1887

Abstract

There is currently no comprehensive meningococcal vaccine, due to difficulties in immunizing against organisms expressing serogroup B capsules. To address this problem, subcapsular antigens, particularly the outer-membrane proteins (OMPs), are being investigated as candidate vaccine components. If immunogenic, however, such antigens are often antigenically variable, and knowledge of the extent and structuring of this diversity is an essential part of vaccine formulation. Factor H-binding protein (fHbp) is one such protein and is included in two vaccines under development. A survey of the diversity of the fHbp gene and the encoded protein in a representative sample of meningococcal isolates confirmed that variability in this protein is structured into two or three major groups, each with a substantial number of alleles that have some association with meningococcal clonal complexes and serogroups. A unified nomenclature scheme was devised to catalogue this diversity. Analysis of recombination and selection on the allele sequences demonstrated that parts of the gene are subject to positive selection, consistent with immune selection on the protein generating antigenic variation, particularly in the C-terminal region of the peptide sequence. The highest levels of selection were observed in regions corresponding to epitopes recognized by previously described bactericidal monoclonal antibodies.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.027995-0
2009-12-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/micro/155/12/4155.html?itemId=/content/journal/micro/10.1099/mic.0.027995-0&mimeType=html&fmt=ahah

References

  1. Ala'Aldeen D. A., Borriello S. P. 1996; The meningococcal transferrin-binding proteins 1 and 2 are both surface exposed and generate bactericidal antibodies capable of killing homologous and heterologous strains. Vaccine 14:49–53
    [Google Scholar]
  2. Bambini S., Muzzi A., Olcen P., Rappuoli R., Pizza M., Comanducci M. 2009; Distribution and genetic variability of three vaccine components in a panel of strains representative of the diversity of serogroup B meningococcus. Vaccine 27:2794–2803
    [Google Scholar]
  3. Beernink P. T., Granoff D. M. 2008; Bactericidal antibody responses induced by meningococcal recombinant chimeric factor H binding protein vaccines. Infect Immun 76:2568–2575
    [Google Scholar]
  4. Beernink P. T., Welsch J. A., Harrison L. H., Leipus A., Kaplan S. L., Granoff D. M. 2007; Prevalence of factor H-binding protein variants and NadA among meningococcal group B isolates from the United States: implications for the development of a multicomponent group B vaccine. J Infect Dis 195:1472–1479
    [Google Scholar]
  5. Beernink P. T., Welsch J. A., Bar-Lev M., Koeberling O., Comanducci M., Granoff D. M. 2008; Fine antigenic specificity and cooperative bactericidal activity of monoclonal antibodies directed at the meningococcal vaccine candidate factor H-binding protein. Infect Immun 76:4232–4240
    [Google Scholar]
  6. Beernink P. T., LoPasso C., Angiolillo A., Felici F., Granoff D. 2009a; A region of the N-terminal domain of meningococcal factor H-binding protein that elicits bactericidal antibody across antigenic variant groups. Mol Immunol 46:1647–1653
    [Google Scholar]
  7. Beernink P. T., Caugant D. A., Welsch J. A., Koeberling O., Granoff D. M. 2009b; Meningococcal factor H-binding protein variants expressed by epidemic capsular group A, W-135, and X strains from Africa. J Infect Dis 199:1360–1368
    [Google Scholar]
