Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Development of vaccines for Candida albicans: fighting a skilled transformer

Nature Reviews Microbiology volume 11, pages 884–891 (2013)Cite this article

Subjects

Abstract

Two univalent subunit vaccines that are based on major virulence traits of Candida albicans have completed Phase I clinical trials in recent years. Although it is hoped that at least one will become the first antifungal vaccine approved for human use, there are some major obstacles to achieving this. The difficulties mostly arise from the remarkable ability of C. albicans to deceive the host immune system. In this Opinion article, I argue that the development of a multivalent vaccine that induces an immune response against multiple, unrelated virulence traits of this human commensal fungus and opportunistic pathogen may be a better approach.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Candida albicans cell wall.
Figure 2: A highly simplified, schematic view of the host immune response to Candida albicans infection.
Figure 3: Properties of an effective Candida albicans vaccine.

Similar content being viewed by others

References

  1. Cutler, J. E., Deepe, G. S. & Klein, D. Advances in combating fungal diseases: vaccines on the threshold. Nature Rev. Microbiol. 5, 13–28 (2007).

    Article  CAS  Google Scholar 

  2. Cassone, A. Fungal vaccines: real progress from real challenge. Lancet Infect. Dis. 8, 114–124 (2008).

    Article  CAS  Google Scholar 

  3. Cassone, A. & Casadevall, A. Recent progress in vaccines against fungal diseases. Curr. Opin. Microbiol. 15, 1–7 (2012).

    Article  Google Scholar 

  4. Edwards, J. E. Fungal cell wall vaccines: an update. J. Med. Microbiol. 61, 895–903 (2012).

    Article  CAS  Google Scholar 

  5. De Bernardis, F. et al. A virosomal vaccine against candidal vaginitis: immunogenicity, efficacy and safety profile in animal models. Vaccine 30, 4490–4498 (2012).

    Article  CAS  Google Scholar 

  6. Schmidt, C. S. et al. NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus is safe and immunogenic in healthy adults. Vaccine 30, 7594–7600 (2012).

    Article  CAS  Google Scholar 

  7. Torosantucci, A. et al. A novel glyco-conjugate vaccine against fungal pathogens. J. Exp. Med. 202, 597–606 (2005).

    Article  CAS  Google Scholar 

  8. Bromuro, C. et al. β-glucan–CRM197 conjugates as candidates antifungal vaccines. Vaccine 28, 2615–2623 (2010).

    Article  CAS  Google Scholar 

  9. Xin, H., Dziadek, S., Bundle, D. R. & Cutler, J. E. Synthetic glycopeptide vaccines combining β-mannan and peptide epitopes induce protection against candidiasis. Proc. Natl Acad. Sci. USA 105, 13526–13531 (2008).

    Article  CAS  Google Scholar 

  10. Han, Y. & Rhew, K. Y. Comparison of two Candida mannan vaccines: the role of complement in protection against disseminated candidiasis. Arch. Pharm. Res. 35, 2021–2027 (2012).

    Article  CAS  Google Scholar 

  11. Cassone, A. & Rappuoli, R. Universal vaccines: shifting to one for many. mBio 1, e00042–10 (2010).

    Article  Google Scholar 

  12. Pfaller, M. A. & Diekema, D. J. Epidemiology of invasive mycoses in North America. Crit. Rev. Microbiol. 36, 1–53 (2010).

    Article  Google Scholar 

  13. Cassone, A. & Cauda, R. Candida and candidiasis in HIV-infected subjects. Where commensalism, opportunistic behavior and frank pathogenicity lose their borders. AIDS 26, 1457–1472 (2012).

    Article  CAS  Google Scholar 

  14. Foxman, B., Muraglia, R., Dietz, J., Sobel, J. D. & Wagner, J. Prevalence of recurrent vulvovaginal candidiasis in 5 European countries and the United States: results from an internal panel survey. J. Low. Genit. Tract Dis. 17, 340–345 (2013).

