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Structural vaccinology starts to deliver

Nature Reviews Microbiology volume 10, pages 807–813 (2012)Cite this article

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Abstract

Following the impact of the genomics revolution on vaccine research and the development of reverse vaccinology, it was predicted that another new approach, structure-based antigen design, would become a driving force for vaccine innovation. Now, 5 years on, there are several examples of how structure-based design, or structural vaccinology, can deliver new vaccine antigens that were not possible before. Here, we discuss some of these examples and the contribution of structural vaccinology to our understanding of the protective epitopes of important bacterial and viral pathogens.

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Figure 1: Rational design of a cross-protective factor H-binding protein.
Figure 2: Targeting the group B Streptococcus pilus backbone protein.
Figure 3: Targeting the respiratory syncytial virus fusion protein.

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References

  1. Rappuoli, R., Mandl, C. W., Black, S. & De Gregorio, E. Vaccines for the twenty-first society. Nature Rev. Immunol. 11, 865–872 (2011).

    Article  CAS  Google Scholar 

  2. Rappuoli, R. Reverse vaccinology. Curr. Opin. Microbiol. 3, 445–550 (2000).

    Article  CAS  Google Scholar 

  3. Dormitzer, P. R., Ulmer, J. B. & Rappuoli, R. Structure-based antigen design: a strategy for next generation vaccines. Trends Biotechnol. 26, 659–667 (2008).

    Article  CAS  Google Scholar 

  4. Masignani, V. et al. Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870. J. Exp. Med. 197, 789–799 (2003).

    Article  CAS  Google Scholar 

  5. Scarselli, M. et al. Rational design of a meningococcal antigen inducing broad protective immunity. Sci. Transl. Med. 3, 91ra62 (2011).

    Article  CAS  Google Scholar 

  6. Jiang, H. Q. et al. Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein based vaccine to prevent serogroup B meningococcal disease. Vaccine 28, 6086–6093 (2010).

    Article  CAS  Google Scholar 

  7. Fletcher, L. D. et al. Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect. Immun. 72, 2088–2100 (2004).

    Article  CAS  Google Scholar 

  8. Giuliani, M. M. et al. A universal vaccine for serogroup B meningococcus. Proc. Natl Acad. Sci. USA 103, 10834–10839 (2006).

    Article  CAS  Google Scholar 

  9. Mascioni, A. et al. Structural basis for the immunogenic properties of the meningococcal vaccine candidate LP2086. J. Biol. Chem. 284, 8738–8746 (2009).

    Article  CAS  Google Scholar 

  10. Cantini, F. et al. Solution structure of the factor H-binding protein, a survival factor and protective antigen of Neisseria meningitidis. J. Biol. Chem. 284, 9022–9026 (2009).

    Article  CAS  Google Scholar 

  11. Schneider, M. C. et al. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature 458, 890–893 (2009).

    Article  CAS  Google Scholar 

  12. Giuntini, S., Reason, D. C. & Granoff, D. M. Complement-mediated bactericidal activity of anti-factor H binding protein monoclonal antibodies against the meningococcus relies upon blocking factor H binding. Infect. Immun. 79, 3751–3759 (2011).

    Article  CAS  Google Scholar 

  13. Scarselli, M. et al. Epitope mapping of a bactericidal monoclonal antibody against the factor H binding protein of Neisseria meningitidis. J. Mol. Biol. 386, 97–108 (2011).

    Article  Google Scholar 

  14. Beernink, P. T. et al. A meningococcal factor H binding protein mutant that eliminates factor H binding enhances protective antibody responses to vaccination. J. Immunol. 186, 3606–3614 (2011).

    Article  CAS  Google Scholar 

  15. Pajon, R., Beernink, P. T. & Granoff, D. M. Design of meningococcal factor H binding protein mutant vaccines that do not bind human complement factor H. Infect. Immun. 80, 2667–2677 (2012).

    Article  CAS  Google Scholar 

  16. Beernink, P. T. & Granoff, D. M. Bactericidal antibody responses induced by meningococcal recombinant chimeric factor H-binding protein vaccines. Infect. Immun. 76, 2568–2575 (2008).