  8. Bennett J. S., Thompson E. A., Kriz P., Jolley K. A., Maiden M. C. 2009; A common gene pool for the Neisseria FetA antigen. Int J Med Microbiol 299:133–139
    [Google Scholar]
  9. Bernfield L., Fletcher D. L., Howell A., Farley J. E., Zagursky R., Knauf M., Zlotnick G. 2002; Identification of a novel vaccine candidate for group B Neisseria meningitidis . In Abstracts of the Thirteenth International Pathogenic Conference p 116 Edited by Caugant D. A., Wedege E. Oslo, Norway: Division of Infectious Disease Control, Norwegian Institute of Public Health;
    [Google Scholar]
  10. Bjune G., Høiby E. A., Grønnesby J. K., Arnesen O., Fredriksen J. H., Halstensen A., Holten E., Lindbak A. K., Nøkleby H. other authors 1991; Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 338:1093–1096
    [Google Scholar]
  11. Brehony C., Jolley K. A., Maiden M. C. 2007; Multilocus sequence typing for global surveillance of meningococcal disease. FEMS Microbiol Rev 31:15–26
    [Google Scholar]
  12. Buckee C. O., Jolley K. A., Recker M., Penman B., Kriz P., Gupta S., Maiden M. C. 2008; Role of selection in the emergence of lineages and the evolution of virulence in Neisseria meningitidis . Proc Natl Acad Sci U S A 105:15082–15087
    [Google Scholar]
  13. Callaghan M. J., Jolley K. A., Maiden M. C. 2006; Opacity-associated adhesin repertoire in hyperinvasive Neisseria meningitidis . Infect Immun 74:5085–5094
    [Google Scholar]
  14. Callaghan M. J., Buckee C., McCarthy N. D., Ibarz-Pavon A. B., Jolley K., Faust S., Gray S. J., Kaczmarski E. B., Levin M. other authors 2008; Opa protein repertoires of disease-causing and carried meningococci. J Clin Microbiol 46:3033–3041
    [Google Scholar]
  15. Cantini F., Savino S., Scarselli M., Masignani V., Pizza M., Romagnoli G., Swennen E., Veggi D., Banci L., Rappuoli R. 2006; Solution structure of the immunodominant domain of protective antigen GNA1870 of Neisseria meningitidis . J Biol Chem 281:7220–7227
    [Google Scholar]
  16. Cantini F., Veggi D., Dragonetti S., Savino S., Scarselli M., Romagnoli G., Pizza M., Banci L., Rappuoli R. 2009; Solution structure of the factor H binding protein, a survival factor and protective antigen of Neisseria meningitidis . J Biol Chem 284:9022–9026
    [Google Scholar]
  17. Caugant D. A. 2001; Global trends in meningococcal disease. In Meningococcal Disease: Methods and Protocols pp 273–292 Edited by Pollard A. J., Maiden M. C. J. Totowa, NJ: Humana Press;
    [Google Scholar]
  18. Caugant D. A., Maiden M. C. J. 2009; Meningococcal carriage and disease – population biology and evolution. Vaccine 27 (suppl. 2):B64–B70
    [Google Scholar]
  19. Claus H., Stoevesandt J., Frosch M., Vogel U. 2001; Genetic isolation of meningococci of the electrophoretic type 37 complex. J Bacteriol 183:2570–2575
    [Google Scholar]
  20. Comanducci M., Bambini S., Brunelli B., Adu-Bobie J., Arico B., Capecchi B., Giuliani M. M., Masignani V., Santini L. other authors 2002; NadA, a novel vaccine candidate of Neisseria meningitidis . J Exp Med 195:1445–1454
    [Google Scholar]
  21. Derrick J. P., Urwin R., Suker J., Feavers I. M., Maiden M. C. J. 1999; Structural and evolutionary inference from molecular variation in Neisseria porins. Infect Immun 67:2406–2413
    [Google Scholar]
  22. Didelot X., Falush D. 2007; Inference of bacterial microevolution using multilocus sequence data. Genetics 175:1251–1266
    [Google Scholar]
  23. Finne J., Leinonen M., Makela P. H. 1983; Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet 2:355–357
    [Google Scholar]
  24. Fletcher L. D., Bernfield L., Barniak V., Farley J. E., Howell A., Knauf M., Ooi P., Smith R. P., Weise P. other authors 2004; Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun 72:2088–2100