    Article  Google Scholar 

  15. Pappas, P. G. Invasive candidiasis. Infect. Dis. Clin. North Am. 20, 485–506 (2006).

    Article  Google Scholar 

  16. Diekema, D., Arbefeville, S., Boyken, L., Kroeger, J. & Pfaller, M. The changing epidemiology of healthcare-associated candidemia over three decades. Diagn. Microbiol. Infect. Dis. 73, 45–48 (2012).

    Article  Google Scholar 

  17. Klis, F. M., de Koster, C. G. & Brul, S. A mass spectrometric view of the fungal wall proteome. Future Microbiol. 6, 941–951 (2011).

    Article  CAS  Google Scholar 

  18. Plain, A. et al. Functional analysis of Candida albicans GPI-anchored proteins: roles in cell wall integrity and caspofungin sensitivity. Fungal Genet. Biol. 45, 1404–1414 (2008).

    Article  Google Scholar 

  19. LeibundGut-Landman, S., Wutrich, M. & Hohl, T. Immunity to fungi. Curr. Opin. Immunol. 24, 1–10 (2012).

    Article  Google Scholar 

  20. Romani, L. Immunity to fungal infections. Nature Rev. Immunol. 11, 275–288 (2011).

    Article  CAS  Google Scholar 

  21. Gaffen, S. L. Hernández-Santos, N. & Peterson, A. C. IL-17 signaling in host defense against Candida albicans. Immunol. Res. 50, 181–187 (2011).

    Article  CAS  Google Scholar 

  22. Carvalho, A. et al. Host defense pathways against fungi: the basis for vaccines and immunotherapy. Front. Microbiol. 3, 1–9 (2012).

    Article  Google Scholar 

  23. Zelante, T. et al. IL-17/Th17 in anti-fungal immunity: what's new? Eur. J. Immunol. 39, 645–648 (2009).

    Article  CAS  Google Scholar 

  24. Kaufmann, S. The contribution of immunology to the rational design of novel antibacterial vaccines. Nature Rev. Microbiol. 5, 491–504 (2007).

    Article  CAS  Google Scholar 

  25. Lin, L. et al. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathog. 5, e1000703 (2009).

    Article  Google Scholar 

  26. Spellberg, B. et al. Antibody titer threshold predicts anticandidal vaccine efficacy even though the mechanism of protection is induction of cell-mediated immunity. J. Infect. Dis. 197, 957–971 (2008).

    Article  Google Scholar 

  27. Luo, G. et al. Human anti-Als3p antibodies enhance phagocyte-mediated killing of C. albicans and S. aureus and prevent Als3 function. Abstract 178A in: 11th American Society for Microbiology Conference on Candida and Candidiasis (2012).

  28. Almond, J. W. Vaccine renaissance. Nature Rev. Microbiol. 5, 479–482 (2007).

    Article  Google Scholar 

  29. Kniemeyer, O. Schmidt, A. D., Vödisch, M. Wartenberg, D. & Brakhage, A. A. Identification of virulence determinants of the human pathogenic fungi Aspergillus fumigatus and Candida albicans by proteomics. Int. J. Med. Microbiol. 301, 368–377 (2011).

    Article  Google Scholar 

  30. Mayer, F. L., Wilson, D. & Hube, B. Candida albicans pathogenicity mechanisms. Virulence 42, 1–10 (2013).

    Google Scholar 

  31. Lesiak-Markowicz, I. et al. Candida albicans Hgt1p, a multifunctional evasion molecule: complement inhibitory, CR3 analogue and human immunodeficiency virus-binding molecule. J. Infect. Dis. 204, 802–809 (2009).

    Article  Google Scholar 

  32. Luo, S., Hoffmann, R., Sharka, C. & Zipfel, P. E. Glycerol-3-phosphate dehydrogenase 2 is a novel factor H-,factor H-like protein 1-, and plasminogen-binding surface protein of Candida albicans. J. Infect. Dis. 207, 594–603 (2013).