    Article  CAS  Google Scholar 

  17. Edmond, K. M., et al. Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis. Lancet 379, 547–556 (2012).

    Article  Google Scholar 

  18. Lin, F. C. et al. Level of maternal IgG anti-group B Streptococcus type III antibody correlated with protection of neonates against early-onset disease caused by this pathogen. J. Infect. Dis. 190, 928–934 (2004).

    Article  CAS  Google Scholar 

  19. Lauer, P. et al. Genome analysis reveals pili in Group B Streptococcus. Science 309, 105 (2005).

    Article  CAS  Google Scholar 

  20. Mora, M. et al. Group A Streptococcus produce pilus-like structures containing protective antigens and Lancefield T antigens. Proc. Natl Acad. Sci. USA 102, 15641–15646 (2005).

    Article  CAS  Google Scholar 

  21. Telford, J. L., Barocchi, M. A., Margarit, I., Rappuoli, R. & Grandi, G. Pili in Gram-positive pathogens. Nature Rev. Microbiol. 4, 509–519 (2006).

    Article  CAS  Google Scholar 

  22. Margarit, I. et al. Preventing bacterial infections with pilus-based vaccines: the group B Streptococcus paradigm. J. Infect. Dis. 199, 108–115 (2009).

    Article  Google Scholar 

  23. Nuccitelli, A. et al. Structure-based approach to rationally design a chimeric protein for an effective vaccine against Group B Streptococcus infections. Proc. Natl Acad. Sci. USA 108, 10278–10283 (2011).

    Article  CAS  Google Scholar 

  24. Stockman, L. J., Corns, A. T., Anderson, L. J. & Fischer-Langley, G. Respiratory syncytial virus-associated hospitalizations among infants and young children in the United States, 1997–2006. Pediatr. Infect. Dis. J. 31, 5–9 (2012).

    Article  Google Scholar 

  25. Kim, H. W. et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89, 422–434 (1969).

    Article  CAS  Google Scholar 

  26. Wright, P. F. et al. The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines. Vaccine 25, 7372–7378 (2007).

    Article  CAS  Google Scholar 

  27. Swanson, K. A. et al. Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. Proc. Natl Acad. Sci. USA 108, 9619–9624 (2011).

    Article  CAS  Google Scholar 

  28. McLellan, J. S., Yang, Y., Graham, B. S. & Kwong, P. D. Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J. Virol. 85, 7788–7796 (2011).

    Article  CAS  Google Scholar 

  29. Yin, H. S., Wen, X., Paterson, R. G., Lamb, R. A. & Jardetzky, T. S. Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation. Nature 439, 38–44 (2006).

    Article  CAS  Google Scholar 

  30. Magro, M. et al. Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention. Proc. Natl Acad. Sci. USA 109, 3089–3094 (2012).

    Article  CAS  Google Scholar 

  31. Yin, H. S., Paterson, R. G., Wen, X., Lamb, R. A. & Jardetzky, T. S. Structure of the uncleaved ectodomain of the paramyxovirus (hPIV3) fusion protein. Proc. Natl Acad. Sci. USA 102, 9288–9293 (2005).

    Article  CAS  Google Scholar 

  32. Calder, L. J. et al. Electron microscopy of the human respiratory syncytial virus fusion protein and complexes that it forms with monoclonal antibodies. Virology 271, 122–131 (2000).

    Article  CAS  Google Scholar 

  33. Langley, J. M. et al. A dose-ranging study of a subunit Respiratory Syncytial Virus subtype A vaccine with and without aluminum phosphate adjuvantation in adults ≥65 years of age. Vaccine 27, 5913–5919 (2009).

    Article  CAS  Google Scholar 

  34. Piedra, P. A. et al. Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: a multi-center trial in children with cystic fibrosis. Vaccine 21, 2448–2460 (2003).

    Article  CAS  Google Scholar 

  35. McLellan, J. S. et al. Structural basis of respiratory syncytial virus neutralization by motavizumab. Nature Struct. Mol. Biol. 17, 248–250 (2010).

    Article  CAS  Google Scholar 

  36. McLellan, J. S. et al. Structure of a major antigenic site on the respiratory syncytial virus fusion glycoprotein in complex with neutralizing antibody 101F. J. Virol. 84, 12236–12244 (2010).