    [Google Scholar]
  25. Giuliani M. M., Santini L., Brunelli B., Biolchi A., Arico B., Di Marcello F., Cartocci E., Comanducci M., Masignani V. other authors 2005; The region comprising amino acids 100 to 255 of Neisseria meningitidis lipoprotein GNA 1870 elicits bactericidal antibodies. Infect Immun 73:1151–1160
    [Google Scholar]
  26. Granoff D. M., Welsch J. A., Ram S. 2009; Binding of complement factor H (fH) to Neisseria meningitidis is specific for human fH and inhibits complement activation by rat and rabbit sera. Infect Immun 77:764–769
    [Google Scholar]
  27. Grundmann H., Hori S., Tanner G. 2001; Determining confidence intervals when measuring genetic diversity and the discriminatory abilities of typing methods for microorganisms. J Clin Microbiol 39:4190–4192
    [Google Scholar]
  28. Gupta S., Maiden M. C., Feavers I. M., Nee S., May R. M., Anderson R. M. 1996; The maintenance of strain structure in populations of recombining infectious agents. Nat Med 2:437–442
    [Google Scholar]
  29. Harrison O. B., Maiden M. C., Rokbi B. 2008; Distribution of transferrin binding protein B gene ( tbpB) variants among Neisseria species. BMC Microbiol 8:66
    [Google Scholar]
  30. Hunter P. R., Gaston M. A. 1988; Numerical index of discriminatory ability of typing systems: an application of Simpson's index of diversity. J Clin Microbiol 26:2465–2466
    [Google Scholar]
  31. Jacobsson S., Thulin S., Molling P., Unemo M., Comanducci M., Rappuoli R., Olcen P. 2006; Sequence constancies and variations in genes encoding three new meningococcal vaccine candidate antigens. Vaccine 24:2161–2168
    [Google Scholar]
  32. Jodar L., Feavers I. M., Salisbury D., Granoff D. M. 2002; Development of vaccines against meningococcal disease. Lancet 359:1499–1508
    [Google Scholar]
  33. Jolley K. A., Maiden M. C. 2006; AgdbNet – antigen sequence database software for bacterial typing. BMC Bioinformatics 7:314
    [Google Scholar]
  34. Jolley K. A., Feil E. J., Chan M. S., Maiden M. C. 2001; Sequence type analysis and recombinational tests (START. Bioinformatics 17:1230–1231
    [Google Scholar]
  35. Jones D. M. 1995; Epidemiology of meningococcal disease in Europe and the USA. In Meningococcal Disease pp 147–157 Edited by Cartwright K. Chichester, UK: Wiley;
    [Google Scholar]
  36. Kumar S., Tamura K., Nei M. 2004; mega3: integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 5:150–163
    [Google Scholar]
  37. Lambris J. D., Ricklin D., Geisbrecht B. V. 2008; Complement evasion by human pathogens. Nat Rev Microbiol 6:132–142
    [Google Scholar]
  38. Madico G., Welsch J. A., Lewis L. A., McNaughton A., Perlman D. H., Costello C. E., Ngampasutadol J., Vogel U., Granoff D. M., Ram S. 2006; The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol 177:501–510
    [Google Scholar]
  39. Maiden M. C. J., Bygraves J. A., Feil E., Morelli G., Russell J. E., Urwin R., Zhang Q., Zhou J., Zurth K. other authors 1998; Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 95:3140–3145
    [Google Scholar]
  40. Maiden M. C., Ibarz-Pavon A. B., Urwin R., Gray S. J., Andrews N. J., Clarke S. C., Walker A. M., Evans M. R., Kroll J. S. other authors 2008; Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity. J Infect Dis 197:737–743
    [Google Scholar]
  41. Martin D., Cadieux N., Hamel J., Brodeur B. R. 1997; Highly conserved Neisseria meningitidis surface protein confers protection against experimental infection. J Exp Med 185:1173–1183
    [Google Scholar]
