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Author

Zeev Altboum

Bio: Zeev Altboum is an academic researcher from Israel Institute for Biological Research. The author has contributed to research in topics: Bacillus anthracis & Anthrax vaccines. The author has an hindex of 20, co-authored 37 publications receiving 1493 citations. Previous affiliations of Zeev Altboum include University of Maryland, Baltimore.

Papers
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Journal ArticleDOI
TL;DR: Results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.
Abstract: Vaccination by anthrax protective antigen (PA)-based vaccines requires multiple immunization, underlying the need to develop more efficacious vaccines or alternative vaccination regimens. In spite of the vast use of PA-based vaccines, the definition of a marker for protective immunity is still lacking. Here we describe studies designed to help define such markers. To this end we have immunized guinea pigs by different methods and monitored the immune response and the corresponding extent of protection against a lethal challenge with anthrax spores. Active immunization was performed by a single injection using one of two methods: (i) vaccination with decreasing amounts of PA and (ii) vaccination with constant amounts of PA that had been thermally inactivated for increasing periods. In both studies a direct correlation between survival and neutralizing-antibody titer was found (r2 = 0.92 and 0.95, respectively). Most significantly, in the two protocols a similar neutralizing-antibody titer range provided 50% protection. Furthermore, in a complementary study involving passive transfer of PA hyperimmune sera to naive animals, a similar correlation between neutralizing-antibody titers and protection was found. In all three immunization studies, neutralization titers of at least 300 were sufficient to confer protection against a dose of 40 50% lethal doses (LD50) of virulent anthrax spores of the Vollum strain. Such consistency in the correlation of protective immunity with anti-PA antibody titers was not observed for antibody titers determined by an enzyme-linked immunosorbent assay. Taken together, these results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.

233 citations

Journal ArticleDOI
TL;DR: Results suggest that some B. anthracisspore-associated antigen(s) may contribute in a significant manner to protective immunity and appear to be more efficacious than the vegetative cell vaccine.
Abstract: The etiological agent of anthrax disease in animals and humans is the spore-forming bacterium Bacillus anthracis. The major factors of virulence of B. anthracis are located on two plasmids, pXO1 and pXO2. pXO2 encodes a poly-d-glutamic acid capsule (19, 41), while pXO1 encodes two binary exotoxins, the lethal toxin (LT) and the edema toxin (ET) (43, 46, 61). These two toxins are composed of three different proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF) (for a review, see reference 36). PA is the common receptor binding domain of the toxins and can interact with the two different effector domains, EF and LF, to mediate their entry into target cells (14). EF is a calmodulin-dependent adenylate cyclase (37) responsible for the edema seen at the site of infection in experimental animals (17). The LF is a metalloprotease (34) recently shown to cleave the amino termini of the mitogen-activated protein kinase kinases 1 and 2, which results in their inactivation (13). It remains to be determined whether these are the main physiological substrates for the LT activity in vivo (5, 22). Two types of anthrax vaccines are licensed for use in humans: the spores of the toxigenic, nonencapsulated B. anthracis STI-1 strain (55) and the cell-free PA-based vaccines consisting of aluminum hydroxide-adsorbed supernatant material from cultures of the toxigenic, nonencapsulated B. anthracis strain V770-NPI-R (49) or alum-precipitated culture filtrate from the Sterne strain (6). The use of the live attenuated STI-1 occasionally results in general and local adverse responses, observed both after primary application and revaccination, and the frequency of responses increases with the number of vaccinations (58). Furthermore, it was reported that the STI-1 vaccine has a relatively low immunogenicity (reviewed by Stepanov et al. in reference 58). To increase the immunogenicity, a combined vaccine of live STI-1 supplemented with cell-free PA formulation was evaluated and proposed for veterinary use (1). While the cell-free PA-based vaccines appear to be safer, they require numerous boosters (8) and were shown to have reduced ability to protect laboratory animals against certain virulent strains of B. anthracis (39, 60). In addition, these vaccines contain variable amounts of PA, as well as undefined quantities of LF and EF, adsorbed to aluminum hydroxide (4, 21, 49, 59). It appears, therefore, that there is a need for a safe and more efficient vaccine which could generate stable and prolonged immunity in humans (59). These conclusions led to the evaluation of various adjuvants with purified PA (2, 16, 29, 59) and to the creation of two types of live vaccines: vaccines based on nonvirulent B. anthracis (pXO1+) mutated strains (31, 47) and vaccines expressing PA from a cloned pagA gene using heterologous hosts such as the vaccinia virus, Bacillus subtilis, Salmonella typhimurium (10, 27, 28, 30, 31, 64), or a nontoxinogenic strain of B. anthracis (4). These pioneering studies suggest that recombinant B. anthracis live vaccines may have potential as a future anthrax vaccine. We report here the construction of several recombinant, nonencapsulated, and nontoxinogenic B. anthracis spore-forming strains expressing different levels of PA. We demonstrate that one of these strains, containing the pagA gene under a potent heterologous constitutive promoter, can be safely used to provide efficacious long-lasting immunity in experimental animals following a single immunization dose.

