Finding Protective Bacterial Antigens

  • Guido GrandiEmail author
  • Eszter NagyEmail author


Current vaccine development efforts are mainly focused on opportunistic pathogens that are frequent colonizers and have complex pathogenesis and interaction with the human host. Therefore, more sophisticated and comprehensive vaccine development approaches have to be considered than for strictly pathogenic bacteria with well-defined virulence mechanisms that typically rely on toxin production. Multigenome analysis and genomic DNA-based screening approaches represent powerful strategies for identifying proteinaceous vaccine candidates. The two approaches we review here are the reverse vaccinology and the ANTIGENome technologies that have been applied for numerous human pathogens and resulted in clinical vaccine candidates. In both cases, the primary selections—that are based on in silico prediction or human antibody response, respectively—are complemented with a series of in vitro assays to preselect vaccine candidates for testing in animal models of efficacy to ultimately single out the vaccine antigens destined to move into development. When applied to the same pathogen, the two approaches appear to identify overlapping pools of antigens that not completely superimpose, suggesting that the methods might complement each other. Importantly, the conclusions from the application of two technologies are similar: broadly protective antigens rarely exist, and combination of several protein antigens is necessary for the development of universal vaccines.


Vaccine Candidate Chlamydia Trachomatis Biological Assay Protective Antigen Moraxella Catarrhalis 
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. Barocchi MA, Ries J, Zogaj X, Hemsley C, Albiger B, Kanth A, Dahlberg S, Fernebro J, Moschioni M, Masignani V, Hultenby K, Taddei AR, Beiter K, Wartha F, von Euler A, Covacci A, Holden DW, Normark S, Rappuoli R, Henriques-Normark B (2006) Proc Natl Acad Sci USA 103:2857–2862PubMedCrossRefGoogle Scholar
  2. Barry MA, Lai WC, Johnston SA (1995) Protection against Mycoplasma infection using expression library immunization. Nature 377:632–635PubMedCrossRefGoogle Scholar
  3. Berlanda Scorza F, Doro F, Rodríguez-Ortega MJ, Stella M, Liberatori S, Taddei AR, Serino L, Gomes Moriel D, Nesta B, Fontana MR, Spagnuolo A, Pizza M, Norais N, Grandi G (2008) Proteomic characterization of outer membrane vesicles from the extraintestinal pathogenic Escherichia coli tolR IHE3034 mutant. Mol Cell Proteomics 7:473–485PubMedGoogle Scholar
  4. Brodeur BR, Boyer M, Charlebois I, Hamel J, Couture F, Rioux CR, Martin D (2000) Identification of Group B Streptococcus Sip protein, which elicits cross-protective immunity. Infect Immun 68:5610–5618PubMedCrossRefGoogle Scholar
  5. Brown M, Kowalski R, Zorman J, Wang XM, Towne V, Zhao Q, Secore S, Finnefrock AC, Ebert T, Pancari G, Isett K, Zhang Y, Anderson AS, Montgomery D, Cope L, McNeely T (2009) Selection and characterization of murine monoclonal antibodies to Staphylococcus aureus iron-regulated surface determinant B with functional activity in vitro and in vivo. Clin Vaccine Immunol 16:1095–1110PubMedCrossRefGoogle Scholar
