Efficacy trial of a parenteral gonococcal pilus vaccine in men

Boslego, John W.; Tramont, Edmund C.; Chung, Raymond; McChesney, Daniel G.; Ciak, Jennie; Sadoff, Jerald C.; Piziak, M; Brown, J E; BRINTONJR, C; Wood, Sarah W.

doi:10.1016/0264-410x(91)90147-x

Cited by 169 publications

(122 citation statements)

References 34 publications

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“…Ample evidence indicates that antibodies to the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) (2)(3)(4), are a major component of protective immunity, particularly during early childhood (5)(6)(7)(8). Variant antigens, however, are used by organisms to evade immunity and are not considered as good vaccine targets to control infection (9). Vast diversity, multiple copies, and clonal antigenic variation are the hallmark of these variant antigens leading to variant specific immune response (10,11).…”

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confidence: 99%

Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line

Baruch

Gamain

Barnwell

et al. 2002

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

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Immunity to Plasmodium falciparum in African children has been correlated with antibodies to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) variant gene family expressed on the surface of infected red cells. We immunized Aotus monkeys with a subregion of the Malayan Camp variant antigen (MCvar1) that mediates adhesion to the host receptor CD36 on the endothelial surface and present data that PfEMP1 is an important target for vaccine development. The immunization induced a high level of protection against the homologous strain. Protection correlated with the titer of agglutinating antibodies and occurred despite the expression of variant copies of the gene during recurrent waves of parasitemia. A second challenge with a different P. falciparum strain, to which there was no agglutinating activity, showed no protection but boosted the immune response to this region during the infection. The level of protection and the evidence of boosting during infection encourage further exploration of this concept for malaria vaccine development.

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confidence: 99%

Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line

Baruch

Gamain

Barnwell

et al. 2002

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

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“…For N. gonorrhoeae and N. meningitidis Tfp, such concerns are complicated by the extensive antigenic variability of the PilE pilin subunit that arises due to gene conversion-like events between a single expression locus and multiple, variable partial gene copies (9). The high degree of PilE antigenic variation likely contributes to both the failure of gonococcal infection to engender protective immunity (10) and the lack of efficacy associated with N. gonorrhoeae Tfp-based vaccines (11).…”

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confidence: 99%

Neisseria gonorrhoeae Type IV Pili Undergo Multisite, Hierarchical Modifications with Phosphoethanolamine and Phosphocholine Requiring an Enzyme Structurally Related to Lipopolysaccharide Phosphoethanolamine Transferases

Aas

Egge-Jacobsen

Winther‐Larsen

et al. 2006

Journal of Biological Chemistry

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The zwitterionic phospho-forms phosphoethanolamine and phosphocholine are recognized as influential and important substituents of pathogen cell surfaces. PilE, the major pilin subunit protein of the type IV pilus (Tfp) colonization factor of Neisseria gonorrhoeae undergoes unique, post-translational modifications with these moieties. These phospho-form modifications have been shown to be O-linked alternately to a specific, conserved serine residue of PilE. However, the enzymes and precursors involved in their addition are unknown, and the full spectrum of PilE posttranslational modifications has yet to be defined. Here, an intact protein-based mass spectrometric approach was integrated with bioinformatics and reverse genetics to address these matters. Specifically we show that a protein limited in its distribution to pathogenic Neisseria species and structurally related to enzymes implicated in phosphoethanolamine modification of lipopolysaccharide is necessary for PilE covalent modification with phosphoethanolamine and phosphocholine. These findings strongly suggest that protein phospho-form modification is mechanistically similar to processes underlying analogous modifications of prokaryotic saccharolipid glycans. We also show that PilE undergoes multisite and hierarchical phospho-form modifications and that the stoichiometries of site occupancy can be influenced by PilE primary structure and the abundance of the pilin-like protein PilV. Together, these findings have important implications for the structure and antigenicity of PilE.Covalent post-translational modifications of surface proteins in microbial pathogens are now a well established phenomenon. By modifying structure and potentially function, such post-translational modifications are likely to play an important role in the parasite-host interaction. Moreover, post-translational modifications provide effective means to augment the information content of compact genomes, to generate diversity, and to influence antigenicity. By way of example, covalent protein modifications with N-and O-linked carbohydrate appear more and more as common features of proteins of bacterial pathogens (1). Studies have revealed a surprisingly high degree of conservation and relatedness in a number of these systems, and in some instances glycosylation-defective mutants have been shown to be attenuated in virulence-associated properties (2, 3) and colonization (4 -7). Nonetheless, the full significance of protein glycosylation has yet to be precisely defined in any prokaryotic system. Type IV pili (Tfp) 4 are proteinaceous polymeric filaments that serve critical roles in disease pathogenesis and prokaryotic cell biology in many Gram-negative species. Important human pathogens expressing Tfp include Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pseudomonas aeruginosa, and enteropathogenic strains of Escherichia coli (8). Tfp contribute to colonization by virtue of promoting binding to epithelial cells, motility-generating capacity, and the ability to aggregate ...

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“…In response to natural gonococcal infection, the antibody response is primarily directed against pili, outer membrane proteins, and lipo-oligosaccharide (LOS) 1 (1,2). Prior vaccine attempts using gonococcal pilus, porin, and opacity protein have failed to produce a broadly protective immune response (3)(4)(5). Therefore, several investigators have been concentrating efforts to utilize LOS as potential vaccines.…”

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confidence: 99%

Structural and Immunochemical Characterization of aNeisseria gonorrhoeae Epitope Defined by a Monoclonal Antibody 2C7; the Antibody Recognizes a Conserved Epitope on Specific Lipo-oligosaccharides in Spite of the Presence of Human Carbohydrate Epitopes

Yamasaki

Koshino²,

Kurono³

et al. 1999

Journal of Biological Chemistry

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Efficacy trial of a parenteral gonococcal pilus vaccine in men

Cited by 169 publications

References 34 publications

Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line

Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line

Neisseria gonorrhoeae Type IV Pili Undergo Multisite, Hierarchical Modifications with Phosphoethanolamine and Phosphocholine Requiring an Enzyme Structurally Related to Lipopolysaccharide Phosphoethanolamine Transferases

Structural and Immunochemical Characterization of aNeisseria gonorrhoeae Epitope Defined by a Monoclonal Antibody 2C7; the Antibody Recognizes a Conserved Epitope on Specific Lipo-oligosaccharides in Spite of the Presence of Human Carbohydrate Epitopes

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