154 citations

Journal ArticleDOI
TL;DR: Results further emphasizes the importance of anti-PA antibodies in conferring protection against B. anthracis infection and demonstrated the ability of such antibodies to be effectively applied as an efficient postexposure treatment against anthrax disease.
Abstract: The efficacy of passive immunization as a postexposure prophylactic measure for treatment of guinea pigs intranasally infected with Bacillus anthracis spores was evaluated. Antisera directed either against the lethal toxin components (PA or LF) or against a toxinogenic strain (Sterne) were used for this evaluation. All antisera exhibited high enzyme-linked immunosorbent assay titers against the corresponding antigens, high titers of neutralization of cytotoxicity activity in an in vitro mouse macrophages cell line (J774A.1), as well as in vivo neutralization of toxicity when administered either directly to Fisher rats prior to challenge with the lethal toxin or after incubation with the lethal toxin. In these tests, anti-LF antiserum exhibited the highest neutralization efficiency, followed by anti-Sterne and anti-PA. The time dependence and antibody dose necessary for conferring postexposure protection by the various antibodies of guinea pigs infected with 25 50% lethal doses of Vollum spores was examined. Rabbit anti-PA serum was found to be the most effective. Intraperitoneal injections of anti-PA serum given 24 h postinfection protected 90% of the infected animals, whereas anti-Sterne and anti-LF were less effective. These results further emphasizes the importance of anti-PA antibodies in conferring protection against B. anthracis infection and demonstrated the ability of such antibodies to be effectively applied as an efficient postexposure treatment against anthrax disease.

115 citations

Journal ArticleDOI
TL;DR: It is proposed that MntA is a novel B.’anthracis virulence determinant essential for the development of anthrax disease, and that B. anthracisΔmntA strains have the potential to serve as platform for future live attenuated vaccines.
Abstract: Here we describe the characterization of a lipoprotein previously proposed as a potential Bacillus anthracis virulence determinant and vaccine candidate. This protein, designated MntA, is the solute-binding component of a manganese ion ATP-binding cassette transporter. Coupled proteomic-serological screen of a fully virulent wild-type B. anthracis Vollum strain, confirmed that MntA is expressed both in vitro and during infection. Expression of MntA is shown to be independent of the virulence plasmids pXO1 and pXO2. An mntA deletion, generated by allelic replacement, results in complete loss of MntA expression and its phenotypic analysis revealed: (i) impaired growth in rich media, alleviated by manganese supplementation; (ii) increased sensitivity to oxidative stress; and (iii) delayed release from cultured macrophages. The DeltamntA mutant expresses the anthrax-associated classical virulence factors, lethal toxin and capsule, in vitro as well as in vivo, and yet the mutation resulted in severe attenuation; a 10(4)-fold drop in LD(50) in a guinea pig model. MntA expressed in trans allowed to restore, almost completely, the virulence of the DeltamntA B. anthracis strain. We propose that MntA is a novel B. anthracis virulence determinant essential for the development of anthrax disease, and that B. anthracisDeltamntA strains have the potential to serve as platform for future live attenuated vaccines.

