Bacterial Genomes and Vaccine Design

  • Valeria Cafardi
  • John L. Telford
  • Davide Serruto
Part of the Immunomics Reviews: book series (IMMUN, volume 5)


Since its introduction, vaccinology has been very effective in controlling and eliminating life-threatening infectious diseases. However, in several cases, the conventional approach to identifying protective antigens, based on biochemical, immunological, and microbiological methods, has failed to deliver successful vaccine candidates against major human pathogens. The availability of complete bacterial genome sequences has allowed scientists to change the paradigm and approach vaccine development starting from genomic information, a process named reverse vaccinology. This can be considered as one of the most powerful examples of how genomic information can be used to develop vaccines that were difficult or impossible to tackle with conventional approaches. The ever-growing genomic data, the new genome-based approaches and high-throughput sequencing technologies will help to complement reverse vaccinology to enable timely development of new vaccine antigens against emerging infectious diseases.


Vaccine Candidate Protective Antigen Vaccine Antigen Genome Mining Potential Vaccine Candidate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Fleischmann RD et al (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269(5223):496–512PubMedCrossRefGoogle Scholar
  2. 2.
    Medini D et al (2008) Microbiology in the post-genomic era. Nat Rev Microbiol 6(6):419–430PubMedGoogle Scholar
  3. 3.
    Raskin DM et al (2006) Bacterial genomics and pathogen evolution. Cell 124(4):703–714PubMedCrossRefGoogle Scholar
  4. 4.
    Rappuoli R (2001) Reverse vaccinology, a genome-based approach to vaccine development. Vaccine 19(17–19):2688–2691PubMedCrossRefGoogle Scholar
  5. 5.
    Stephens DS, Greenwood B, Brandtzaeg P (2007) Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 369(9580):2196–2210PubMedCrossRefGoogle Scholar
  6. 6.
    Caugant DA, Maiden MC (2009) Meningococcal carriage and disease—population biology and evolution. Vaccine 27(suppl 2):B64–B70PubMedCrossRefGoogle Scholar
  7. 7.
    Tettelin H et al (2000) Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287(5459):1809–1815PubMedCrossRefGoogle Scholar
  8. 8.
    Pizza M et al (2000) Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287(5459):1816–1820PubMedCrossRefGoogle Scholar
  9. 9.
    Borrow R, Balmer P, Miller E (2005) Meningococcal surrogates of protection–serum bactericidal antibody activity. Vaccine 23(17–18):2222–2227PubMedCrossRefGoogle Scholar
  10. 10.
    Goldschneider I, Gotschlich EC, Artenstein MS (1969) Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 129(6):1307–1326PubMedCrossRefGoogle Scholar
  11. 11.
    Serruto D et al (2010) Neisseria meningitidis GNA2132, a heparin-binding protein that induces protective immunity in humans. Proc Natl Acad Sci USA 107(8):3770–3775PubMedCrossRefGoogle Scholar
  12. 12.
    Masignani V et al (2003) Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870. J Exp Med 197(6):789–799PubMedCrossRefGoogle Scholar
  13. 13.
    Seib KL et al (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(1):292–299PubMedCrossRefGoogle Scholar
  14. 14.
    Capecchi B et al (2005) Neisseria meningitidis NadA is a new invasin which promotes bacterial adhesion to and penetration into human epithelial cells. Mol Microbiol 55(3):687–698PubMedCrossRefGoogle Scholar
  15. 15.
    Comanducci M et al (2002) NadA, a novel vaccine candidate of Neisseria meningitidis. J Exp Med 195(11):1445–1454PubMedCrossRefGoogle Scholar
  16. 16.
    Giuliani MM et al (2006) A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci USA 103(29):10834–10839PubMedCrossRefGoogle Scholar
  17. 17.
    Kimura A et al (2011) Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates. Clin Vaccine Immunol 18(3):483–486PubMedCrossRefGoogle Scholar
  18. 18.
    Findlow J et al (2010) Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis 51(10):1127–1137PubMedCrossRefGoogle Scholar
  19. 19.
    Snape MD et al (2010) Immunogenicity and reactogenicity of a 13-valent-pneumococcal conjugate vaccine administered at 2, 4, and 12 months of age: a double-blind randomized active-controlled trial. Pediatr Infect Dis J 29(12):e80–e90PubMedCrossRefGoogle Scholar
  20. 20.
