Immunogenicity of
            <i>Bacillus anthracis</i>
            Protective Antigen Domains and Efficacy of Elicited Antibody Responses Depend on Host Genetic Background

Abboud, Nareen; Casadevall, Arturo

doi:10.1128/cvi.00015-08

Cited by 46 publications

(47 citation statements)

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“…This is likely due to the fact that a large number of anti-PA antibodies are directed against non-neutralizing (or possibly even toxin-enhancing) epitopes (29,41). Pioneering work by Little et al (23) suggests that at least 20 antigenic determinants exist on PA. At present, only a few of these epitopes has been described in detail; several have been shown to be targets of monoclonal antibodies (MAbs) capable of effective neutralization in vivo or in vitro (1,8,10,17,44,45). The fact that key neutralizing epitopes on PA remain widely unidentified poses a significant barrier to the evaluation of the efficacy of vaccines based on full-length and truncated PA subunits.…”

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confidence: 99%

“…This MAb contacts the face of domain 4 that is involved in receptor recognition, and has been proposed to encompass residues 671 to 721. Certainly, additional neutralizing epitopes exist on domain 4 (1,46). In particular, Abboud and Casadevall (1) suggested a linear epitope, immediately adjacent to or possibly overlapping the 14B7 binding site, as the target of neutralizing antibodies.…”

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confidence: 99%

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Neutralizing Monoclonal Antibodies Directed against Defined Linear Epitopes on Domain 4 of Anthrax Protective Antigen

Kelly-Cirino

Mantis

2009

Infect Immun

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The anthrax protective antigen (PA) is the receptor-binding subunit common to lethal toxin (LT) and edema toxin (ET), which are responsible for the high mortality rates associated with inhalational Bacillus anthracis infection. Although recombinant PA (rPA) is likely to be an important constituent of any future anthrax vaccine, evaluation of the efficacies of the various candidate rPA vaccines is currently difficult, because the specific B-cell epitopes involved in toxin neutralization have not been completely defined. In this study, we describe the identification and characterization of two murine monoclonal immunoglobulin G1 antibodies (MAbs), 1-F1 and 2-B12, which recognize distinct linear neutralizing epitopes on domain 4 of PA. 1-F1 recognized a 12-mer peptide corresponding to residues 692 to 703; this epitope maps to a region of domain 4 known to interact with the anthrax toxin receptor CMG-2 and within a conformation-dependent epitope recognized by the well-characterized neutralizing MAb 14B7. As expected, 1-F1 blocked PA's ability to associate with CMG-2 in an in vitro solid-phase binding assay, and it protected murine macrophage cells from intoxication with LT. 2-B12 recognized a 12-mer peptide corresponding to residues 716 to 727, an epitope located immediately adjacent to the core 14B7 binding site and a stretch of amino acids not previously identified as a target of neutralizing antibodies. 2-B12 was as effective as 1-F1 in neutralizing LT in vitro, although it only partially inhibited PA binding to its receptor. Mice passively administered 1-F1 or 2-B12 were partially protected against a lethal challenge with LT. These results advance our fundamental understanding of the mechanisms by which antibodies neutralize anthrax toxin and may have future application in the evaluation of candidate rPA vaccines.Bacillus anthracis has long been recognized as a serious public health threat, given the ease with which B. anthracis spores can be disseminated via aerosol and due to the high mortality rate that accompanies spore inhalation. These fears were realized in the fall of 2001, when B. anthracis spores were circulated through the U.S. postal system, resulting in five deaths, 22 known cases of infection, and the possible exposure of more than 30,000 people (7). Although routine vaccination of civilians against anthrax is neither necessary nor desirable, certain segments of the population, notably emergency first responders and research laboratory personnel, remain at risk of exposure and are in need of an effective preexposure vaccine. In the United States, the only licensed anthrax vaccine, Anthrax Vaccine Adsorbed (AVA) or Biothrax, has been subject to controversy for years, due to safety concerns (3), and is not considered an ideal vaccine due to its protracted vaccination schedule (six injections over 18 months). AVA, which consists of formalin-treated culture filtrate from an attenuated strain of B. anthracis adsorbed to aluminum hydroxide, is also inherently difficult to manufacture and to standardize. ...

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confidence: 99%

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confidence: 99%

Neutralizing Monoclonal Antibodies Directed against Defined Linear Epitopes on Domain 4 of Anthrax Protective Antigen

Kelly-Cirino

Mantis

2009

Infect Immun

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“…Recent studies have demonstrated that a strong humoral response to truncated recombinant PA contributes to a protective immune response to anthrax (3,4). Accordingly, there is considerable interest in ascertaining the location and immunogenicity of B-cell epitopes on the PA molecule.…”

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confidence: 99%

Identification of Linear Epitopes in Bacillus anthracis Protective Antigen Bound by Neutralizing Antibodies

Abboud¹,

Jesus²,

Nakouzi³

et al. 2009

Journal of Biological Chemistry

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Protective antigen (PA), the binding subunit of anthrax toxin, is the major component in the current anthrax vaccine, but the fine antigenic structure of PA is not well defined. To identify linear neutralizing epitopes of PA, 145 overlapping peptides covering the entire sequence of the protein were synthesized. Six monoclonal antibodies (mAbs) and antisera from mice specific for PA were tested for their reactivity to the peptides by enzyme-linked immunosorbent assays. Two mAbs with toxin-neutralizing activity recognized two different epitopes in close proximity to the furin cleavage site in domain 1. The three-dimensional complex structure of PA and its neutralizing mAbs 7.5G and 19D9 were modeled using the molecular docking method providing models for the interacting epitope and paratope residues. For both mAbs, LeTx neutralization was associated with interference with furin cleavage, but they differed in effectiveness depending on whether they bound on the N-or C-terminal aspect of the cleaved products. The two peptides containing these epitopes that include amino acids Leu 156 -Ser 170 and Val 196 -Ile 210 were immunogenic and elicited neutralizing antibody responses to PA. These results identify the first linear neutralizing epitopes of PA and show that peptides containing epitope sequences can elicit neutralizing antibody responses, a finding that could be exploited for vaccine design.

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“…However, A83 exhibited the highest immune response showing that all four domains are required for the maximum protection. Previously, the immunogenicity of different domains has been found variable in within and between genetically different strains of mice 28 . However, in mouse model, domain 1 elicited the highest immune response, whereas domain 2 or 4 were significantly less effective in eliciting the higher antibody titre 28 .…”

Section: Pad1 Pad2 Pad4mentioning

confidence: 99%

“…Previously, the immunogenicity of different domains has been found variable in within and between genetically different strains of mice 28 . However, in mouse model, domain 1 elicited the highest immune response, whereas domain 2 or 4 were significantly less effective in eliciting the higher antibody titre 28 . Because the host genetics plays a very important role in antibody response, therefore domains could elicit different immune response in mouse and human.…”

Section: Pad1 Pad2 Pad4mentioning

confidence: 99%

The Humoral Immune Response to Various Domains of Protective Antigen of Bacillus anthracis in Cutaneous Anthrax Cases in India

et al. 2016

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Anthrax, caused by Bacillus anthracis is known to occur globally since antiquity. Besides being an important bio-threat agent, it is an important public health importance pathogen also in countries like India. B. anthracis secretes three distinct toxins, namely protective antigen (PA), lethal factor (LF) and edema factor (EF). PA is the central moiety of the anthrax toxin complex and therefore has been a molecule of choice for vaccine development. PA has four different domains with different functions. In this study, the major domains of PA were cloned and expressed in bacterial system. The purified recombinant proteins were used to determine the humoral immune response by ELISA using 43 human cutaneous anthrax serum samples. The maximum immunoreactivity was observed with the whole PA protein followed by domain 2, 4 and 1. The study corroborated that in addition to full PA, individual domain 2 and 4 can also be good target for vaccine development as well as for serodiagnostic assays for cutaneous anthrax.

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Immunogenicity of Bacillus anthracis Protective Antigen Domains and Efficacy of Elicited Antibody Responses Depend on Host Genetic Background

Abstract: Neutralizing antibodies to

Cited by 46 publications

References 51 publications

Neutralizing Monoclonal Antibodies Directed against Defined Linear Epitopes on Domain 4 of Anthrax Protective Antigen

Neutralizing Monoclonal Antibodies Directed against Defined Linear Epitopes on Domain 4 of Anthrax Protective Antigen

Identification of Linear Epitopes in Bacillus anthracis Protective Antigen Bound by Neutralizing Antibodies

The Humoral Immune Response to Various Domains of Protective Antigen of Bacillus anthracis in Cutaneous Anthrax Cases in India

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