84 citations

Journal ArticleDOI
TL;DR: Analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) was applied for the characterization of Bacillus anthracis spore biomarkers, which were isotopically resolved and reproducibly detected in the highly accurate MALDI-toFMS reflectron mode and may be useful as a basis for rapid and specific identification of B. anthracIS strains.
Abstract: Analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) was applied for the characterization of Bacillus anthracis spore biomarkers. B. anthracis spores were extracted under a simple procedure, followed by linear mode analysis, using sinapinic acid as the matrix. Several markers with a mass range of 4-7 kDa were detected in three B. anthracis strains: Vollum, Sterne and V770-NP1-R. Similar spectra were also obtained for spore extracts of two members of the B. cereus group: B. thuringiensis and B. cereus, but not for B. mycoides, B. subtilis or B. licheniformis, suggesting that these markers are specific to closely related members of the B. cereus group. When alpha-cyano-4-hydroxycinnamic acid was used as the matrix, at least four additional new markers within a mass range of 2-4 kDa could be detected in all B. anthracis spore extracts. These markers, corresponding to a molecular weight of 2528.3, 2792.4, 3077.4, and 3590.7 Da, have not been observed in extracts of the three closely related Bacillus species - B. cereus, B. thuringiensis and B. mycoides. These unique B. anthracis biomarkers, which were isotopically resolved and reproducibly detected in the highly accurate MALDI-TOFMS reflectron mode, may be useful as a basis for rapid and specific identification of B. anthracis strains.

84 citations


Cited by
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Journal ArticleDOI
TL;DR: This paper attempts to summarize current knowledge about immune responses to vaccines that correlate with protection, finding some vaccines have no true correlates, but only useful surrogates, for an unknown protective response.
Abstract: This paper attempts to summarize current knowledge about immune responses to vaccines that correlate with protection. Although the immune system is redundant, almost all current vaccines work through antibodies in serum or on mucosa that block infection or bacteremia/viremia and thus provide a correlate of protection. The functional characteristics of antibodies, as well as quantity, are important. Antibody may be highly correlated with protection or synergistic with other functions. Immune memory is a critical correlate: effector memory for short-incubation diseases and central memory for long-incubation diseases. Cellular immunity acts to kill or suppress intracellular pathogens and may also synergize with antibody. For some vaccines, we have no true correlates, but only useful surrogates, for an unknown protective response.

1,350 citations

Journal ArticleDOI
TL;DR: The pathogenesis of ETEC-induced diarrhea is similar to that of cholera and includes the production of enterotoxins and colonization factors, and clinical symptoms can range from mild diarrhea to a severe choline-like syndrome.
Abstract: ETEC is an underrecognized but extremely important cause of diarrhea in the developing world where there is inadequate clean water and poor sanitation. It is the most frequent bacterial cause of diarrhea in children and adults living in these areas and also the most common cause of traveler's diarrhea. ETEC diarrhea is most frequently seen in children, suggesting that a protective immune response occurs with age. The pathogenesis of ETEC-induced diarrhea is similar to that of cholera and includes the production of enterotoxins and colonization factors. The clinical symptoms of ETEC infection can range from mild diarrhea to a severe cholera-like syndrome. The effective treatment of ETEC diarrhea by rehydration is similar to treatment for cholera, but antibiotics are not used routinely for treatment except in traveler's diarrhea. The frequency and characterization of ETEC on a worldwide scale are inadequate because of the difficulty in recognizing the organisms; no simple diagnostic tests are presently available. Protection strategies, as for other enteric infections, include improvements in hygiene and development of effective vaccines. Increases in antimicrobial resistance will dictate the drugs used for the treatment of traveler's diarrhea. Efforts need to be made to improve our understanding of the worldwide importance of ETEC.