    Johri AK et al (2006) Group B Streptococcus: global incidence and vaccine development. Nat Rev Microbiol 4(12):932–942PubMedCrossRefGoogle Scholar
  21. 21.
    Tettelin H et al (2002) Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae. Proc Natl Acad Sci USA 99(19):12391–12396PubMedCrossRefGoogle Scholar
  22. 22.
    Tettelin H et al (2005) Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial "pan-genome". Proc Natl Acad Sci USA 102(39):13950–13955PubMedCrossRefGoogle Scholar
  23. 23.
    Maione D et al (2005) Identification of a universal Group B streptococcus vaccine by multiple genome screen. Science 309(5731):148–150PubMedCrossRefGoogle Scholar
  24. 24.
    Lauer P et al (2005) Genome analysis reveals pili in Group B Streptococcus. Science 309(5731):105PubMedCrossRefGoogle Scholar
  25. 25.
    Rosini R et al (2006) Identification of novel genomic islands coding for antigenic pilus-like structures in Streptococcus agalactiae. Mol Microbiol 61(1):126–141PubMedCrossRefGoogle Scholar
  26. 26.
    Margarit I et al (2009) Preventing bacterial infections with pilus-based vaccines: the group B streptococcus paradigm. J Infect Dis 199(1):108–115PubMedCrossRefGoogle Scholar
  27. 27.
    Brzuszkiewicz E et al (2006) How to become a uropathogen: comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains. Proc Natl Acad Sci USA 103(34):12879–12884PubMedCrossRefGoogle Scholar
  28. 28.
    Hain T et al (2007) Pathogenomics of Listeria spp. Int J Med Microbiol 297(7–8):541–557PubMedCrossRefGoogle Scholar
  29. 29.
    Perrin A et al (2002) Comparative genomics identifies the genetic islands that distinguish Neisseria meningitidis, the agent of cerebrospinal meningitis, from other Neisseria species. Infect Immun 70(12):7063–7072PubMedCrossRefGoogle Scholar
  30. 30.
    Perrin A, Nassif X, Tinsley C (1999) Identification of regions of the chromosome of Neisseria meningitidis and Neisseria gonorrhoeae which are specific to the pathogenic Neisseria species. Infect Immun 67(11):6119–6129PubMedGoogle Scholar
  31. 31.
    Moriel DG et al (2010) Identification of protective and broadly conserved vaccine antigens from the genome of extraintestinal pathogenic Escherichia coli. Proc Natl Acad Sci USA 107(20):9072–9077PubMedCrossRefGoogle Scholar
  32. 32.
    Madico G et al (2007) Factor H binding and function in sialylated pathogenic neisseriae is influenced by gonococcal, but not meningococcal, porin. J Immunol 178(7):4489–4497PubMedGoogle Scholar
  33. 33.
    Schneider MC et al (2007) Interactions between Neisseria meningitidis and the complement system. Trends Microbiol 15(5):233–240PubMedCrossRefGoogle Scholar
  34. 34.
    Telford JL et al (2006) Pili in gram-positive pathogens. Nat Rev Microbiol 4(7):509–519PubMedCrossRefGoogle Scholar
  35. 35.
    Barocchi MA et al (2006) A pneumococcal pilus influences virulence and host inflammatory responses. Proc Natl Acad Sci USA 103(8):2857–2862PubMedCrossRefGoogle Scholar
  36. 36.
    Mora M et al (2005) Group A Streptococcus produce pilus-like structures containing protective antigens and Lancefield T antigens. Proc Natl Acad Sci USA 102(43):15641–15646PubMedCrossRefGoogle Scholar
  37. 37.
    Adu-Bobie J et al (2003) Two years into reverse vaccinology. Vaccine 21(7–8):605–610PubMedCrossRefGoogle Scholar
  38. 38.
    Bambini S et al (2009) Distribution and genetic variability of three vaccine components in a panel of strains representative of the diversity of serogroup B meningococcus. Vaccine 27(21):2794–2803PubMedCrossRefGoogle Scholar
  39. 39.
    Donnelly J et al (2010) Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci USA 107(45):19490–19495PubMedCrossRefGoogle Scholar
  40. 40.
    Telford JL (2008) Bacterial genome variability and its impact on vaccine design. Cell Host Microbe 3(6):408–416PubMedCrossRefGoogle Scholar
  41. 41.
