Poly(γ-<scp>d</scp>-glutamic acid) protein conjugates induce IgG antibodies in mice to the capsule of<i>Bacillus anthracis</i>: A potential addition to the anthrax vaccine

Schneerson, Rachel; Kübler-Kiełb, Joanna; Liu, Teh‐Yung; Dai, Zhongdong; Leppla, Stephen H.; Yergey, Alfred L.; Backlund, Peter S.; Shiloach, Joseph; Majadly, Fathy; Robbins, John B.

doi:10.1073/pnas.1633512100

Cited by 128 publications

(125 citation statements)

References 39 publications

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“…If this observation can be extrapolated to humans, then universal protection may not be achievable in an outbred human population with a vaccine based on a single B. anthracis component such as PA. Consequently, the findings could be interpreted to imply a need to develop additional B. anthracis antigens for use in vaccine development. In this regard, we note encouraging reports of antibodies to the capsule elicited by a poly(gamma-Dglutamic acid)-rPA conjugate vaccine that mediate protection (18,37).…”

Section: Discussionmentioning

confidence: 68%

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

Abboud

Casadevall

2008

Clin Vaccine Immunol

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Section: Discussionmentioning

confidence: 68%

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

Abboud

Casadevall

2008

Clin Vaccine Immunol

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“…Pfs25-Br/SHPfs25. Pfs25 was derivatized with N-succinimidyl 3-(bromoacetamido) propionate and assayed for protein and antigenicity as described (Pfs25-Br) (29). Another aliquot of Pfs25 was derivatized with N-succinimidyl 3-(2-pyridyldithio)-propionate and assayed for protein, thiolation, and antigenicity (Pfs25-SH).…”

Section: Methodsmentioning

confidence: 99%

Long-lasting and transmission-blocking activity of antibodies toPlasmodium falciparumelicited in mice by protein conjugates of Pfs25

Kübler-Kiełb

Majadly

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Malaria is a leading cause of morbidity and mortality, estimated to cause >1 million childhood deaths annually. Plasmodium falciparum causes the most severe form of the disease. There is as yet no licensed vaccine for this disease, despite over a half century of research. In this study, we investigated a transmission-blocking vaccine candidate, the ookinete surface protein Pfs25. Antibodies against Pfs25, drawn in during a bite, can block parasite development in the mosquito midgut, preventing transmission to other individuals. Pfs25 is a low-molecular-weight protein, by itself not immunogenic. To increase its immunogenicity, we investigated several methods of conjugating Pfs25 to itself and to other proteins: recombinant Pseudomonas aeruginosa exotoxin A, and ovalbumin, using amide, hydrazone, or thioether linkages. All conjugates were immunogenic and induced booster responses in mice. The scheme to form amide bonds between proteins by using adipic acid dihydrizide as a linker produced the most immunogenic conjugates. Adsorption of the conjugates onto aluminum hydroxide further increased the antibody response. Remarkably, the antibody levels 3 or 7 months after the last injection were significantly higher than those 1 wk after that injection. The observed transmission-blocking activity of immune sera correlated with antibody levels measured by ELISA. malaria ͉ vaccine O ne approach for a vaccine against malaria is to block transmission of the parasite from mosquitoes to humans. When ingested by a mosquito with the blood meal, antibodies against the sexual and the mosquito stage-specific surface antigens can block parasite development inside the vector (1). Four proteins have been identified as potential inducers of transmission-blocking antibodies (2-5). Two of these are expressed on the surface of gametes and in intracellular gameotocytes. The other two are the Plasmodium falciparum surface proteins with apparent molecular masses of 25 kDa (Pfs25) and 28 kDa (Pfs28), expressed exclusively on the zygote and ookinete surfaces during the mosquito stage of the infection. No antibody response to these two proteins has been shown in people infected with malaria and living in endemic countries (6). Pfs25 from different parts of the world has shown minimal variation in its amino acid sequence (7). This relative homogeneity, likely a result from not being subjected to immune pressure in the human host, makes Pfs25 an attractive candidate for a malaria transmission-blocking vaccine (8). Pfs25 is poorly immunogenic in mice and in humans, even if administered with adjuvant (9, 10). In this article, we show that Pfs25 bound onto itself or onto another protein induced high levels of transmission-blocking antibodies in mice.

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“…Macrophages (60) and neutrophils (23,32) are reported to phagocytize and kill B. anthracis, and macrophages are required for resistance to infection in mice (7). Recent work suggests that antibody to the B. anthracis capsule enhances phagocytosis and killing of encapsulated bacilli (6,46,59) and that active (6) and passive (27) vaccination with capsule protects against experimental infection. Taken together, these data suggest that methods to increase the phagocytosis of encapsulated anthrax bacilli may be valuable in the treatment of anthrax.…”

mentioning

confidence: 99%

Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis

Scorpio

Chabot

Day

et al. 2007

Antimicrob Agents Chemother

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The poly-␥-D-glutamic acid capsule confers antiphagocytic properties on Bacillus anthracis and is essential for virulence. In this study, we showed that CapD, a ␥-polyglutamic acid depolymerase encoded on the B. anthracis capsule plasmid, degraded purified capsule and removed the capsule from the surface of anthrax bacilli. Treatment with CapD induced macrophage phagocytosis of encapsulated B. anthracis and enabled human neutrophils to kill encapsulated organisms. A second glutamylase, PghP, a ␥-polyglutamic acid hydrolase encoded by Bacillus subtilis bacteriophage ⌽NIT1, had minimal activity in degrading B. anthracis capsule, no effect on macrophage phagocytosis, and only minimal enhancement of neutrophil killing. Thus, the levels of both phagocytosis and killing corresponded to the degree of enzyme-mediated capsule degradation. The use of enzymes to degrade the capsule and enable phagocytic killing of B. anthracis offers a new approach to the therapy of anthrax.

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Poly(γ-d-glutamic acid) protein conjugates induce IgG antibodies in mice to the capsule ofBacillus anthracis: A potential addition to the anthrax vaccine

Cited by 128 publications

References 39 publications

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

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

Long-lasting and transmission-blocking activity of antibodies toPlasmodium falciparumelicited in mice by protein conjugates of Pfs25

Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis

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