  6. Carneiro CR, Postol E, Nomizo R, Reis LF, Brentani RR (2004) Identification of enolase as a laminin-binding protein on the surface of Staphylococcus aureus. Microbes Infect 6:604–608PubMedCrossRefGoogle Scholar
  7. Cork AJ, Jergic S, Hammerschmidt S, Kobe B, Pancholi V, Benesch JL, Robinson CV, Dixon NE, Aquilina JA, Walker MJ (2009) Defining the structural basis of human plasminogen binding by streptococcal surface enolase. J Biol Chem 284:17129–17137PubMedCrossRefGoogle Scholar
  8. Daniels CC, Coan P, King J, Hale J, Benton KA, Briles DE, Hollingshead SK (2010) The proline-rich region of pneumococcal surface proteins A and C contains surface-accessible epitopes common to all pneumococci and elicits antibody-mediated protection against sepsis. Infect Immun 78:2163–2172PubMedCrossRefGoogle Scholar
  9. Doro F, Liberatori S, Rodríguez-Ortega MJ, Rinaudo CD, Rosini R, Mora M, Scarselli M, Altindis E, D’Aurizio R, Stella M, Margarit I, Maione D, Telford JL, Norais N, Grandi G (2009) Surfome analysis as a fast track to vaccine discovery: identification of a novel protective antigen for group B Streptococcus hyper-virulent strain COH1. Mol Cell Proteomics 8:1728–1737PubMedCrossRefGoogle Scholar
  10. Dryla A, Gelbmann D, von Gabain A, Nagy E (2003) Identification of a novel iron regulated staphylococcal surface protein with haptoglobin–hemoglobin binding activity. Mol Microbiol 49:37–53PubMedCrossRefGoogle Scholar
  11. Dryla A, Hoffmann B, Gelbmann D, Giefing C, Hanner M, Meinke A, Anderson AS, Koppensteiner W, Konrat R, von Gabain A, Nagy E (2007) High-affinity binding of the staphylococcal HarA protein to haptoglobin and hemoglobin involves a domain with an antiparallel eight-stranded beta-barrel fold. J Bacteriol 189:254–264PubMedCrossRefGoogle Scholar
  12. Ebert T, Smith S, Pancari G, Clark D, Hampton R, Secore S, Towne V, Fan H, Wang XM, Wu X, Ernst R, Harvey BR, Finnefrock AC, Wang F, Tan C, Durr E, Cope L, Anderson A, An Z, McNeely T (2010) A fully human monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) with functional activity in vitro and in vivo. Hum Antibodies 19:113–128PubMedGoogle Scholar
  13. Ebert T, Smith S, Pancari G, Wu X, Zorman J, Clark D, Cook J, Burns C, Antonello JM, Cope L, Nagy E, Meinke A, McNeely T (2011) Development of a rat central venous catheter model for evaluation of vaccines to prevent Staphylococcus epidermidis and Staphylococcus aureus early biofilms. Hum Vaccine 7:630–638CrossRefGoogle Scholar
  14. Etz HH, Bui-Minh D, Nagy E, Meinke A (2001) Bacterial phage receptors, versatile tools for display of polypeptides on the cell surface. J Bacteriol 183:6924–6935PubMedCrossRefGoogle Scholar
  15. Etz HH, Minh DB, Henics T, Dryla A, Winkler B, Triska BAP, Söllner J, Schmidt W, von Ahsen U, Buschle M, Gill SR, Kolonay J, Khalak H, Fraser CM, von Gabain A, Nagy E, Meinke A (2002) Identification of in vivo expressed vaccine candidate antigens from Staphylococcus aureus. Proc Natl Acad Sci USA 99:6573–6578PubMedCrossRefGoogle Scholar
  16. Feng Y, Pan X, Sun W, Wang C, Zhang H, Li X, Ma Y, Shao Z, Ge J, Zheng F, Gao GF, Tang J (2009) Streptococcus suis enolase functions as a protective antigen displayed on the bacterial cell surface. J Infect Dis 200:1583–1592PubMedCrossRefGoogle Scholar
