scholarly journals Identification of a Protein Subset of the Anthrax Spore Immunome in Humans Immunized with the Anthrax Vaccine Adsorbed Preparation

2005 ◽  
Vol 73 (9) ◽  
pp. 5685-5696 ◽  
Author(s):  
Indira T. Kudva ◽  
Robert W. Griffin ◽  
Jeonifer M. Garren ◽  
Stephen B. Calderwood ◽  
Manohar John
Keyword(s):  
Drug Targets ◽  
Protective Antigen ◽  
Hypothetical Protein ◽  
The United States ◽  
Surface Proteins ◽  
Spore Surface ◽  
Expression Library ◽  
Anthrax Vaccine ◽  
Anthrax Spore ◽  
Anthrax Vaccines

ABSTRACTWe identified spore targets of Anthrax Vaccine Adsorbed (AVA)-induced immunity in humans by screening recombinant clones of a previously generated, limited genomicBacillus anthracisSterne (pXO1+, pXO2−) expression library of putative spore surface (spore-associated [SA]) proteins with pooled sera from human adults immunized with AVA (immune sera), the anthrax vaccine currently approved for use by humans in the United States. We identified 69 clones that reacted specifically with pooled immune sera but not with pooled sera obtained from the same individuals prior to immunization. Positive clones expressed proteins previously identified as localized on the anthrax spore surface, proteins highly expressed during spore germination, orthologs of proteins of diverse pathogens under investigation as drug targets, and orthologs of proteins contributing to the virulence of both gram-positive and gram-negative pathogens. Among the reactive clones identified by this immunological screen was one expressing a 15.2-kDa hypothetical protein encoded by a gene with no significant homology to sequences contained in databases. Further studies are required to define the subset of SA proteins identified in this study that contribute to the virulence of this pathogen. We hypothesize that optimal delivery of a subset of SA proteins identified by such studies to the immune system in combination with protective antigen (PA), the principal immunogen in AVA, might facilitate the development of defined, nonreactogenic, more-efficacious PA-based anthrax vaccines. Future studies might also facilitate the identification of SA proteins with potential to serve as targets for drug design, spore inactivation, or spore detection strategies.

scholarly journals Current State of Anthrax Vaccines and Key R&D Gaps Moving Forward

2020 ◽  
Vol 8 (5) ◽  
pp. 651 ◽  
Author(s):  
Adam Clark ◽  
Daniel N. Wolfe
Keyword(s):  
Vaccine Development ◽  
The United States ◽  
Post Exposure Prophylaxis ◽  
Vaccine Research ◽  
Anthrax Vaccine ◽  
Current State ◽  
Naturally Occurring ◽  
Regulatory Frameworks ◽  
Exposure Prophylaxis ◽  
Anthrax Vaccines

A licensed anthrax vaccine has been available for pre-exposure prophylaxis in the United States since 1970, and it was approved for use as a post-exposure prophylaxis, in combination with antibiotic treatment, in 2015. A variety of other vaccines are available in other nations, approved under various regulatory frameworks. However, investments in anthrax vaccines continue due to the severity of the threat posed by this bacterium, as both a naturally occurring pathogen and the potential for use as a bioweapon. In this review, we will capture the current landscape of anthrax vaccine development, focusing on those lead candidates in clinical development. Although approved products are available, a robust pipeline of candidate vaccines are still in development to try to address some of the key research gaps in the anthrax vaccine field. We will then highlight some of the most pressing needs in terms of anthrax vaccine research.