    Article  CAS  Google Scholar 

  37. López, J. A. et al. Conformational constraints of conserved neutralizing epitopes from a major antigenic area of human respiratory syncytial virus fusion glycoprotein. J. Gen. Virol. 74, 2567–2577 (1993).

    Article  Google Scholar 

  38. Toiron, C. et al. Conformational studies of a short linear peptide corresponding to a major conserved neutralizing epitope of human respiratory syncytial virus fusion glycoprotein. Biopolymers 39, 537–548 (1996).

    Article  CAS  Google Scholar 

  39. McLellan, J. S. et al. Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus. J. Mol. Biol. 409, 853–866 (2011).

    Article  CAS  Google Scholar 

  40. Lingwood, D. et al. Structural and genetic basis for development of broadly neutralizing influenza antibodies. Nature 489, 566–571 (2012).

    Article  CAS  Google Scholar 

  41. Okuno, Y., Isegawa, Y., Sasao, F. & Ueda, S. A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J. Virol. 67, 2552–2558 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ekiert, D. C. et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246–251 (2009).

    Article  CAS  Google Scholar 

  43. Throsby, M. et al. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS ONE 3, e3942 (2008).

    Article  Google Scholar 

  44. Sui, J. et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nature Struct. Mol. Biol. 16, 265–273 (2009).

    Article  CAS  Google Scholar 

  45. Corti, D. et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850–856 (2011).

    Article  CAS  Google Scholar 

  46. Wiley, D. C., Wilson, I. A. & Skehel, J. J. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289, 373–378 (1981).

    Article  CAS  Google Scholar 

  47. Whittle, J. R. R. et al. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc. Natl Acad. Sci. USA 108 14216–14221 (2011).

    Article  CAS  Google Scholar 

  48. Steel, J. et al. Influenza virus vaccine based on the conserved hemagglutinin stalk domain. MBio 1, e00018–e00010 (2010).

    Article  Google Scholar 

  49. Liu, G. et al. Immunogenicity and efficacy of flagellin-fused vaccine candidates targeting 2009 pandemic H1N1 influenza in mice. PLoS ONE 6, e20928 (2011).

    Article  CAS  Google Scholar 

  50. Song, L. et al. Efficacious recombinant influenza vaccines produced by high yield bacterial expression: a solution to global pandemic and seasonal needs. PLoS ONE 3, e2257 (2008).

    Article  Google Scholar 

  51. Khurana, S. et al. Properly folded bacterially expressed H1N1 hemagglutinin globular head and ectodomain vaccines protect ferrets against H1N1 pandemic influenza virus. PLoS ONE 5, e11548 (2011).

    Article  Google Scholar 

  52. McLellan, J. S. et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336–343 (2011).

    Article  CAS  Google Scholar 

  53. Johnson, S. et al. Design and evaluation of meningococcal vaccines through structure-based modification of host and pathogen molecules. 25 Oct 2012 (doi:10.1371/journal.ppat.1002981)

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to M. Scarselli and F. Grassiccia for help with the figures, and to C. Mallia for help with the manuscript. The authors also acknowledge the partial contribution of the ADITEC Project (funded by the European Union Seventh Framework Programme, grant 280873) and of the grant P01AI089618 (funded by the National Institutes of Allergy and Infectious Diseases, US National Institutes of Health).

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Authors and Affiliations

  1. Philip R. Dormitzer is at Novartis Vaccines and Diagnostics Inc., 350 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.,

    Philip R. Dormitzer

  2. Guido Grandi and Rino Rappuoli are at Novartis Vaccines and Diagnostics Srl, Via Fiorentina 1, 53100 Siena, Italy.,

    Guido Grandi & Rino Rappuoli

Authors
  1. Philip R. Dormitzer
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  2. Guido Grandi
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Corresponding author

Correspondence to Rino Rappuoli.

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Competing interests

Philip R. Dormitzer, Guido Grandi and Rino Rappuoli are employees of Novartis Vaccines and Diagnostics and are Novartis shareholders.

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Dormitzer, P., Grandi, G. & Rappuoli, R. Structural vaccinology starts to deliver. Nat Rev Microbiol 10, 807–813 (2012). https://doi.org/10.1038/nrmicro2893

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