  17. Ferrari G, Garaguso I, Adu-Bobie J, Doro F, Taddei AR, Biolchi A, Brunelli B, Giuliani MM, Pizza M, Norais N, Grandi G (2006) Outer membrane vescicles from group B Neisseria meningitidis Δgna33 mutant: proteomic and immunological comparison with detergent-derived outer membrane vesicles. Proteomics 6:1856–1866PubMedCrossRefGoogle Scholar
  18. Finco O, Frigimelica E, Buricchi F, Petracca R, Galli G, Faenzi E, Meoni E, Bonci A, Agnusdei M, Nardelli F, Bartolini E, Scarselli M, Caproni E, Laera D, Zedda L, Skibinski D, Giovinazzi S, Bastone R, Ianni E, Cevenini R, Grandi G, Grifantini R (2011) Approach to discover T and B cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines. Proc Natl Acad Sci USA 108:9969–9974PubMedCrossRefGoogle Scholar
  19. Fritzer A, Noiges B, Schweiger D, Rek A, Kungl AJ, von Gabain A, Nagy E, Meinke AL (2009) Chemokine degradation by the Group A streptococcal serine proteinase ScpC can be reconstituted in vitro and requires two separate domains. Biochem J 422:533–542PubMedCrossRefGoogle Scholar
  20. Fritzer A, Senn BM, Minh DB, Hanner M, Gelbmann D, Noiges B, Henics T, Schulze K, Guzman CA, Goodacre J, von Gabain A, Nagy E, Meinke AL (2010) Novel conserved group A streptococcal proteins identified by the ANTIGENome technology as vaccine candidates for a non-M protein based vaccine. Infect Immun 78:4051–4056PubMedCrossRefGoogle Scholar
  21. Giefing C, Meinke AL, Hanner M, Henics T, Minh DB, Gelbmann D, Lundberg U, Senn BM, Schunn M, Habel A, Henriques-Normark B, Örtqvist Å, Kalin M, von Gabain A, Nagy E (2008) Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies. J Exp Med 205:117–131PubMedCrossRefGoogle Scholar
  22. Giefing C, Jelencsics K, Gelbmann D, Senn BM, Nagy E (2010) The pneumococcal Eukaryotic-Type Serine/Threonine Protein Kinase co-localizes with the cell division apparatus and interacts with FtsZ in vitro. Microbiology 156:1697–1707PubMedCrossRefGoogle Scholar
  23. Giefing-Kröll C, Jelencsics KE, Reipert S, Nagy E (2011) Absence of pneumococcal PcsB is associated with overexpression of LysM domain containing proteins. Microbiology 157:1897–1909PubMedCrossRefGoogle Scholar
  24. Giuliani MM, Adu-Bobie J, Comanducci M, Aricò B, Savino S, Santini L, Brunelli B, Bambini S, Biolchi A, Capecchi B, Cartocci E, Ciucchi L, Di Marcello F, Ferlicca F, Galli B, Luzzi E, Masignani V, Serruto D, Veggi D, Contorni M, Morandi M, Bartalesi A, Cinotti V, Mannucci D, Titta F, Ovidi E, Welsch JA, Granoff D, Rappuoli R, Pizza M (2006) A universal vaccine for Serogroup B Meningococcus. Proc Natl Acad Sci USA 103:10834–10839PubMedCrossRefGoogle Scholar
  25. Grandi G (2001) Antibacterial vaccine design using genomics and proteomics. Trends Biotechnol 19:181–188PubMedCrossRefGoogle Scholar
  26. Henics T, Winkler B, Pfeifer U, Gill SR, Buschle M, von Gabain A, Meinke AL (2003) Small-fragment genomic libraries for the display of putative epitopes from clinically significant pathogens. Biotechniques 35:196–202PubMedGoogle Scholar
  27. Hidalgo-Grass C, Mishalian I, Dan-Goor M, Belotserkovsky I, Eran Y, Nizet V, Peled A, Hanski E (2006) A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues. EMBO J 25:4628–4637PubMedCrossRefGoogle Scholar
