Fine Antigenic Specificity and Cooperative Bactericidal Activity of Monoclonal Antibodies Directed at the Meningococcal Vaccine Candidate Factor H-Binding Protein

Beernink, Peter T.; Welsch, Jo Anne; Bar-Lev, Michal; Koeberling, Oliver; Comanducci, Maurizio; Granoff, Dan M.

doi:10.1128/iai.00367-08

Cited by 81 publications

(175 citation statements)

References 30 publications

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“…This is consistent with a model where the protein is anchored to the bacterial cell wall through the palmitic acid extension of Cys-1 (5) and exposes the upper part to the outside, where it is under the selective pressure of the immune system. Accordingly, the amino acids known to be part of epitopes (8,9,10,11) are all localized in correspondence of the zone of higher variability (Fig. 2B).…”

Section: Discussionmentioning

confidence: 92%

“…2B). Arg-204, Gly-121, and the loop formed by Glu-146 until Arg-149 were identified as involved in the formation of bactericidal v.1 epitopes (8,9,11). Arg-204 is located in the loop between ␤ 12 and ␤ 13 , whereas the segment 146 -149 corresponds to the region connecting the two fHbp domains and containing the second short helix ␣2.…”

Section: Discussionmentioning

confidence: 99%

“…The same epitope was later shown to contain also Phe-277, Gly-228, Lys-230, and Glu-233 (10). Recently, Beernink et al (11) used a panel of monoclonal antibodies obtained by immunizing mice with all three variants of fHbp and identified Gly-121 and Lys-122 as critical for binding by anti-v.1 antibodies. Ser-216 was shown to be important for variant 2 (v.2), whereas amino acid positions 174, 180, and 192 were shown to be key residues to discriminate between variant 2 and variant 3 (v.3).…”

mentioning

confidence: 99%

“…This incompleteness of information hampered a detailed evaluation of the molecular distribution of variant-specific epitopes, as well as the opportunity to rationalize the reported differences in the ability of monoclonals to induce complement-mediated killing and inhibit the protein binding to human factor H (11). In the present study, we determined the structure of the full-length fHbp by NMR, which improves the knowledge about the distribution of protective epitopes on the protein surface and provides useful indications on the possible localization of the factor H (fH) binding site.…”

mentioning

confidence: 99%

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Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis

Cantini

Veggi

Dragonetti

et al. 2009

Journal of Biological Chemistry

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Factor H-binding protein is a 27-kDa lipoprotein of Neisseria meningitidis discovered while screening the bacterial genome for vaccine candidates. In addition to being an important component of a vaccine against meningococcus in late stage of development, the protein is essential for pathogenesis because it allows the bacterium to survive and grow in human blood by binding the human complement factor H. We recently reported the solution structure of the C-terminal domain of factor H-binding protein, which contains the immunodominant epitopes. In the present study, we report the structure of the full-length molecule, determined by nuclear magnetic resonance spectroscopy. The protein is composed of two independent barrels connected by a short link. Mapping the residues recognized by monoclonal antibodies with bactericidal or factor H binding inhibition properties allowed us to predict the sites involved in the function of the protein. The structure therefore provides the basis for designing improved vaccine molecules.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis

Cantini

Veggi

Dragonetti

et al. 2009

Journal of Biological Chemistry

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“…fHbp confers serum resistance to meningococci by recruiting fH, which subsequently inhibits APmediated complement activation or amplification on the bacterial surface. Abs against fHbp would be expected to have a two-tiered effect: Abs bound to fHbp can initiate the CP, while simultaneously blocking fH recruitment, thus preventing the bacteria from exploiting fH as a means of defense against complement attack (41). Having demonstrated in this study that Y. pseudotuberculosis C4BP can bind Ail, it is worth considering the possibility that Abs against Ail would be bactericidal by the mechanism described above, although it is possible that YadA or other surface factors could mediate serum resistance in the absence of Ail function.…”

Section: Discussionmentioning

confidence: 99%

Functional Recruitment of the Human Complement Inhibitor C4BP to Yersinia pseudotuberculosis Outer Membrane Protein Ail

Riva

Kirjavainen

et al. 2012

The Journal of Immunology

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Ail is a 17-kDa chromosomally encoded outer membrane protein that mediates serum resistance (complement resistance) in the pathogenic Yersiniae (Yersinia pestis, Y. enterocolitica, and Y. pseudotuberculosis). In this article, we demonstrate that Y. pseudotuberculosis Ail from strains PB1, 2812/79, and YPIII/pIB1 (serotypes O:1a, O:1b, and O:3, respectively) can bind the inhibitor of the classical and lectin pathways of complement, C4b-binding protein (C4BP). Binding was observed irrespective of serotype tested and independently of YadA, which is the primary C4BP receptor of Y. enterocolitica. Disruption of the ail gene in Y. pseudotuberculosis resulted in loss of C4BP binding. Cofactor assays revealed that bound C4BP is functional, because bound C4BP in the presence of factor I cleaved C4b. In the absence of YadA, Ail conferred serum resistance to strains PB1 and YPIII, whereas serum resistance was observed in strain 2812/79 in the absence of both YadA and Ail, suggesting additional serum resistance factors. Ail from strain YPIII/pIB1 alone can mediate serum resistance and C4BP binding, because its expression in a serum-sensitive laboratory strain of Escherichia coli conferred both of these phenotypes. Using a panel of C4BP mutants, each deficient in a single complement control protein domain, we observed that complement control protein domains 6–8 are important for binding to Ail. Binding of C4BP was unaffected by increasing heparin or salt concentrations, suggesting primarily nonionic interactions. These results indicate that Y. pseudotuberculosis Ail recruits C4BP in a functional manner, facilitating resistance to attack from complement.

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Meningococcal factor H binding protein as immune evasion factor and vaccine antigen

Principato

Pizza²,

Rappuoli³

2020

FEBS Letters

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Factor H binding protein (fHbp) is a key virulence factor of Neisseria meningitidis and a main component of the two licensed vaccines against serogroup B meningococcus (Bexsero and Trumenba). fHbp is a surface‐exposed lipoprotein that enables the bacterium to survive in human blood by binding the human complement regulator factor H (fH). When used as vaccine, the protein induces antibodies with potent bactericidal activity. While the fHbp gene is present in the majority of N. meningitidis serogroup B isolates, the expression level varies up to 15 times between different strains and more than 700 different sequence variants have been described. Antigenically, the protein has been divided into three variants or two subfamilies. The 3D structure of fHbp alone, in combination with fH or in complex with bactericidal antibodies, has been key to understanding the molecular details of the protein. In this article, we will review the biochemical and immunological properties of fHbp, and its key role in meningococcal pathogenesis, complement regulation, and immune evasion.

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Fine Antigenic Specificity and Cooperative Bactericidal Activity of Monoclonal Antibodies Directed at the Meningococcal Vaccine Candidate Factor H-Binding Protein

Abstract: No broadly protective vaccine is available for the prevention of group B meningococcal disease. One promising candidate is factor H-binding protein (fHbp), which is present in all strains but often sparsely expressed. We prepared seven murine immunoglobulin G monoclonal antibodies (

Cited by 81 publications

References 30 publications

Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis

Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis

Functional Recruitment of the Human Complement Inhibitor C4BP to Yersinia pseudotuberculosis Outer Membrane Protein Ail

Meningococcal factor H binding protein as immune evasion factor and vaccine antigen

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