    Article  CAS  Google Scholar 

  33. Frohner, I. E., Bourgeois, C., Yatsik, K., Mayer, O. & Kuchler, K. Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immunity surveillance. Mol. Microbiol. 71, 240–252 (2009).

    Article  CAS  Google Scholar 

  34. Cheng, S. et al. Candida albicans dampens host defence by downregulating IL-17 production. J. Immunol. 185, 2450–2457 (2010).

    Article  CAS  Google Scholar 

  35. Zelante, T. et al. Sensing of mammalian IL-17A regulates fungal adaptation and virulence. Nature Commun. 3, 683–687 (2013).

    Article  Google Scholar 

  36. Bromuro, C. et al. Interplay between protective and inhibitory antibodies dictates the outcome of experimentally disseminated candidiasis in recipients of a Candida albicans vaccine. Infect. Immun. 70, 5462–5470 (2002).

    Article  CAS  Google Scholar 

  37. Cutler, J. E., Corti, M., Lambert, P., Ferris, M. & Xin, H. Horizontal transmission of Candida albicans and evidence for a vaccine response in mice colonized with the fungus. PLoS ONE 6, e22030 (2011).

    Article  CAS  Google Scholar 

  38. Moffitt, K. L. & Malley, R. Next generation pneumococcal vaccines. Curr. Opin. Immunol. 145, 277–286 (2011).

    Google Scholar 

  39. Guiso, N. Bordetella pertussis and pertussis vaccines. Clin. Infect. Dis. 49, 1565–1569 (2009).

    Article  Google Scholar 

  40. Amdahl, H. et al. Interactions between Bordetella pertussis and the complement inhibitor factor H. Mol. Immunol. 48, 697–705 (2011).

    Article  CAS  Google Scholar 

  41. Plotkin, S. A. & Orenstein, W. A. (eds) Vaccines (Saunders, 1999).

  42. Liu, M. et al. Immune responses induced by heat-killed Saccharomyces cerevisiae: a vaccine against fungal infection. Vaccine 29, 1745–1753 (2011).

    Article  CAS  Google Scholar 

  43. Cheng, S., Joosten, L. A. B., Kullberg, B. & Netea, M. G. Interplay between Candida albicans and the mammalian innate host defense. Infect. Immun. 80, 1304–1313 (2012).

    Article  CAS  Google Scholar 

  44. Nanjappa, S. G., Henninger, E., Wuthrich, M., Gasper, D. J. & Klein, B. S. Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune-deficient hosts lacking CD4+T cells. PLoS Pathog. 8, e1002771 (2012).

    Article  CAS  Google Scholar 

  45. Hung, C. Y., Gonzales, A., Wuthrich, M., Klein, B. S. & Cole, G. T. Vaccine immunity to coccidiodomycosis occurs by early activation of three signal pathways of T helper cell responses (Th1,Th2 and Th17). Infect. Immun. 79, 4511–4522 (2011).

    Article  CAS  Google Scholar 

  46. Bistoni, F. et al. Evidence for macrophage-mediated protection against lethal Candida albicans infection. Infect. Immun. 51, 668–674 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Saville, S. P. et al. Efficacy of a genetically engineered Candida albicans tet-NRG1 strain as an experimental live attenuated vaccine against hemathogeneously disseminated candidiasis. Clin. Vaccine Immunol. 16, 430–432 (2009).

    Article  CAS  Google Scholar 

  48. Ahmad, E., Fatima, M. T., Salemeddin, M. & Owais, M. Plasma beads loaded with Candida albicans cytosolic proteins impart protection against the fungal infection in Balb/c mice. Vaccine 30, 6851–6858 (2012).

    Article  CAS  Google Scholar 

  49. Salgado, P. S. et al. Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans. Proc. Natl Acad. Sci. USA 108, 15775–15779 (2011).

    Article  CAS  Google Scholar 

  50. Aoki, W. et al. Comprehensive characterization of secreted aspartic proteases encoded by a virulence gene family in Candida albicans. J. Biochem. 150, 431–438 (2011).