  28. Hughes MJ, Moore JC, Lane JD, Wilson R, Pribul PK, Younes ZN, Dobson RJ, Everest P, Reason AJ, Redfern JM, Greer FM, Paxton T, Panico M, Morris HR, Feldman RG, Santangelo JD (2002) Identification of major outer surface proteins of Streptococcus agalactiae. Infect Immun 70:1254–1259PubMedCrossRefGoogle Scholar
  29. Kaur SJ, Nerlich A, Bergmann S, Rohde M, Fulde M, Zähner D, Hanski E, Zinkernagel A, Nizet V, Chhatwal GS, Talay SR (2010) The CXC chemokine-degrading protease SpyCep of Streptococcus pyogenes promotes its uptake into endothelial cells. J Biol Chem 285:27798–27805PubMedCrossRefGoogle Scholar
  30. Kim HK, DeDent A, Cheng AG, McAdow M, Bagnoli F, Missiakas DM, Schneewind O (2010) IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge. Vaccine 28:6382–6392PubMedCrossRefGoogle Scholar
  31. Kuklin NA, Clark DJ, Secore S, Cook J, Cope LD, McNeely T, Noble L, Brown MJ, Zorman JK, Wang XM, Pancari G, Fan H, Isett K, Burgess B, Bryan J, Brownlow M, George H, Meinz M, Liddell ME, Kelly R, Schultz L, Montgomery D, Onishi J, Losada M, Martin M, Ebert T, Tan CY, Schofield TL, Nagy E, Meineke A, Joyce JG, Kurtz MB, Caulfield MJ, Jansen KU, McClements W, Anderson AS (2006) A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in Rhesus Macaques and specific increased survival in a murine S. aureus sepsis model. Infect Immun 74:2215–2223PubMedCrossRefGoogle Scholar
  32. Lauer P, Rinaudo D, Soriani M, Margarit y Ros I, Maione D, Rosini R, Taddei AR, Mora M, Rappuoli R, Grandi G, Telford JL (2005) Genome analysis reveals pili in Group B Streptococcus. Science 309:105PubMedCrossRefGoogle Scholar
  33. Lu YJ, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, Kolls JK, Srivastava A, Lundgren A, Forte S, Thompson CM, Harney KF, Anderson PW, Lipsitch M, Malley R (2008) Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 4:e1000159PubMedCrossRefGoogle Scholar
  34. Maione D, Margarit y Ros I, Rinaudo D, Masignani V, Mora M, Scarselli M, Tettelin H, Brettoni C, Iacobini ET, Rosini R, D’Agostino N, Miorin L, Buccato S, Mariani M, Galli G, Nogarotto R, Nardi Dei V, Vegni F, Fraser C, Mancuso G, Teti G, Madoff LC, Paoletti LC, Rappuoli R, Kasper DL, Telford JL, Grandi G (2005) Identification of a universal Group B Streptococcus vaccine by multiple genome screen. Science 309:148–150PubMedCrossRefGoogle Scholar
  35. Margarit I, Rinaudo CD, Galeotti CL, Maione D, Ghezzo C, Buttazzoni E, Rosini R, Runci Y, Mora M, Buccato S, Pagani M, Tresoldi E, Berardi A, Creti R, Baker CJ, Telford JL, Grandi G (2009) Preventing bacterial infections with pilus-based vaccines: the group B streptococcus paradigm. J Infect Dis 199:108–115PubMedCrossRefGoogle Scholar
  36. Meinke A, Henics T, Hanner M, Minh D, Nagy E (2005) Antigenome technology: a novel approach for the selection of bacterial vaccine candidate antigens. Vaccine 23:2035–2041PubMedCrossRefGoogle Scholar
  37. Meinke A, Senn BM, Visram Z, Henics TZ, Duc Bui Minh D, Schüler W, Neubauer C, Gelbmann D, Noiges B, Sinzinger J, Hanner M, Dewasthaly S, Lundberg U, Hordnes K, Masoud H, Sevelda P, von Gabain A, Nagy E (2010) Immunological fingerprinting of group B streptococci: from circulating human antibodies to protective antigens. Vaccine 28:6997–7008PubMedCrossRefGoogle Scholar
