Safety and immunogenicity of a Pseudomonas aeruginosa O-polysaccharide toxin A conjugate vaccine in humans.

Cryz, Stanley J.; Fürer, E; Cross, Alan S.; Wegmann, A; Germanier, R; Sadoff, Jerald C.

doi:10.1172/jci113062

Cited by 94 publications

(41 citation statements)

References 31 publications

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“…Patients with CF show adequate functional immune response to PA with regard to IgG antibodies to LPS of PA. It is possible that vaccination against PA of CF patients who have not vet been colonized with PA could induce ~rotective immunity: Safety and immunogenicity of PA poly~accharide Tox A conjugate vaccines in humans have been satisfactorily documented (34).…”

Section: Discussionmentioning

confidence: 99%

Serotype-Specific Serum IgG Antibodies to Lipopolysaccharides of Pseudomonas aeruginosa in Cystic Fibrosis: Correlation to Disease, Subclass Distribution, and Experimental Protective Capacity

et al. 1990

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ABSTRACT. Various studies have demonstrated pronounced systemic IgG response to Pseudomonas aevuginosa (PA) infection in cystic fibrosis (CF). However, antibody response to serotype-specific lipopolysaccharides (LPS) has never been studied. ELISA for detection of IgG antibodies to L P S of nine PA-serotypes and to toxin A were performed with serum of 78 C F patients. Anti-LPS profiles of antibodies were confirmed by SDS-PAGE and immunoblotting techniques. The most frequent PA-serotypes found were immunotypes (IT) IT-1 and IT-2, and Habs-3 and Habs-4. Ten patients without PA colonization showed no detectable antibody titers. In patients with chronic PA colonization (n = 46), these antibody titers were significantly (p < 0.005) higher than in patients with intermittent PA colonization (n = 22). Mean serum antibody titers to L P S of PA IT-1, IT-2, Habs-3, and Habs-4 correlated with duration of PA colonization and with disease severity. Subclass analysis of anti-LPS antibodies revealed elevated levels for all four IgG subclasses and for IgA,. The IgG antibodies to L P S of PA proved to be protective in a murine burn wound sepsis model. We conclude that anti-LPS antibodies to specific P A serotypes in serum may be a sensitive measure of severity and prognosis of CF. Patients with C F show adequate functional immune response to L P S of PA, and it is possible that vaccination against PA before colonization could induce protective immunity. (Pediatv Res 27: 508-513, 1990) Abbreviations CF, cystic fibrosis IT, immunotype LPS, lipopolysaccharide PA, Pseudomonas aeruginosa Tox A. toxin A PA is a persistent sputum pathogen in most patients with advanced CF (1). Pseudomonas pulmonary infections are the major determinant of quality and duration of life in these patients. Mechanisms of virulence and pathogenesis of PA are

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Section: Discussionmentioning

confidence: 99%

Serotype-Specific Serum IgG Antibodies to Lipopolysaccharides of Pseudomonas aeruginosa in Cystic Fibrosis: Correlation to Disease, Subclass Distribution, and Experimental Protective Capacity

et al. 1990

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“…Additionally, PE can stimulate fluid absorption from distal airspaces of the lung (52), disrupt neutrophil function (41), inhibit gamma interferon (IFN-␥) synthesis to suppress specific and nonspecific defense mechanisms associated with bacterial clearance (39), stimulate macrophage-based tumor necrosis factor (TNF)-mediated apoptosis (58), and impede the restoration of epithelial tight junction structures damaged by the actions of neutrophilderived elastase (2). Neutralizing antibodies to PE have been shown to not only promote uptake and killing of P. aeruginosa by neutrophils (11) but also be beneficial in clearing P. aeruginosa infections (18,59). Antibodies to PE can also reduce the binding of both piliated and nonpiliated P. aeruginosa to tracheal cells in vitro (42), and several studies have described strategies to generate neutralizing immune responses to PE as a method of reducing the clinical impact of this virulence factor (8,20,25,50).…”