898 citations

Journal ArticleDOI
TL;DR: Correlates of protection after vaccination are sometimes absolute quantities but often are relative, such that most infections are prevented at a particular level of response but some will occur above that level because of a large challenge dose or deficient host factors.
Abstract: The immune system is redundant, and B and T cells collaborate. However, almost all current vaccines work through induction of antibodies in serum or on mucosa that block infection or interfere with microbial invasion of the bloodstream. To protect, antibodies must be functional in the sense of neutralization or opsonophagocytosis. Correlates of protection after vaccination are sometimes absolute quantities but often are relative, such that most infections are prevented at a particular level of response but some will occur above that level because of a large challenge dose or deficient host factors. There may be >1 correlate of protection for a disease, which we term "cocorrelates." Either effector or central memory may correlate with protection. Cell-mediated immunity also may operate as a correlate or cocorrelate of protection against disease, rather than against infection. In situations where the true correlate of protection is unknown or difficult to measure, surrogate tests (usually antibody measurements) must suffice as predictors of protection by vaccines. Examples of each circumstance are given.

741 citations

Journal ArticleDOI
07 Jan 1956-BMJ
TL;DR: It is doubtful whether a general work of this calibre should contain even brief accounts and exiguous illustrations of operations, but the editors have produced a magnunm opus which for many years will be indispensable to those who practise obstetrics and gynaecology.
Abstract: These companion volumes have been edited by two of the leading personalities in British obstetrics and gynaecology. Both have made notable contributions to their subjects, and each is an outstanding teacher who has always subscribed to the dictum that teaching needs research and research needs teaching. With such a philosophy inspiring their professional work, it would follow, therefore, that any publication of theirs would be devoid of pedantry. The reader will not be disappointed and will find an original, lucid, and constructive presentation. Their aim has been to present, so far as possible, a description of obstetrics and gynaecology as practised in Britain. It may be pertinently asked in what way British practice differs from that in other countries. The editors have forestalled this question. They believe that in obstetrics the chief modern contribution from Britain has been \" the results of the study of the relation of social and economic conditions to the health of the pregnant woman and the condition of her child.\" In gynaecology it is conservatism that has been the characteristic British contribution. Sir Eardley Holland has been responsible for the general editorship of the volume on obstetrics and has been assisted by 38 contributors selected from almost all the university and teaching centres. Professor Bruce Mayes, of Sydney University, is the sole overseas contributor. Included in this obstetric oligarchy are physicians, paediatricians, anatomists, a psychiatrist, a venereologist, a medical statistician, and a barrister. The co-authors have been allocated subjects in which they are acknowledged experts; thus each chapter is authoritative and at the same time original. Mr. Aleck Bourne has enlisted the help of 21 authors for the volume on gynaecology, and among these is an anatomist, a psychiatrist, a venereologist, and a barrister. He has always emphasized the importance of the basic sciences in relation to clinical medicine ; the reader will appreciate this from the contents and their presentation. It is doubtful whether a general work of this calibre should contain even brief accounts and exiguous illustrations of operations. The excellent chapter on the cervix uteri is impaired by the descriptions (and diagrams) of the operations for amputation of the cervix and trachelorrhaphy. Those who need pictorial assistance for their surgical technique would refer to a tome on operative surgery. Both volumes are illustrated with diagrams and plates of artistic distinction, and the publishers are to be congratulated on their production. The editors have succeeded in their aim. Their task has been sisyphean, but they have produced a magnunm opus which for many years will be indispensable to those who practise obstetrics and gynaecology. W. C. W. NIXON.

669 citations

Journal ArticleDOI
TL;DR: This assay is used to demonstrate that the anthrax vaccine (AVA; BioThrax) elicits a substantial population of protective-antigen (PA) specific memory B cells, and these B cells satisfy the canonical surface phenotype of humanMemory B cells.

437 citations