  42. Mascioni A., Bentley B. E., Camarda R., Dilts D. A., Fink P., Gusarova V., Hoiseth S. K., Jacob J., Lin S. L. other authors 2009; Structural basis for the immunogenic properties of the meningococcal vaccine candidate LP2086. J Biol Chem 284:8738–8746
    [Google Scholar]
  43. Masignani V., Comanducci M., Giuliani M. M., Bambini S., Adu-Bobie J., Arico B., Brunelli B., Pieri A., Santini L. other authors 2003; Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870. J Exp Med 197:789–799
    [Google Scholar]
  44. Murphy E., Andrew L., Lee K., Dilts D. A., Nunez L., Fink P. S., Ambrose K., Borrow R., Findlow J. other authors 2009; Sequence diversity of the factor H binding protein vaccine candidate in epidemiologically relevant strains of serogroup B Neisseria meningitidis . J Infect Dis 200:379–389
    [Google Scholar]
  45. Ngampasutadol J., Ram S., Gulati S., Agarwal S., Li C., Visintin A., Monks B., Madico G., Rice P. A. 2008; Human factor H interacts selectively with Neisseria gonorrhoeae and results in species-specific complement evasion. J Immunol 180:3426–3435
    [Google Scholar]
  46. O'Hallahan J., Lennon D., Oster P., Lane R., Reid S., Mulholland K., Stewart J., Penney L., Percival T., Martin D. 2005; From secondary prevention to primary prevention: a unique strategy that gives hope to a country ravaged by meningococcal disease. Vaccine 23:2197–2201
    [Google Scholar]
  47. Pollard A. J., Scheifele D., Rosenstein N. 2001; Epidemiology of meningococcal disease in North America. In Meningococcal Disease: Methods and Protocols pp 341–356 Edited by Pollard A. J., Maiden M. C. Totowa, NJ: Humana Press;
    [Google Scholar]
  48. Rappuoli R. 2000; Reverse vaccinology. Curr Opin Microbiol 3:445–450
    [Google Scholar]
  49. Rodriguez A. P., Dickinson F., Baly A., Martinez R. 1999; The epidemiological impact of antimeningococcal B vaccination in Cuba. Mem Inst Oswaldo Cruz 94:433–440
    [Google Scholar]
  50. Rodríguez de Córdoba S., Esparza-Gordillo J., Goicoechea de Jorge E., Lopez-Trascasa M., Sánchez-Corral P. 2004; The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367
    [Google Scholar]
  51. Rokbi B., Renauld-Mongenie G., Mignon M., Danve B., Poncet D., Chabanel C., Caugant D. A., Quentin-Millet M. J. 2000; Allelic diversity of the two transferrin binding protein B gene isotypes among a collection of Neisseria meningitidis strains representative of serogroup B disease: implication for the composition of a recombinant TbpB-based vaccine. Infect Immun 68:4938–4947
    [Google Scholar]
  52. Russell J. E., Jolley K. A., Feavers I. M., Maiden M. C., Suker J. 2004; PorA variable regions of Neisseria meningitidis . Emerg Infect Dis 10:674–678
    [Google Scholar]
  53. Scarselli M., Cantini F., Santini L., Veggi D., Dragonetti S., Donati C., Savino S., Giuliani M. M., Comanducci M. other authors 2009; Epitope mapping of a bactericidal monoclonal antibody against the factor H binding protein of Neisseria meningitidis . J Mol Biol 386:97–108
    [Google Scholar]
  54. Schneider M. C., Exley R. M., Chan H., Feavers I., Kang Y.-H., Sim R. B., Tang C. M. 2006; Functional significance of factor H binding to Neisseria meningitidis . J Immunol 176:7566–7575
    [Google Scholar]
  55. Schneider M. C., Prosser B. E., Caesar J. J. E., Kugelberg E., Li S., Zhang Q., Quoraishi S., Lovett J. E., Deane J. E. other authors 2009; Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature 458:890–893
    [Google Scholar]