    Article  CAS  Google Scholar 

  51. Villar, C. C. et al. Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p. Infect. Immun. 75, 2126–2135 (2007).

    Article  CAS  Google Scholar 

  52. Liu, Y. & Filler, S. G. Candida albicans Als3, a multifunctional adhesin and invasin. Eukaryot. Cell 10, 168–173 (2011).

    Article  Google Scholar 

  53. Gropp, K. et al. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol. Immunol. 47, 463–475 (2009).

    Article  Google Scholar 

  54. Pietrella, D. et al. Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome. Eur. J. Immunol. 43, 679–692 (2013).

    Article  CAS  Google Scholar 

  55. Vilanova, M. et al. Protection against systemic candidiasis in mice immunized with secreted aspartic proteinase 2. Immunology. 111, 334–342 (2004).

    Article  CAS  Google Scholar 

  56. Luo, G. et al. Candida albicans Hyr1p confers resistance to neutrophil killing and is a potential vaccine target. J. Infect. Dis. 201, 1718–1728 (2019).

    Article  Google Scholar 

  57. Johnson, M. A. & Bundle, D. R. Designing a new antifungal glycoconjugate vaccine. Chem. Soc. Rev. 42, 4327–4344 (2012).

    Article  Google Scholar 

  58. Torosantucci, A. et al. Protection by anti-β-glucan antibodies is associated with restricted β-1,3 glucan binding specificity and inhibition of fungal growth and adherence. PLoS ONE 4, e5392 (2009).

    Article  Google Scholar 

  59. Cassone, A. Bromuro, C., Chiani, P. & Torosantucci, A. Hyr1 protein and β-glucan conjugates as anti-Candida vaccines. J. Infect. Dis. 202, 1930 (2010).

    Article  Google Scholar 

  60. Xin, U. et al. Self-adjuvanting glycopeptide conjugate vaccine against disseminated candidiasis. PLoS ONE 7, e35106 (2012).

    Article  CAS  Google Scholar 

  61. Lipinski, T. et al. Enhanced immunogenicity of a tricomponent mannan tetanus toxoid conjugate vaccine targeted to dendritic cells via dectin-1 by incorporating β-glucan J. Immunol. 190, 4116–4128 (2013).

    Article  CAS  Google Scholar 

  62. Li, W. Long, K. & Gao, X. Adjuvanticity of recombinant calreticulin fragment 39–372 in assisting anti- β-glucan IgG responses in T cell deficient mice. Clin. Vacc. Immunol. 20, 582–597 (2013).

    Article  CAS  Google Scholar 

  63. Cutfield, S. M. et al. The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors. Structure 3, 1261–1271 (1995).

    Article  CAS  Google Scholar 

  64. Calugi, C. et al. Bicyclic peptidomimetics targeting secreted aspartic protease 2 (SAP2) from Candida albicans reveal a constrained inhibitory chemotype. Bioorgan. Med. Chem. 20, 7206–7213 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The author is very grateful to several people who provided suggestions, critiques and materials for this Opinion article. E. Cota, A. Trabocchi and A. R. Stringaro kindly provided images for the figures. He is also greatly indebted to A. Torosantucci for the inspiration for the cell wall schemes in figure 1 and for many helpful discussions on the subject of this Opinion article, as well as to P. Chiani and C. Bromuro for their invaluable research and technical activity. A. Marella helped in the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Antonio Cassone is at the Department of Experimental Medicine and Biochemical Sciences, Medical School, University of Perugia, Perugia 06126, Italy.,

    Antonio Cassone

Authors
  1. Antonio Cassone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio Cassone.

Ethics declarations

Competing interests

A.C. is a fungal vaccine patent holder and consultant.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cassone, A. Development of vaccines for Candida albicans: fighting a skilled transformer. Nat Rev Microbiol 11, 884–891 (2013). https://doi.org/10.1038/nrmicro3156

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro3156

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology