Anthrax Vaccines

Friedlander, A. M.; Welkos, Susan L.; Ivins, Bruce E.

doi:10.1007/978-3-662-05767-4_3

Cited by 54 publications

(57 citation statements)

References 62 publications

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“…In brief, PA was added to cultured RAW264.7 cells and incubated for a period of 5,15,25,30,45 and 60 min at 37 °C. PA was removed and the cells were washed by fresh culture medium, followed by the addition of LF and incubation at 37 °C for 4 hr before conducting the MTT assay.…”

Section: Screening Of Human Pa Neutralization Fabsmentioning

confidence: 99%

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Zhou

Carney

Janda

2008

Bioorganic & Medicinal Chemistry

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A less than adequate therapeutic plan for the treatment of anthrax in the 2001 bioterrorism attacks has highlighted the importance of developing alternative or complementary therapeutic approaches for biothreat agents. In these regards passive immunization possesses several important advantages over active vaccination and the use of antibiotics, as it can provide immediate protection against Bacillus anthracis. Herein, we report the selection and characterization of several human monoclonal neutralizing antibodies against the toxin of B. anthracis from a phage displayed human scFv library. In total fifteen clones were selected with distinct sequences and high specificity to protective antigen and thus were the subject of a series of both biophysical and cell-based cytotoxicity assays. From this panel of antibodies a set of neutralizing antibodies were identified, of which clone A8 recognizes the lethal (and/or edema) factor binding domain, and clone F1, G11 and G12 recognize the cellular receptor binding domain within protective antigen. It was noted that all clones distinguish a conformational epitope existing on the protective antigen; this steric relationship was uncovered using a sequential epitope mapping approach. For each neutralizing antibody, the kinetic constants were determined by surface plasmon resonance, while the potency of protection was established using a two-tier macrophage cytotoxicity assay. Among the neutralizing antibodies identified, clone F1 possessed the highest affinity to protective antigen, and provided superior protection from lethal toxin in the cell cytotoxicity assay. The data presented provides to the ever-growing arsenal of immunological and functional analysis of monoclonal antibodies to the exotoxins of anthrax. In addition it grants new candidates for the prophylaxis and therapeutic treatment against this toxin.

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Section: Screening Of Human Pa Neutralization Fabsmentioning

confidence: 99%

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Zhou

Carney

Janda

2008

Bioorganic & Medicinal Chemistry

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“…The tripartite anthrax toxin is comprised of three interacting partners, protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa) and edema factor (EF, 89 kDa). Although PA has been the principal target for numerous vaccine development strategies [16,17], inclusion of LF and EF could elicit additional protective immune responses [18,19], which may be necessary to develop a more robust next generation anthrax vaccine. We fused multiple anthrax toxins and their domains to Hoc and assembled them in vitro on phage T4 in various combinations.…”

Section: Introductionmentioning

confidence: 99%

Multicomponent anthrax toxin display and delivery using bacteriophage T4

Shivachandra

Peachman

et al. 2007

Vaccine

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We describe a multicomponent antigen display and delivery system using bacteriophage T4. Two dispensable outer capsid proteins, Hoc (highly antigenic outer capsid protein, 155 copies) and Soc (small outer capsid protein, 810 copies), decorate phage T4 capsid. These proteins bind to the symmetrically localized capsid sites, which appear following prohead assembly and expansion. We hypothesized that multiple antigens fused to Hoc can be displayed on the same capsid and such particles can elicit broad immunological responses. Anthrax toxin proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF), and their functional domains, were fused to Hoc with an N-terminal hexa-histidine tag and the recombinant proteins were over-expressed in E. coli and purified. Using a defined in vitro assembly system, the anthrax-Hoc fusion proteins were efficiently displayed on T4 capsid, either individually or in combinations. All of the 155 Hoc binding sites can be occupied by one antigen, or they can be split among two or more antigens by varying their molar ratio in the binding reaction. Immunization of mice with T4 phage carrying PA, LF, and EF elicited strong antigen-specific antibodies against all antigens as well as lethal toxin neutralization titers. The triple antigen T4 phage elicited stronger PA-specific immune responses than the phage displaying PA alone. These features offer novel avenues to develop customized multicomponent vaccines against anthrax and other pathogenic diseases.

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“…In the United States, the only anthrax vaccine approved for human use is an acellular vaccine that involves a cumbersome immunization regimen with considerable side effects and questionable efficacy (32). A live attenuated vaccine has been shown to confer better protection than the acellular vaccine and has been used in humans in the former Soviet Union (32).…”

Section: Discussionmentioning

confidence: 99%

“…A live attenuated vaccine has been shown to confer better protection than the acellular vaccine and has been used in humans in the former Soviet Union (32). However, the live attenuated vaccine is only approved for use in livestock in the United States due to safety concerns.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol-Specific Phospholipase C of Bacillus anthracis Down-Modulates the Immune Response

Zenewicz

Wei

Goldfine

et al. 2005

The Journal of Immunology

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Phosphatidylinositol-specific phospholipases (PI-PLCs) are virulence factors produced by many pathogenic bacteria, including Bacillus anthracis and Listeria monocytogenes. Bacillus PI-PLC differs from Listeria PI-PLC in that it has strong activity for cleaving GPI-anchored proteins. Treatment of murine DCs with Bacillus, but not Listeria, PI-PLC inhibited dendritic cell (DC) activation by TLR ligands. Infection of mice with Listeria expressing B. anthracis PI-PLC resulted in a reduced Ag-specific CD4 T cell response. These data indicate that B. anthracis PI-PLC down-modulates DC function and T cell responses, possibly by cleaving GPI-anchored proteins important for TLR-mediated DC activation.

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Anthrax Vaccines

Cited by 54 publications

References 62 publications

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Multicomponent anthrax toxin display and delivery using bacteriophage T4

Phosphatidylinositol-Specific Phospholipase C of Bacillus anthracis Down-Modulates the Immune Response

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