Safety, Reactogenicity, and Immunogenicity of a Recombinant Protective Antigen Anthrax Vaccine Given to Healthy Adults

Campbell, James D.; Clement, Kristin H.; Wasserman, Steven S.; Donegan, Sarah; Chrisley, Lisa; Kotloff, Karen L.

doi:10.4161/hv.3.5.4459

Cited by 69 publications

(53 citation statements)

References 21 publications

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“…Considering that rPA will most certainly be a constituent of the next-generation anthrax vaccine (9,14,15,15,18), much remains to be done in terms of identifying the specific regions of PA that elicit neutralizing (and non-neutralizing) antibodies, and to better understand how these antibodies interfere (or not) with toxin attachment, oligomerization, and translocation (17,36,45). For example, in our screen to identify domain 4 MAbs, we identified 33 MAbs that reacted with domains 1 or 2.…”

Section: Discussionmentioning

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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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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Section: Discussionmentioning

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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“…As PA is the major protective antigen in the anthrax vaccine adsorbed (AVA, the only U.S.-licensed anthrax vaccine [57]), efforts to develop next-generation anthrax vaccines have been focused on strategies using purified PA (23) (24). In this murine study, we showed that the immunogenicity of PA was enhanced by formulation with Advax adjuvant and to a lesser extent with murabutide and that this translated into enhanced protection against a B. anthracis aerosol challenge compared to mice immunized with PA administered alone.…”

Section: Discussionmentioning

confidence: 99%

“…Although, to date, human trials of PA vaccines have used alum adjuvant (23,24), other adjuvants, including Ribi adjuvant formulation for parenteral formulations (25) and cholera toxin and poly(I·C) for intranasal formulations (26,27), have been shown to be effective in animal studies. Hence, use of alternative adjuvant technologies (28) may allow the development of moreeffective and better-tolerated PA vaccines.…”

mentioning

confidence: 99%

Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant

Feinen

Petrovsky

Verma

et al. 2014

Clin Vaccine Immunol

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bSubunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ϳ4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.

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“…Recombinant PA-based vaccines have demonstrated protective properties in several animal models, including rhesus macaques, against B. anthracis subcutaneous (SQ) and aerosol challenges (2)(3)(4). Vaccines based on recombinant PA (rPA) are being considered as novel anthrax vaccine candidates (5,6).…”

mentioning

confidence: 99%

Human Leukocyte Antigens and Cellular Immune Responses to Anthrax Vaccine Adsorbed

et al. 2013

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. Similarly, we found that class I (HLA-A) and class II (HLA-DQA1 and HLA-DQB1) homozygosity was significantly associated with an overall decrease in LP compared with heterozygosity at those three loci. Specifically, individuals who were homozygous at these loci had significantly lower PA-specific LP than subjects heterozygous for HLA-A (median SI, 1.48 versus 2.13, P ‫؍‬ 0.005), HLA-DQA1 (median SI, 1.75 versus 2.11, P ‫؍‬ 0.007), and HLA-DQB1 (median SI, 1.48 versus 2.13, P ‫؍‬ 0.002) loci, respectively. Finally, homozygosity at an increasing number (>4) of HLA loci was significantly correlated with a reduction in LP response (P < 0.001) in a dose-dependent manner. Additional studies are needed to reproduce these findings and determine whether HLA-heterozygous individuals generate stronger cellular immune response to other virulence factors (Bacillus anthracis LF and EF) than HLA-homozygous subjects.

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Safety, Reactogenicity, and Immunogenicity of a Recombinant Protective Antigen Anthrax Vaccine Given to Healthy Adults

Cited by 69 publications

References 21 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

Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant

Human Leukocyte Antigens and Cellular Immune Responses to Anthrax Vaccine Adsorbed

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