    Hall N (2007) Advanced sequencing technologies and their wider impact in microbiology. J Exp Biol 210(Pt 9):1518–1525PubMedCrossRefGoogle Scholar
  42. 42.
    Schuster SC (2008) Next-generation sequencing transforms today's biology. Nat Methods 5(1):16–18PubMedCrossRefGoogle Scholar
  43. 43.
    Margulies M et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437(7057):376–380PubMedGoogle Scholar
  44. 44.
    Bennett ST et al (2005) Toward the 1,000 dollars human genome. Pharmacogenomics 6(4):373–382PubMedCrossRefGoogle Scholar
  45. 45.
    Shendure J et al (2005) Accurate multiplex polony sequencing of an evolved bacterial genome. Science 309(5741):1728–1732PubMedCrossRefGoogle Scholar
  46. 46.
    Ansorge WJ (2009) Next-generation DNA sequencing techniques. N Biotechnol 25(4):195–203PubMedCrossRefGoogle Scholar
  47. 47.
    Metzker ML (2010) Sequencing technologies—the next generation. Nat Rev Genet 11(1):31–46PubMedCrossRefGoogle Scholar
  48. 48.
    Harris SR et al (2010) Evolution of MRSA during hospital transmission and intercontinental spread. Science 327(5964):469–474PubMedCrossRefGoogle Scholar
  49. 49.
    Croucher NJ et al (2011) Rapid pneumococcal evolution in response to clinical interventions. Science 331(6016):430–434PubMedCrossRefGoogle Scholar
  50. 50.
    Grifantini R et al (2002) Previously unrecognized vaccine candidates against group B meningococcus identified by DNA microarrays. Nat Biotechnol 20(9):914–921PubMedCrossRefGoogle Scholar
  51. 51.
    Wizemann TM et al (2001) Use of a whole genome approach to identify vaccine molecules affording protection against Streptococcus pneumoniae infection. Infect Immun 69(3):1593–1598PubMedCrossRefGoogle Scholar
  52. 52.
    Hoskins J et al (2001) Genome of the bacterium Streptococcus pneumoniae strain R6. J Bacteriol 183(19):5709–5717PubMedCrossRefGoogle Scholar
  53. 53.
    Etz H et al (2002) Identification of in vivo expressed vaccine candidate antigens from Staphylococcus aureus. Proc Natl Acad Sci USA 99(10):6573–6578PubMedCrossRefGoogle Scholar
  54. 54.
    Vytvytska O et al (2002) Identification of vaccine candidate antigens of Staphylococcus aureus by serological proteome analysis. Proteomics 2(5):580–590PubMedCrossRefGoogle Scholar
  55. 55.
    Ross BC et al (2001) Identification of vaccine candidate antigens from a genomic analysis of Porphyromonas gingivalis. Vaccine 19(30):4135–4142PubMedCrossRefGoogle Scholar
  56. 56.
    Hughes MJ et al (2002) Identification of major outer surface proteins of Streptococcus agalactiae. Infect Immun 70(3):1254–1259PubMedCrossRefGoogle Scholar
  57. 57.
    Reid SD et al (2002) Postgenomic analysis of four novel antigens of group a streptococcus: growth phase-dependent gene transcription and human serologic response. J Bacteriol 184(22):6316–6324PubMedCrossRefGoogle Scholar
  58. 58.
    Rodriguez-Ortega MJ et al (2006) Characterization and identification of vaccine candidate proteins through analysis of the group A Streptococcus surface proteome. Nat Biotechnol 24(2):191–197PubMedCrossRefGoogle Scholar
  59. 59.
    Montigiani S et al (2002) Genomic approach for analysis of surface proteins in Chlamydia pneumoniae. Infect Immun 70(1):368–379PubMedCrossRefGoogle Scholar
  60. 60.
    Berlanda Scorza F et al (2008) Proteomics characterization of outer membrane vesicles from the extraintestinal pathogenic Escherichia coli DeltatolR IHE3034 mutant. Mol Cell Proteomics 7(3):473–485PubMedGoogle Scholar
  61. 61.
    Serruto D et al (2004) Biotechnology and vaccines: application of functional genomics to Neisseria meningitidis and other bacterial pathogens. J Biotechnol 113(1–3):15–32PubMedCrossRefGoogle Scholar
  62. 62.