  38. Mora M, Bensi G, Capo S, Falugi F, Zingaretti C, Manetti AGO, Maggi T, Taddei A, Grandi G, Telford JL (2005) Group A Streptococcus produce pilus-like structures containing protective antigens and Lancefield T antigens. Proc Natl Acad Sci USA 102:15641–15646PubMedCrossRefGoogle Scholar
  39. Pizza M, Scarlato V, Masignani V, Giuliani MM, Aricò B, Comanducci M, Jennings GT, Baldi L, Bartolini E, Capecchi B, Galeotti CL, Luzzi E, Manetti R, Marchetti E, Mora M, Nuti S, Ratti G, Santini L, Savino S, Scarselli M, Storni E, Zuo P, Broecker M, Hundt E, Knapp B, Blair E, Mason T, Tettelin H, Hood DW, Jeffries AC, Saunders NJ, Granoff DM, Venter JC, Moxon ER, Grandi G, Rappuoli R (2000) Identification of vaccine candidates against serogroup B meningococcus genome sequencing. Science 287:1816–1820PubMedCrossRefGoogle Scholar
  40. Rodríguez-Ortega MJ, Norais N, Bensi G, Liberatori S, Capo S, Mora M, Scarselli M, Doro F, Ferrari G, Garaguso I, Maggi T, Neumann A, Covre A, Telford JL, Grandi G (2006) Characterization and identification of vaccine candidate proteins through analysis of the group A Streptococcus surface proteome. Nat Biotechnol 24:191–197PubMedCrossRefGoogle Scholar
  41. Schmid P, Selak S, Keller M, Luhan B, Magyarics Z, Seidel S, Schlick P, Reinisch C, Lingnau K, Nagy E, Grubeck-Loebenstein B (2011) Th17/Th1 biased immunity to the pneumococcal proteins PcsB, StkP and PsaA in adults of different age. Vaccine 29:3982–3989PubMedCrossRefGoogle Scholar
  42. Senn BM, Visram Z, Meinke AL, Neubauer C, Gelbmann D, Sinzinger J, Hanner M, Lundberg U, Boisvert H, Reinscheid D, von Gabain A, Nagy E (2011) Monoclonal antibodies targeting different cell wall antigens of group B streptococcus mediate protection in both Fc-dependent and independent manner. Vaccine 29:4116–4124PubMedCrossRefGoogle Scholar
  43. Stranger-Jones YK, Bae T, Schneewind O (2006) Vaccine assembly from surface proteins of Staphylococcus aureus. Proc Natl Acad Sci USA 103:16942–16947PubMedCrossRefGoogle Scholar
  44. Tettelin H, Masignani V, Cieslewicz MJ, Donati C, Medini D, Ward NL, Angiuoli SV, Crabtree J, Jones AL, Durkin AS, Deboy RT, Davidsen TM, Mora M, Scarselli M, Margarit I, Ros Y, Peterson JD, Hauser CR, Sundaram JP, Nelson WC, Madupu R, Brinkac LM, Dodson RJ, Rosovitz MJ, Sullivan SA, Daugherty SC, Haft DH, Selengut J, Gwinn ML, Zhou L, Zafar N, Khouri H, Radune D, Dimitrov G, Watkins K, O’Connor KJ, Smith S, Utterback TR, White O, Rubens CE, Grandi G, Madoff LC, Kasper DL, Telford JL, Wessels MR, Rappuoli R, Fraser CM (2005) Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial “pan-genome”. Proc Natl Acad Sci USA 102:13950–13955PubMedCrossRefGoogle Scholar
  45. Zhang Z, Clarke TB, Weiser JN (2009) Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest 119:1899–1909PubMedGoogle Scholar

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© Springer-Verlag Wien 2012

Authors and Affiliations

  1. 1.Novartis VaccinesSienaItaly
  2. 2.Arsanis IncViennaAustria

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