  56. Seib K. L., Serruto D., Oriente F., Delany I., Adu-Bobie J., Veggi D., Arico B., Rappuoli R., Pizza M. 2009; Factor H-binding protein is important for meningococcal survival in human whole blood and serum and in the presence of the antimicrobial peptide LL-37. Infect Immun 77:292–299
    [Google Scholar]
  57. Simpson E. H. 1949; Measurement of diversity. Nature 163:688
    [Google Scholar]
  58. Staden R. 1996; The Staden sequence analysis package. Mol Biotechnol 5:233–241
    [Google Scholar]
  59. Statacorp. 2007 Stata Statistical Software: Release 10. College Station, TX: StataCorp LP;
    [Google Scholar]
  60. Swofford D. L. 1998 Phylogenetic Analysis Using Parsimony (paup), version 4. Sunderland, MA: Sinauer Associates;
    [Google Scholar]
  61. Thompson E. A. L. 2001 Antigenic variation in the potential meningococcal vaccine candidate FetA PhD thesis University of Oxford;
    [Google Scholar]
  62. Thompson E. A. L., Feavers I. M., Maiden M. C. J. 2003; Antigenic diversity of meningococcal enterobactin receptor FetA, a vaccine component. Microbiology 149:1849–1858
    [Google Scholar]
  63. Trotter C. L., Chandra M., Cano R., Larrauri A., Ramsay M. E., Brehony C., Jolley K. A., Maiden M. C., Heuberger S., Frosch M. 2007; A surveillance network for meningococcal disease in Europe. FEMS Microbiol Rev 31:27–36
    [Google Scholar]
  64. Urwin R., Holmes E. C., Fox A. J., Derrick J. P., Maiden M. C. 2002; Phylogenetic evidence for frequent positive selection and recombination in the meningococcal surface antigen PorB. Mol Biol Evol 19:1686–1694
    [Google Scholar]
  65. Urwin R., Russell J. E., Thompson E. A., Holmes E. C., Feavers I. M., Maiden M. C. 2004; Distribution of surface protein variants among hyperinvasive meningococci: implications for vaccine design. Infect Immun 72:5955–5962
    [Google Scholar]
  66. van den Dobbelsteen G. P. J. M., van Dijken H. H., Pillai S., van Alphen L. 2007; Immunogenicity of a combination vaccine containing pneumococcal conjugates and meningococcal PorA OMVs. Vaccine 25:2491–2496
    [Google Scholar]
  67. Welsch J. A., Ram S. 2008; Factor H and Neisserial pathogenesis. Vaccine 26 (suppl. 8):I40–I45
    [Google Scholar]
  68. Welsch J. A., Rossi R., Comanducci M., Granoff D. M. 2004; Protective activity of monoclonal antibodies to genome-derived neisserial antigen 1870, a Neisseria meningitidis candidate vaccine. J Immunol 172:5606–5615
    [Google Scholar]
  69. Welsch J. A., Ram S., Koeberling O., Granoff D. M. 2008; Complement-dependent synergistic bactericidal activity of antibodies against factor H-binding protein, a sparsely distributed meningococcal vaccine antigen. J Infect Dis 197:1053–1061
    [Google Scholar]
  70. Wilson D. J., McVean G. 2006; Estimating diversifying selection and functional constraint in the presence of recombination. Genetics 172:1411–1425
    [Google Scholar]
  71. Womble D. D. 2000; GCG: the Wisconsin Package of sequence analysis programs. Methods Mol Biol 132:3–22
    [Google Scholar]
  72. Yazdankhah S. P., Caugant D. A. 2004; Neisseria meningitidis: an overview of the carriage state. J Med Microbiol 53:821–832
    [Google Scholar]
  73. Yazdankhah S. P., Kriz P., Tzanakaki G., Kremastinou J., Kalmusova J., Musilek M., Alvestad T., Jolley K. A., Wilson D. J. other authors 2004; Distribution of serogroups and genotypes among disease-associated and carried isolates of Neisseria meningitidis from the Czech Republic, Greece, and Norway. J Clin Microbiol 42:5146–5153
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.027995-0
Loading
/content/journal/micro/10.1099/mic.0.027995-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Supplementary material 2

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error