Phase 1 Study of a Recombinant Mutant Protective Antigen of Bacillus anthracis

Bellanti, Joseph A.; Lin, Feng-Ying C.; Chu, Chiayung; Shiloach, Joseph; Leppla, Stephen H.; Benavides, German; Karpas, Arthur B.; Moayeri, Mahtab; Guo, Chunyan; Robbins, John B.; Schneerson, Rachel

doi:10.1128/cvi.05556-11

Cited by 23 publications

(17 citation statements)

References 31 publications

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“…However, work from our group has previously shown that the toxin-neutralizing quality of PA antibodies from AVA recipients is highly variable (42). This has led to research seeking to develop more effective anthrax vaccines, including recombinant PA (43)(44)(45)(46), alternative adjuvants (47,48), and additional vaccine targets (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Dumas

Gross

Larabee

et al. 2017

Clin Vaccine Immunol

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Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of Bacillus anthracis that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with Bacillus anthracis spores or ET. This study compared humoral responses to ET in recipients of AVP (n ϭ 33) versus anthrax vaccine adsorbed (AVA; n ϭ 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 Ϯ 58.6) of EF antibodies than AVA (4.2% and 7.8 Ϯ 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG-positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines.

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Section: Discussionmentioning

confidence: 99%

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Dumas

Gross

Larabee

et al. 2017

Clin Vaccine Immunol

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“…Recently advances in enhancement of the immune response through cofactors targeting TLR signaling have been reported as well (219). A new vaccine using recombinant PA has not yet been approved; however, several, including those utilizing mutant PA variants with less toxicity and higher immunogenicity, are in development or clinical trials (17,25,68,86,118,136,188,189,277).…”

Section: Vaccinesmentioning

confidence: 99%

Anthrax Pathogenesis

Moayeri

Leppla

Vrentas

et al. 2015

Annu. Rev. Microbiol.

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240

213

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Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium's major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

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“…Currently, most anthrax vaccines are toxin‐based. The FDA‐licensed anthrax vaccine BioThrax ® , also known as AVA (Anthrax Vaccine Adsorbed, Emergent Biosolutions, Rockville, MD), contains a PA‐aluminum hydroxide‐adsorbed precipitate derived from a B. anthracis pXO1 + pXO2 − culture supernatant, and rPA‐based next‐generation anthrax vaccines are currently undergoing clinical trials (Brown et al ., ; Bellanti et al ., ). In addition, vaccine‐engineered plasmids expressing PA and LF can protect A/J mice against lethal challenge with aerosolized B. anthracis spores (Albrecht et al ., , b).…”

Section: Tna Serum Fractions Compared With Total Antigen‐specific Iggmentioning

confidence: 99%

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge withBacillus cereusG9241

Palmer¹,

Bell²,

Darko³

et al. 2014

Pathogens Disease

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In the past decade, several Bacillus cereus strains have been isolated from otherwise healthy individuals who succumbed to bacterial pneumonia presenting symptoms resembling inhalational anthrax. One strain was indistinguishable from B. cereus G9241, previously cultured from an individual who survived a similar pneumonia-like illness and which was shown to possess a complete set of plasmid-borne anthrax toxin-encoding homologs. The finding that B. cereus G9241 pathogenesis in mice is dependent on pagA1-derived protective antigen (PA) synthesis suggests that an anthrax toxin-based vaccine may be effective against this toxin-encoding B. cereus strain. Dunkin Hartley guinea pigs were immunized with protein- and DNA-based anthrax toxin-based vaccines, immune responses were evaluated and survival rates were calculated after lethal aerosol exposure with B. cereus G9241 spores. Each vaccine induced seroconversion with the protein immunization regimen eliciting significantly higher serum levels of antigen-specific antibodies at the prechallenge time-point compared with the DNA-protein prime-boost immunization schedule. Complete protection against lethal challenge was observed in all groups with a detectable prechallenge serum titer of toxin neutralizing antibodies. For the first time, we demonstrated that the efficacy of fully defined anthrax toxin-based vaccines was protective against lethal B. cereus G9241 aerosol challenge in the guinea pig animal model.

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Phase 1 Study of a Recombinant Mutant Protective Antigen of Bacillus anthracis

Cited by 23 publications

References 31 publications

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

Anthrax Pathogenesis

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge withBacillus cereusG9241

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