Contribution of the B oligomer to the protective activity of genetically attenuated pertussis toxin

Arciniega, Juan; Shahin, Roberta D.; Burnette, W N; Bartley, Timothy D.; Whiteley, D W; Mar, V L; Burns, Drusilla L

doi:10.1128/iai.59.10.3407-3410.1991

Cited by 17 publications

(8 citation statements)

References 25 publications

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“…Research on protection has traditionally been focused on the role of humoral pertussisspecific antibodies, which are induced in humans and rodents following natural infection or immunization with whole-cell vaccines or defined pertussis antigens (3,33,46,53). In animal models, passive transfer of antibodies against several pertussis antigens (25,48,52) as well as antibodies elicited after active immunization with whole-cell or acellular vaccines (4,10,43) can confer different degrees of protection against subsequent intracerebral or respiratory challenge. However, such models are not truly representative of human pertussis.…”

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confidence: 99%

Pertussis-specific cell-mediated immunity in infants after vaccination with a tricomponent acellular pertussis vaccine

et al. 1996

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The aim of this study was to investigate pertussis-specific cell-mediated immunity in infants vaccinated with a tricomponent acellular vaccine. Infants were investigated during a primary vaccination schedule from the third month of life to the sixth month as well as before and after a booster at 15 to 24 months. This is the first report of specific cell-mediated immune responses to pertussis-related antigens in infants below the age of 12 months. Our data show that the vaccine induces T-cell responses specific for the vaccine components, detoxified pertussis toxin, filamentous hemagglutinin, and pertactin, that increase progressively over the course of the vaccination schedule. In contrast to declining antibody titers, cell-mediated immune responses are stable over the postprimary to prebooster period. Vaccination results in a progressive increase in the number of T cells that express activation marker CD45RO preferentially on CD4-positive T cells after stimulation with pertussis antigens. Measurements of cytokine secretion profiles demonstrated a preferential induction of interleukin 2-and gamma interferon-producing T-helper 1 cells and only low production of interleukin 10. The observed persistence of the specific cell-mediated immunity may have a bearing on the protective mechanisms induced by pertussis vaccination. Cell-mediated immunity requires further study, particularly to improve our understanding of the persistence of protection afforded by vaccination up to the administration of booster doses.

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Pertussis-specific cell-mediated immunity in infants after vaccination with a tricomponent acellular pertussis vaccine

et al. 1996

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“…Current acellular pertussis vaccines contain PT that has been inactivated by chemical treatment (28). Discovery that a specific amino acid substitution in the Si subunit of PT could result in an inactive toxin that retains its immunogenic potential (3,5,11) implied that a safe and effective toxoid vaccine component could be manufactured by recombinant means. Recently, a strain of B. pertussis has been molecularly modified to produce such a genetic toxoid (25); this protein has been purified and included in vaccines presently undergoing clinical evaluation (26).…”

Section: Discussionmentioning

confidence: 99%

“…The observations that B oligomer alone is apparently sufficient to stimulate protective immune responses in animals (31), that such immunity is equivalent to that conferred by a genetically attenuated holotoxin (3), and that the purified B moiety lacks the potent activities attributed to PT (2) suggested to us that this multimeric protein might be a suitable vaccine component. However, methods currently available for obtaining B oligomer are impractical for commercial-scale production.…”

Section: Discussionmentioning

confidence: 99%

“…As a chemical toxoid, the holotoxin elicits immunoprotection in mice against intracerebral challenge with B. pertussis (21,27) and has been demonstrated to be efficacious for prevention of disease in human clinical studies (1,6,22,23,32). It was recently demonstrated that the B oligomer alone may be sufficient to provoke protective immune responses (2,31) and that it confers protection in mice equivalent to that of a genetically attenuated holotoxin molecule (3). While biochemically purified B oligomer that is 99.8% free of the S1 subunit can be obtained (2), the possibility remains that the residual holotoxin actually elicits the immunoprotection or enhances the immunogenicity of the B oligomer through an adjuvant effect (18).…”

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Properties of pertussis toxin B oligomer assembled in vitro from recombinant polypeptides produced by Escherichia coli

et al. 1992

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The subunits that make up the pentameric B oligomer of pertussis toxin (S2, S3, S4, and S5) were individually synthesized as recombinant polypeptides in Escherichia coli, isolated as insoluble inclusion bodies, and assembled into a multimeric form in vitro by spontaneous association following treatment with a chaotropic agent, reduction, and reoxidation. The recombinant B multimer, purified by fetuin-Sepharose affinity 2252 Vol. 60,No. 6

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“…Active or passive immunization with PT is protective against lethal infection with virulent B. pertussis in animal models and at least partially protective against disease in humans (1,31,41). The A protomer and the B oligomer are able to induce neutralizing antibodies in mice and protect against challenge with PT (2,14,34) or infection with virulent B. pertussis (3,34,46). Pertussis infection or vaccination in mice and also in humans gives rise to antibodies predominantly against subunit S1 (38,49).…”

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Identification of murine T-cell epitopes on the S4 subunit of pertussis toxin

et al. 1993

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The aim of the present study was to identify murine T-cell epitopes on pertussis toxin subunit S4. Six mouse strains with five different haplotypes at the H-2 locus were immunized with the pertussis toxin B oligomer. Lymph node lymphocytes were isolated and stimulated in an in vitro proliferation assay with pertussis toxin components and 11 overlapping synthetic peptides synthesized on the basis of the primary sequence of S4. In vitro proliferative responses to the synthetic peptides revealed the presence of four distinct murine T-cell epitopes on subunit S4. The recognition of the peptides was major histocompatibility complex restricted.Immunizing four of the six mouse strains with the synthetic peptides showed that the peptides which were demonstrated to contain T-cell epitopes following immunization with the B oligomer were able to induce proliferative responses to detoxified pertussis toxin and pertussis toxin components containing subunit S4. One of the identified murine T-cell epitopes corresponded to one of the major human T-cell epitopes previously identified on subunit S4. It is hoped that this murine model system will facilitate the development of a synthetic immunogen mimicking the protective properties of pertussis toxin.

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Contribution of the B oligomer to the protective activity of genetically attenuated pertussis toxin

Cited by 17 publications

References 25 publications

Pertussis-specific cell-mediated immunity in infants after vaccination with a tricomponent acellular pertussis vaccine

Pertussis-specific cell-mediated immunity in infants after vaccination with a tricomponent acellular pertussis vaccine

Properties of pertussis toxin B oligomer assembled in vitro from recombinant polypeptides produced by Escherichia coli

Identification of murine T-cell epitopes on the S4 subunit of pertussis toxin

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