    Sorek R, Cossart P (2010) Prokaryotic transcriptomics: a new view on regulation, physiology and pathogenicity. Nat Rev Genet 11(1):9–16PubMedCrossRefGoogle Scholar
  63. 63.
    Croucher NJ, Thomson NR (2010) Studying bacterial transcriptomes using RNA-seq. Curr Opin Microbiol 13(5):619–624PubMedCrossRefGoogle Scholar
  64. 64.
    Yoder-Himes DR et al (2009) Mapping the Burkholderia cenocepacia niche response via high-throughput sequencing. Proc Natl Acad Sci USA 106(10):3976–3981PubMedCrossRefGoogle Scholar
  65. 65.
    Perkins TT et al (2009) A strand-specific RNA-Seq analysis of the transcriptome of the typhoid bacillus Salmonella typhi. PLoS Genet 5(7):e1000569PubMedCrossRefGoogle Scholar
  66. 66.
    Mraheil MA et al (2011) The intracellular sRNA transcriptome of Listeria monocytogenes during growth in macrophages. Nucleic Acids Res 39(10):4235–4248PubMedCrossRefGoogle Scholar
  67. 67.
    Passalacqua KD et al (2009) Structure and complexity of a bacterial transcriptome. J Bacteriol 191(10):3203–3211PubMedCrossRefGoogle Scholar
  68. 68.
    Camarena L et al (2010) Molecular mechanisms of ethanol-induced pathogenesis revealed by RNA-sequencing. PLoS Pathog 6(4):e1000834PubMedCrossRefGoogle Scholar
  69. 69.
    Albrecht M et al (2010) Deep sequencing-based discovery of the Chlamydia trachomatis transcriptome. Nucleic Acids Res 38(3):868–877PubMedCrossRefGoogle Scholar
  70. 70.
    Sharma CM et al (2010) The primary transcriptome of the major human pathogen Helicobacter pylori. Nature 464(7286):250–255PubMedCrossRefGoogle Scholar
  71. 71.
    Mahan MJ, Slauch JM, Mekalanos JJ (1993) Selection of bacterial virulence genes that are specifically induced in host tissues. Science 259(5095):686–688PubMedCrossRefGoogle Scholar
  72. 72.
    Hensel M et al (1995) Simultaneous identification of bacterial virulence genes by negative selection. Science 269(5222):400–403PubMedCrossRefGoogle Scholar
  73. 73.
    Sun YH et al (2000) Functional genomics of Neisseria meningitidis pathogenesis. Nat Med 6(11):1269–1273PubMedCrossRefGoogle Scholar
  74. 74.
    van Opijnen T, Bodi KL, Camilli A (2009) Tn-seq: high-throughput parallel sequencing for fitness and genetic interaction studies in microorganisms. Nat Methods 6(10):767–772PubMedCrossRefGoogle Scholar
  75. 75.
    van Opijnen, T. and A. Camilli, Genome-wide fitness and genetic interactions determined by Tn-seq, a high-throughput massively parallel sequencing method for microorganisms. Curr Protoc Microbiol, 2010. Chapter 1: p. Unit1E 3.Google Scholar
  76. 76.
    Langridge GC et al (2009) Simultaneous assay of every Salmonella Typhi gene using one million transposon mutants. Genome Res 19(12):2308–2316PubMedCrossRefGoogle Scholar
  77. 77.
    Gawronski JD et al (2009) Tracking insertion mutants within libraries by deep sequencing and a genome-wide screen for Haemophilus genes required in the lung. Proc Natl Acad Sci USA 106(38):16422–16427PubMedCrossRefGoogle Scholar
  78. 78.
    Rappuoli R (2004) From Pasteur to genomics: progress and challenges in infectious diseases. Nat Med 10(11): 1177–85PubMedCrossRefGoogle Scholar
  79. 79.
    Granoff DM et al. (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(2): 764–9PubMedCrossRefGoogle Scholar
  80. 80.
    Metruccio MM et al (2009) A novel phase variation mechanism in the meningococcus driven by a ligand-responsive repressor and differential spacing of distal promoter elements. PLoS Pathog 5(12): e1000710Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Valeria Cafardi
    • 1
  • John L. Telford
    • 1
  • Davide Serruto
    • 1
  1. 1.Microbial Molecular Biology, Novartis Vaccines and DiagnosticsSienaItaly

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