Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to
            <i>Bacillus anthracis</i>
            capsule

Chen, Zhaochun; Schneerson, Rachel; Lovchik, Julie; Lyons, C. Rick; Zhao, Huaying; Dai, Zhongdong; Kübler-Kiełb, Joanna; Leppla, Stephen H.; Purcell, Robert H.

doi:10.1073/pnas.1017677108

Cited by 28 publications

(28 citation statements)

References 30 publications

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“…Accordingly, we plan to evaluate our alum-adsorbed rPA in children. We also plan on evaluating an rPA-␥DPGA (poly-␥-D-glutamic acid; B. anthracis capsule) conjugate clinically (8,22).…”

Section: Figmentioning

confidence: 99%

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

Bellanti

Lin

Chu

et al. 2012

Clin Vaccine Immunol

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A phase 1 study of a recombinant mutant protective antigen (rPA) vaccine was conducted in 186 healthy adults aged 18 to 45 years. Volunteers were randomized to receive one of three formulations of rPA (formalin treated, alum adsorbed, or both), in 10-or 20-g dosages each, or the licensed vaccine, AVA. Three injections were given at 2-month intervals and a 4th 1 year after the 3rd. Vaccinees were examined at the clinic once following each injection, at 48 to 72 h postinjection. Adverse reactions were recorded in diaries for 7 days. Sera were collected before each injection and 1 week after the 1st, 2 weeks after the 3rd and 4th, and 1 year after the 4th. Serum anti-PA IgG was assayed by enzyme-linked immunosorbent assay (ELISA) and toxin neutralization assay (TNA). All formulations at both dosages were safe and immunogenic, inducing booster responses, with the highest antibody levels following the 4th injection (354 to 732 g/ml). The lowest levels were induced by the formalin-only-treated rPA; there was no statistical difference between levels induced by alum-adsorbed and formalin-treated/alum-adsorbed rPA or by the two dosages. The antibody levels declined in all groups during the 1-year intervals after the 3rd and 4th injections but less so during the 2nd year, after the 4th injection (fold decreases were 10 to 25 versus 3.4 to 7.0, P < 0.001). There were too few AVA recipients for statistical comparisons, but their antibody levels followed those of rPA. Anti-rPA measured by ELISA correlated with TNA titers (r ‫؍‬ 0.97). These data support studying alum-adsorbed rPA in children.

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“…Accordingly, we plan to evaluate our alum-adsorbed rPA in children. We also plan on evaluating an rPA-␥DPGA (poly-␥-D-glutamic acid; B. anthracis capsule) conjugate clinically (8,22).…”

Section: Figmentioning

confidence: 99%

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

Bellanti

Lin

Chu

et al. 2012

Clin Vaccine Immunol

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“…Although the ␥DPGA capsule is relatively nonimmunogenic (55,75), recent immunization strategies have been successful in inducing anti-␥DPGA antibody responses (30,61,66,74), and passive immunization with monoclonal antibodies (MAbs) specific for the capsule of B. anthracis protected mice against a lethal pulmonary spore challenge with the fully virulent Ames strain of B. anthracis (9,33). However, the predominant strategy for designing vaccines against inhalation anthrax has focused on the toxins and utilizing PA as the primary antigen.…”

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confidence: 99%

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

et al. 2012

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ABSTRACTThe development of therapeutics against biothreats requires that we understand the pathogenesis of the disease in relevant animal models. The rabbit model of inhalational anthrax is an important tool in the assessment of potential therapeutics againstBacillus anthracis. We investigated the roles ofB. anthraciscapsule and toxins in the pathogenesis of inhalational anthrax in rabbits by comparing infection with the Ames strain versus isogenic mutants with deletions of the genes for the capsule operon (capBCADE), lethal factor (lef), edema factor (cya), or protective antigen (pagA). The absence of capsule or protective antigen (PA) resulted in complete avirulence, while the presence of either edema toxin or lethal toxin plus capsule resulted in lethality. The absence of toxin did not influence the ability ofB. anthracisto traffic to draining lymph nodes, but systemic dissemination required the presence of at least one of the toxins. Histopathology studies demonstrated minimal differences among lethal wild-type and single toxin mutant strains. When rabbits were coinfected with the Ames strain and the PA− mutant strain, the toxin produced by the Ames strain was not able to promote dissemination of the PA− mutant, suggesting that toxigenic action occurs in close proximity to secreting bacteria. Taken together, these findings suggest that a major role for toxins in the pathogenesis of anthrax is to enable the organism to overcome innate host effector mechanisms locally and that much of the damage during the later stages of infection is due to the interactions of the host with the massive bacterial burden.

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“…We showed previously that the ␥-D-PGA MAbs 4C and 11D compete for binding to PGA, indicating that they recognized the same or overlapping epitopes (25). A blocking experiment was performed to assess the specificity of the polyclonal antibodies for this epitope.…”

Section: Methodsmentioning

confidence: 99%

“…Remaining sera (after antibody assays) collected from weekly bleedings of chimpanzee AOA006 immunized with PGA-TT were pooled and concentrated ϳ10-fold using ammonium sulfate precipitation (25% to 45%), caprylic acid precipitation, and Amicon Ultra-15 centrifugal filters. The anti-PGA concentration of this preparation was measured by enzyme-linked immunosorbent assay (ELISA), using mouse monoclonal antibody (MAb) antihuman IgG and rat anti-mouse for detection and a 1-mg/ml solution of MAb D11 as the standard (25).…”

Section: Methodsmentioning

confidence: 99%

Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax

Chen

Schneerson

Lovchik

et al. 2015

Clin Vaccine Immunol

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The immunogenicity of Bacillus anthracis capsule (poly-␥-D-glutamic acid [PGA]) conjugated to recombinant B. anthracis protective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >10 3 were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 103 . An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were <300, with the antibodies peaking above 10 4 following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing of B. anthracis. Most important, the PGA-TT-induced antibodies protected mice from a lethal challenge with virulent B. anthracis spores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines. Bacillus anthracis, the causative agent of anthrax, has two obligatory virulence factors: the toxins and the capsule. The toxins consist of the protective antigen (PA), the lethal factor (LF), and the edema factor (EF). PA is the cell receptor-binding component common to the lethal and edema toxins (1). The capsule is composed of poly-␥-D-glutamic acid (␥-D-PGA). Although licensed PA-based anthrax vaccines are safe and effective, expanding protection by including additional antigens in the vaccine would be desirable as defense against bioterrorism (2, 3). Given the capsule's role in virulence, induction of anticapsular antibodies has been recommended (4-10).The capsule, present in vegetative B. anthracis, is encoded by the capBCADE operon located on plasmid pXO2 (11)(12)(13)(14). Strains that lack pXO2 and capsule are highly attenuated (15-17) and have been used as vaccines to prevent anthrax in domesticated animals for Ͼ50 years and in some countries have been used in humans as well (18). The capsule of B. anthracis contributes to the organism's virulence by its antiphagocytic action (13,(19)(20)(21). The ␥-D-PGA is poorly immunogenic and acts as a T-cell independent antigen (21, 22), but ␥-D-glutamic acid peptides conjugated to carrier proteins such as PA, bovine serum albumin (BSA), or tetanus toxoid (TT) are highly immunogenic in mice, guinea pigs, rabbits, and monkeys (4-9).To further evaluate PGA-based conjugates as vaccine candidat...

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Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Cited by 28 publications

References 30 publications

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

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

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax

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