality and edema formation.
354 citations
"Anthrax vaccination strategies." refers background in this paper
...These toxins play critical roles in B. anthracis pathogenicity (Keppie et al., 1955; Smith et al., 1955a; Smith et al., 1955b; Molnar and Altenburn, 1963; Pezard et al., 1991)....
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TL;DR: Most livestock vaccines in use throughout the world today for immunization against anthrax are derivatives of the live spore vaccine formulated by Sterne in 1937 and still use descendants of his strain 34F2, and room for development of a successor is discussed.
334 citations
"Anthrax vaccination strategies." refers background in this paper
...…a protective response to PA. Compared to AVA, the British AVP contains lower levels of PA and higher concentrations of additional B. anthracis antigens, such as lethal factor (LF), edema factor (EF), and certain bacillus surface proteins (Turnbull, 1991; Baillie et al., 2003; Whiting et al., 2004)....
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