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confidence: 99%

Intranasal Immunization Strategy To Impede Pilin-Mediated Binding ofPseudomonas aeruginosato Airway Epithelial Cells

Hsieh¹,

Tham²,

Feng³

et al. 2005

Infect Immun

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Prevention of pulmonary Pseudomonas aeruginosa infections represents a critical unmet medical need for cystic fibrosis (CF) patients. We have examined the tenet that a mucosal immunization approach can reduce interactions of a piliated form of this opportunistic pathogen with respiratory epithelial cells. Vaccinations were performed using ntPEpilinPAK, a protein chimera composed of a nontoxic form of P. aeruginosa exotoxin A (ntPE), where the C-terminal loop amino acid sequence of the PAK strain pilin protein was inserted in place of the ntPE Ib domain. Intranasal (i.n.) immunization of BALB/c mice with ntPEpilinPAK generated both serum and saliva immune responses. A series of in vitro studies showed that diluted samples of saliva obtained from immunized mice reduced pilin-dependent P. aeruginosa binding to polarized human tracheal epithelial cells, protected human pulmonary epithelial cells from cytotoxic actions associated with bacterial challenge, and reduced exotoxin A toxicity. Overall, i.n. administration of ntPEpilinPAK induced mucosal and systemic immune responses that may be beneficial for blocking early stage adhesion and/or infection events of epithelial cell-P. aeruginosa interactions at oropharyngeal surfaces.

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“…One group of potential vaccine candidates is based on polysaccharide components that P. aeruginosa presents to its host (9,40,50). The outer membrane proteins are a second group because there is a limited number of abundant proteins, three of which, porin protein F (OprF), lipoprotein I (OprI), and protein H2 (OprH2), cross-react immunologically between the different serotypes of P. aeruginosa (35).…”

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confidence: 99%

Pseudomonas aeruginosa outer membrane lipoprotein I gene: molecular cloning, sequence, and expression in Escherichia coli

et al. 1989

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Lipoprotein I (OprI) is one of the major proteins of the outer membrane of Pseudomonas aeruginosa. Like porin protein F (OprF), it is a vaccine candidate because it antigenically cross-reacts with all serotype strains of the International Antigenic Typing Scheme. Since lipoprotein I was expressed in Escherichia coli under the control of its own promoter, we were able to isolate the gene by screening a lambda EMBL3 phage library with a mouse monoclonal antibody directed against lipoprotein I. The monocistronic OprI mRNA encodes a precursor protein of 83 amino acid residues including a signal peptide of 19 residues. The mature protein has a molecular weight of 6,950, not including bound glycerol and lipid. Although the amino acid sequences of protein I of P. aeruginosa and Braun's lipoprotein of E. coli differ considerably (only 30.1% identical amino acid residues), peptidoglycan in E. coli, are identical. Using lipoprotein I expressed in E. coli, it can now be tested whether this protein alone, without P. aeruginosa lipopolysaccharide contaminations, has a protective effect against P. aeruginosa infections.

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Safety and immunogenicity of a Pseudomonas aeruginosa O-polysaccharide toxin A conjugate vaccine in humans.

Cited by 94 publications

References 31 publications

Serotype-Specific Serum IgG Antibodies to Lipopolysaccharides of Pseudomonas aeruginosa in Cystic Fibrosis: Correlation to Disease, Subclass Distribution, and Experimental Protective Capacity

Serotype-Specific Serum IgG Antibodies to Lipopolysaccharides of Pseudomonas aeruginosa in Cystic Fibrosis: Correlation to Disease, Subclass Distribution, and Experimental Protective Capacity

Intranasal Immunization Strategy To Impede Pilin-Mediated Binding ofPseudomonas aeruginosato Airway Epithelial Cells

Pseudomonas aeruginosa outer membrane lipoprotein I gene: molecular cloning, sequence, and expression in Escherichia coli

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