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Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology

Nature Reviews Immunology volume 9, pages 741–747 (2009)Cite this article

Abstract

Despite their great success, we understand little about how effective vaccines stimulate protective immune responses. Two recent developments promise to yield such understanding: the appreciation of the crucial role of the innate immune system in sensing microorganisms and tuning immune responses, and advances in systems biology. Here I review how these developments are yielding insights into the mechanism of action of the yellow fever vaccine, one of the most successful vaccines ever developed, and the broader implications for vaccinology.

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Figure 1: Immune responses to YF-17D.
Figure 2: Innate correlates of YF-17D immunogenicity identified by systems biological approaches.
Figure 3: Predictive signatures of gene expression for other vaccines.
Figure 4: The vaccine chip.

References

  1. Monath, T. P. in Microbe Hunters — Then and Now (eds Oldstone, M. & Koprowski, H.) 95–111 (Medi-Ed, Bloomington, Illinois, 1996).

    Google Scholar 

  2. Monath, T. P. Yellow fever vaccine. Expert Rev. Vaccines 4, 553–574 (2005).

    Article  CAS  Google Scholar 

  3. Barrett, A. D. T. & Teuwen, D. Yellow fever vaccine — how does it work and why do rare cases of serious adverse events take place? Curr. Opin. Immunol. 21, 1–6 (2009).

  4. Theiler, M. & Smith, H. H. The effect of prolonged cultivation in vitro upon the pathogenicity of yellow fever virus. J. Exp. Med. 65, 767–786 (1937).

    Article  CAS  Google Scholar 

  5. Theiler, M. & Smith, H. H. The use of yellow fever virus modified by in vitro cultivation for human immunization. J. Exp. Med. 65, 787–800 (1937).

    Article  CAS  Google Scholar 

  6. Hahn, C. S., Dalrymple, J. M., Strauss, J. M. & Rice, C. M. Comparison of the virulent Asibi strain of yellow fever virus with the 17D vaccine strain derived from it. Proc. Natl Acad. Sci. USA 84, 2019–2023 (1987).

    Article  CAS  Google Scholar 

  7. Ryman, K. D., Xie, H., Ledger, T. N., Campbell, G. A. & Barrett, A. D. Antigenic variants of yellow fever virus with an altered neurovirulence phenotype in mice. Virology 230, 376–380 (1997).

    Article  CAS  Google Scholar 

  8. Guirakhoo, F. et al. A single amino acid substitution in the envelope protein of chimeric yellow fever-dengue 1 vaccine virus reduces neurovirulence for suckling mice and viremia/viscerotropism for monkeys. J. Virol. 78, 9998–10008 (2004).

    Article  CAS  Google Scholar 

  9. Monath, T. P. et al. Single mutation in the flavivirus envelope protein hinge region increases neurovirulence for mice and monkeys but decreases viscerotropism for monkeys: relevance to development and safety testing of live, attenuated vaccines. J. Virol. 76, 1932–1943 (2002).

    Article  CAS  Google Scholar 

  10. Schlesinger, J. J. et al. Replication of yellow fever virus in the mouse central nervous system: comparison of neuroadapted and non-neuroadapted virus and partial sequence analysis of the neuroadapted strain. J. Gen. Virol. 77, 1277–1285 (1996).

    Article  CAS  Google Scholar 

  11. Reinhardt, B., Jaspert, R., Niedrig, M., Kostner, C. & L'Age-Stehr, J. Development of viremia and humoral and cellular parameters of immune activation after vaccination with yellow fever virus strain 17D: a model of human flavivirus infection. J. Med. Virol. 56, 159–167 (1998).

    Article  CAS  Google Scholar 

  12. Co, M. D., Terajima, M., Cruz, J., Ennis, F. A. & Rothman, A. L. Human cytotoxic T lymphocyte responses to live attenuated 17D yellow fever vaccine: identification of HLA-B35-restricted CTL epitopes on nonstructural proteins NS1, NS2b, NS3, and the structural protein E. Virology 293, 151–163 (2002).

    Article  CAS  Google Scholar 

  13. Miller, J. D. et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28, 710–722 (2008).

    Article  CAS  Google Scholar 

  14. David-West, T. S. Concurrent and consecutive infection and immunisations with yellow fever and UGMP-359 viruses. Arch. Virol. 48, 21–28 (1975).

    Article  CAS  Google Scholar 

  15. Sabin, A. B. Research on dengue during World War II. Am. J. Trop. Med. Hyg. 1, 30–50 (1952).

    Article  CAS  Google Scholar 

  16. Takeuchi, O. & Akira, S. Innate immunity to virus infection. Immunol. Rev. 227, 75–86 (2009).

    Article  CAS  Google Scholar 

  17. Steinman, R. M. & Banchereau, J. Taking dendritic cells into medicine. Nature 449, 419–426 (2007).

    Article  CAS  Google Scholar 

  18. Pulendran, B. Variegation of the immune response with dendritic cells and pathogen recognition receptors. J. Immunol. 174, 2457–2465 (2005).

    Article  CAS  Google Scholar 

  19. Querec, T. et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J. Exp. Med. 203, 413–424 (2006).

    Article  Google Scholar 

  20. Sarbassov, D. D., Ali, S. M. & Sabatini, D. M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17, 596–603 (2005).

    Article  CAS  Google Scholar 

  21. Cao, W. et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S76K pathway. Nature Immunol. 9, 1157–1164 (2008).

    Article  CAS  Google Scholar 

  22. Barba-Spaeth, G., Longman, R. S., Albert, M. L. & Rice, C. M. Live attenuated yellow fever 17D infects human DCs and allows for presentation of endogenous and recombinant T cell epitopes. J. Exp. Med. 202, 1179–1184 (2005).

    Article  CAS  Google Scholar 

  23. Palmer, D. R. et al. Restricted replication and lysosomal trafficking of yellow fever 17D vaccine virus in human dendritic cells. J. Gen. Virol. 88, 148–156 (2007).

    Article  CAS  Google Scholar 

  24. Popper, K. Conjectures and Refutations (Routledge and Keagan Paul, London, 1963).

    Google Scholar 

  25. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article  CAS  Google Scholar 

  26. Potti, A. et al. Genomic signatures to guide the use of chemotherapeutics. Nature Med. 12, 1294–1300 (2006).

    Article  CAS  Google Scholar 

  27. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    Article  CAS  Google Scholar 

  28. Ramilo, O. et al. Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109, 2066–2077 (2007).

    Article  CAS  Google Scholar 

  29. Chaussabel, D. et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 29, 150–164 (2008).

    Article  CAS  Google Scholar 

  30. Querec, T. D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nature Immunol. 10, 116–125 (2009).

    Article  CAS  Google Scholar 

  31. Gaucher, D. et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J. Exp. Med. 205, 3119–3131 (2008).

    Article  CAS  Google Scholar 

  32. Chen, J. P. et al. Dengue virus induces expression of CXC chemokine ligand 10/IFN-γ-inducible protein 10, which competitively inhibits viral binding to cell surface heparan sulfate. J. Immunol. 177, 3185–3192 (2006).

    Article  CAS  Google Scholar 

  33. Shirato, K., Kimura, T., Mizutani, T., Kariwa, H. & Takashima, I. Different chemokine expression in lethal and non-lethal murine West Nile virus infection. J. Med. Virol. 74, 507–513 (2004).

    Article  CAS  Google Scholar 

  34. Rothenfusser, S. et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J. Immunol. 175, 5260–5268 (2005).

    Article  CAS  Google Scholar 

  35. Zhao, F. Q. & Keating, A. F. Functional properties and genomics of glucose transporters. Curr. Genomics 8, 113–128 (2007).

    Article  CAS  Google Scholar 

  36. Richter, J. D. & Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433, 477–480 (2005).

    Article  CAS  Google Scholar 

  37. Kedersha, N. & Anderson, P. Mammalian stress granules and processing bodies. Methods Enzymol. 431, 61–81 (2007).

    Article  CAS  Google Scholar 

  38. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol. 8, 519–529 (2007).

    Article  CAS  Google Scholar 

  39. Kaufman, R. J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211–1233 (1999).

    Article  CAS  Google Scholar 

  40. Berlanga, J. J. et al. Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses. EMBO J. 25, 1730–1740 (2006).

    Article  CAS  Google Scholar 

  41. Woodland, R. T., Schmidt, M. R. & Thompson, C. B. BLyS and B cell homeostasis. Semin. Immunol. 18, 318–326 (2006).

    Article  CAS  Google Scholar 

  42. Khromava, A. Y. et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 23, 3256–3263 (2005).

    Article  Google Scholar 

  43. Galler, R., Pugachev, V., Santos, L. S., Ocran, S. W. & Monath, T. P. Phenotypic and molecular analyses of yellow fever 17DD vaccine viruses associated with serious adverse events in Brazil. Virology 290, 309–319 (2001).

    Article  CAS  Google Scholar 

  44. Bae, H. G. et al. Immune response during adverse events after 17D-derived yellow fever vaccination in Europe. J. Infect. Dis. 197, 1577–1584 (2008).

    Article  Google Scholar 

  45. Pulendran, B. et al. Case of yellow fever vaccine--associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes. J. Infect. Dis. 198, 500–507 (2008).

    Article  Google Scholar 

  46. Belsher, J. L. et al. Fatal multi-organ failure due to yellow fever vaccine associated viscerotropic disease. Vaccine 25, 8480–8485 (2007).

    Article  Google Scholar 

  47. Santos, A. P., Matos, D. C., Bertho, A. L., Mendonca, S. C. & Marcovistz, R. Detection of TH1/TH2 cytokine signatures in yellow fever 17DD first-time vaccinees through ELISpot assay. Cytokine 45, 152–155 (2008).

    Article  Google Scholar 

  48. Martins, M. A. et al. Innate immunity phenotypic features point towards simultaneous raise of activation and modulation events following 17DD live attenuated yellow fever first-time vaccination. Vaccine 26, 1173–1184 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

I thank the US National Institutes of Health and the Bill and Melinda Gates Foundation for their generous support of my work. I also thank several outstanding members of my laboratory, both past and present, for their contributions to this work. Finally, I thank R. Ahmed for all his encouragement and support.

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Authors and Affiliations

  1. Bali Pulendran is at the Emory Vaccine Center, Emory University, Atlanta, Georgia 30322, USA. bpulend@emory.edu,

    Bali Pulendran

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Bali Pulendran

Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology. Nature Reviews Immunology 2009 doi:10.1038/nri2629

Part of the work described in this review was funded by a research grant from Sanofi Pasteur, who manufacture the yellow fever vaccine.

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Pulendran, B. Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology. Nat Rev Immunol 9, 741–747 (2009). https://doi.org/10.1038/nri2629

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