A Polymorphic Multigene Family Encoding an Immunodominant Protein from Babesia microti

2000 ◽  
Vol 38 (1) ◽  
pp. 362-368
Author(s):  
M. J. Homer ◽  
E. S. Bruinsma ◽  
M. J. Lodes ◽  
M. H. Moro ◽  
S. Telford ◽  
...  
Keyword(s):  
United States ◽  
Human Blood ◽  
Antigenic Variation ◽  
The United States ◽  
Surface Proteins ◽  
Babesia Microti ◽  
Expression Library ◽  
Potential Threat ◽  
Related Family ◽  
Geographic Clustering

ABSTRACT Human babesiosis in the United States is caused predominantly by Babesia microti , a tick-transmitted blood parasite. Improved testing methods for the detection of infection with this parasite are needed, since asymptomatic B. microti infection represents a potential threat to the blood supply in areas where B. microti is endemic. We performed immunoscreening of an expression library of genomic DNA from a human isolate of B. microti (strain MN1). Among 17 unique immunoreactive clones, we identified 9 which represent a related family of genes with little sequence homology to other known sequences but with an architecture resembling that of several surface proteins of Plasmodium . Within this family, a tandem array of a degenerate six-amino-acid repeat (SEAGGP, SEAGWP, SGTGWP, SGTVGP) was found in various lengths between relatively well conserved segments at the N and C termini. In order to examine within-clone variation, we developed a PCR protocol for direct recovery of a specific bmn1-6 homologue directly from 30 human blood isolates, 4 corresponding hamster isolates, and 5 geographically corresponding Peromyscus leucopus (white-footed mouse) isolates. Isolates from the hamsters had the same sequences as those found in the corresponding human blood, suggesting that genetic variation of bmn1-6 does not occur during passage. However, clones from different patients were often substantially different from each other with regard to the number and location of the degenerate repeats within the bmn1-6 homologue. Moreover, we found that strains that were closely related geographically were also closely related at the sequence level; nine patients, all from Nantucket Island, Mass., harbored clones that were indistinguishable from each other but that were distinct from those found in other northeastern or upper midwestern strains. We conclude that considerable genetic and antigenic diversity exists among isolates of B. microti from the United States and that geographic clustering of subtypes may exist. The nature of the bmn1-6 gene family suggests a mechanism of antigenic variation in B. microti that may occur by recombination, differential expression, or a combination of both mechanisms.

scholarly journals Genetic Construction of Bacillus subtilis Recombinant Strain, Producing Anthrax Protective Antigen

2018 ◽  
Vol 2 (2) ◽  
pp. 51-60
Keyword(s):  
Bacillus Subtilis ◽  
Recombinant Strain ◽  
Protective Antigen ◽  
Shuttle Vector ◽  
Subtilis Strain ◽  
Anthrax Vaccine ◽  
Anthrax Protective Antigen ◽  
Recombinant Bacillus Subtilis ◽  
New Generation ◽  
Anthrax Vaccines

Anthrax is a serious infectious disease with high mortality. The epidemiological security depends on the vaccination of susceptible animals and population at risk. But many of the existing anthrax vaccine strains possess low levels of protective antigen production and high reactogenicity. One of the most promising trends in production of new generation of vaccines is the cloning of particular determinants of immunogenicity of anthrax microbe for the creation of highly effective producers of Bacillus anthracis protective antigen. The aim of the article is to present the results of the study on the construction of recombinant Bacillus subtilis strain, producing B.anthracis protective antigen, promising for use in chemical anthrax vaccines technology. The pHT43PA plasmid containing the gene pag, providing the synthesis of protective antigen of the anthrax microbe and functioning stably in the cells of the recombinant strain Amy21(pHT43РА) of B. subtilis, was constructed on the basis of the shuttle vector pHT43. It is found out during the research, that the microbial cells of the recombinant strain Amy21(pHT43РА) of B. subtilis provide the production of immunologically active protective antigen in quantities, not inferior than anthrax vaccine strains. These data, as well as safety and simplicity of В. subtilis make it possible to continue the research of this recombinant strain as a producer of anthrax protective antigen, promising for use in vaccines production

scholarly journals Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease

2016 ◽  
Vol 84 (12) ◽  
pp. 3408-3422 ◽  
Author(s):  
Miriam A. Balderas ◽  
Chinh T. Q. Nguyen ◽  
Austen Terwilliger ◽  
Wendy A. Keitel ◽  
Angelina Iniguez ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Adverse Reactions ◽  
Protective Antigen ◽  
Protein Vaccine ◽  
Gram Positive ◽  
Anthrax Vaccine ◽  
Content Type ◽  
Critical Residues ◽  
The Military ◽  
Anthrax Vaccines

Bacillus anthracisis a sporulating Gram-positive bacterium that is the causative agent of anthrax and a potential weapon of bioterrorism. The U.S.-licensed anthrax vaccine is made from an incompletely characterized culture supernatant of a nonencapsulated, toxigenic strain (anthrax vaccine absorbed [AVA]) whose primary protective component is thought to be protective antigen (PA). AVA is effective in protecting animals and elicits toxin-neutralizing antibodies in humans, but enthusiasm is dampened by its undefined composition, multishot regimen, recommended boosters, and potential for adverse reactions. Improving next-generation anthrax vaccines is important to safeguard citizens and the military. Here, we report that vaccination with recombinant forms of a conserved domain (near-irontransporter [NEAT]), common in Gram-positive pathogens, elicits protection in a murine model ofB. anthracisinfection. Protection was observed with both Freund's and alum adjuvants, given subcutaneously and intramuscularly, respectively, with a mixed composite of NEATs. Protection correlated with an antibody response against the NEAT domains and a decrease in the numbers of bacteria in major organs. Anti-NEAT antibodies promote opsonophagocytosis of bacilli by alveolar macrophages. To guide the development of inactive and safe NEAT antigens, we also report the crystal structure of one of the NEAT domains (Hal) and identify critical residues mediating its heme-binding and acquisition activity. These results indicate that we should consider NEAT proteins in the development of an improved antianthrax vaccine.

Effect of delayed anthrax vaccine dose on Bacillus anthracis protective antigen IgG response and lethal toxin neutralization activity

Vaccine ◽  
2013 ◽  
Vol 31 (44) ◽  
pp. 5009-5014 ◽  
Author(s):  
Phillip R. Pittman ◽  
Diana Fisher ◽  
Xiaofei Quinn ◽  
Trevor Schmader ◽  
Julio G. Barrera-Oro
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Vaccine Dose ◽  
Lethal Toxin ◽  
Neutralization Activity ◽  
Anthrax Vaccine

scholarly journals Efficacy of a Vaccine Based on Protective Antigen and Killed Spores against Experimental Inhalational Anthrax

2008 ◽  
Vol 77 (3) ◽  
pp. 1197-1207 ◽  
Author(s):  
Yves P. Gauthier ◽  
Jean-Nicolas Tournier ◽  
Jean-Charles Paucod ◽  
Jean-Philippe Corre ◽  
Michèle Mock ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Virulent Strain ◽  
Neutralizing Antibody ◽  
Cutaneous Anthrax ◽  
Anthrax Vaccines ◽  
Mucosal Secretions ◽  
Highly Virulent ◽  
Lethal Doses

ABSTRACTProtective antigen (PA)-based anthrax vaccines acting on toxins are less effective than live attenuated vaccines, suggesting that additional antigens may contribute to protective immunity. Several reports indicate that capsule or spore-associated antigens may enhance the protection afforded by PA. Addition of formaldehyde-inactivated spores (FIS) to PA (PA-FIS) elicits total protection against cutaneous anthrax. Nevertheless, vaccines that are effective against cutaneous anthrax may not be so against inhalational anthrax. The aim of this work was to optimize immunization with PA-FIS and to assess vaccine efficacy against inhalational anthrax. We assessed the immune response to recombinant anthrax PA fromBacillus anthracis(rPA)-FIS administered by various immunization protocols and the protection provided to mice and guinea pigs infected through the respiratory route with spores of a virulent strain ofB. anthracis. Combined subcutaneous plus intranasal immunization of mice yielded a mucosal immunoglobulin G response to rPA that was more than 20 times higher than that in lung mucosal secretions after subcutaneous vaccination. The titers of toxin-neutralizing antibody and antispore antibody were also significantly higher: nine and eight times higher, respectively. The optimized immunization elicited total protection of mice intranasally infected with the virulentB. anthracisstrain 17JB. Guinea pigs were fully protected, both against an intranasal challenge with 100 50% lethal doses (LD50) and against an aerosol with 75 LD50of spores of the highly virulent strain 9602. Conversely, immunization with PA alone did not elicit protection. These results demonstrate that the association of PA and spores is very much more effective than PA alone against experimental inhalational anthrax.

scholarly journals Structures of the surface exposed proteins of Gram positive bacteria

2014 ◽  
Vol 70 (a1) ◽  
pp. C432-C432
Author(s):  
George Minasov ◽  
Salvatore Nocadello ◽  
Ekaterina Filippova ◽  
Andrei Halavaty ◽  
Wayne Anderson
Keyword(s):  
Cell Wall ◽  
Infectious Diseases ◽  
Bacillus Anthracis ◽  
Structural Genomics ◽  
Drug Targets ◽  
Morphological Changes ◽  
Target Selection ◽  
Surface Proteins ◽  
Human Pathogens ◽  
Gram Positive

The Center for Structural Genomics for Infectious Diseases (CSGID) applies structural genomics approaches to biomedically important proteins from human pathogens. It also provides the infectious disease community with a high throughput pipeline for structure determination that carries out all steps of the process, from target selection through structure deposition. Target proteins include drug targets, essential enzymes, virulence factors and vaccine candidates. The CSGID has deposited over 680 structures in the Protein Data Bank. The proteins that are exposed on the surface of Gram positive bacterial pathogens (including Staphylococcus aureus, Bacillus anthracis, Listeria monocytogenes, Streptococcus species and Clostridium species) have been one focus area for the CSGID. So far, the structures of more than 55 of these proteins have been determined. The surface proteins are important in the interactions between the pathogen and its host, but many of them are as yet functionally uncharacterized. Among the examples that will be presented is the Bacillus anthracis SpoIID protein. SpoIID is part of a coordinated cell wall degradation machine that is essential for sporulation and the morphological changes involved. It represents a new family of lytic transglycosylases that degrade the glycan strands of the peptidoglycan cell wall. The two active site clefts in the dimeric enzyme include residues from both subunits, suggesting that the dimer is required for activity. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contracts No. HHSN272200700058C and HHSN272201200026C.

scholarly journals The Anthrax Vaccine Adsorbed Vaccine Generates Protective Antigen (PA)-Specific CD4+ T Cells with a Phenotype Distinct from That of Naïve PA T Cells

2008 ◽  
Vol 76 (10) ◽  
pp. 4538-4545 ◽  
Author(s):  
William W. Kwok ◽  
Junbao Yang ◽  
Eddie James ◽  
John Bui ◽  
Laurie Huston ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Protective Antigen ◽  
Ex Vivo ◽  
Cytokine Profile ◽  
T Cell Epitopes ◽  
Peripheral Blood Mononuclear ◽  
Anthrax Vaccine ◽  
Cellular Immune

ABSTRACT Cellular immune responses against protective antigen (PA) of Bacillus anthracis in subjects that received the anthrax vaccine adsorbed (AVA) vaccine were examined. Multiple CD4+ T-cell epitopes within PA were identified by using tetramer-guided epitope mapping. PA-reactive CD4+ T cells with a CD45RA− phenotype were also detected by direct ex vivo staining of peripheral blood mononuclear cells (PBMC) with PA-specific tetramers. Surprisingly, PA-specific T cells were also detected in PBMC of nonvaccinees after a single cycle of in vitro PA stimulation. However, PA-reactive CD4+ T cells in nonvaccinees occurred at lower frequencies than those in vaccinees. The majority of PA-reactive T cells from nonvaccinees were CD45RA+ and exhibited a Th0/Th1 cytokine profile. In contrast, phenotyping and cytokine profile analyses of PA-reactive CD4+ T cells from vaccinees indicated that vaccination leads to commitment of PA-reactive T cells to a Th2 lineage, including generation of PA-specific, pre-Th2 central memory T cells. These results demonstrate that the current AVA vaccine is effective in skewing the development of PA CD4+ T cells to the Th2 lineage. The data also demonstrated the feasibility of using class II tetramers to analyze CD4+ cell responses and lineage development after vaccination.

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