Journal of Clinical Immunology

, Volume 29, Issue 2, pp 151–157 | Cite as

Human Immune Memory to Yellow Fever and Smallpox Vaccination

  • Jens Wrammert
  • Joe Miller
  • Rama Akondy
  • Rafi Ahmed



Establishment of immunological memory is a hallmark of adaptive immune responses and the biological mechanism for the success of vaccines. However, in humans, much of our knowledge about adaptive immune responses derives from studies of chronic viral infections.


Here, we summarize the work of our laboratory and others on B and T cell responses and the establishment and maintenance of immune memory after acute viral infections induced by vaccination with two of the most successful vaccines to date, the yellow fever and the smallpox vaccines.


B cells T cells vaccine immunological memory human 


  1. 1.
    Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to common viral and vaccine antigens. N Engl J Med 2007;357:1903–15. doi:10.1056/NEJMoa066092.PubMedCrossRefGoogle Scholar
  2. 2.
    Amanna IJ, Slifka MK, Crotty S. Immunity and immunological memory following smallpox vaccination. Immunol Rev 2006;211:320–37. doi:10.1111/j.0105-2896.2006.00392.x.PubMedCrossRefGoogle Scholar
  3. 3.
    Crotty S, Felgner P, Davies H, Glidewell J, Villarreal L, Ahmed R. Cutting edge: long-term B cell memory in humans after smallpox vaccination. J Immunol 2003;171:4969–73.PubMedGoogle Scholar
  4. 4.
    Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, Hanifin JM, Slifka MK. Duration of antiviral immunity after smallpox vaccination. Nat Med 2003;9:1131–7. doi:10.1038/nm917.PubMedCrossRefGoogle Scholar
  5. 5.
    Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science 1996;272:54–60. doi:10.1126/science.272.5258.54.PubMedCrossRefGoogle Scholar
  6. 6.
    Miller JD, van der Most RG, Akondy RS, Glidewell JT, Albott S, Masopust D, Murali-Krishna K, Mahar PL, Edupuganti S, Lalor S, Germon S, Del Rio C, Mulligan MJ, Staprans SI, Altman JD, Feinberg MB, Ahmed R. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 2008;28:710–22. doi:10.1016/j.immuni.2008.02.020.PubMedCrossRefGoogle Scholar
  7. 7.
    Davies DH, Liang X, Hernandez JE, Randall A, Hirst S, Mu Y, Romero KM, Nguyen TT, Kalantari-Dehaghi M, Crotty S, Baldi P, Villarreal LP, Felgner PL. Profiling the humoral immune response to infection by using proteome microarrays: high-throughput vaccine and diagnostic antigen discovery. Proc Natl Acad Sci U S A 2005;102:547–52. doi:10.1073/pnas.0408782102.PubMedCrossRefGoogle Scholar
  8. 8.
    Davies DH, McCausland MM, Valdez C, Huynh D, Hernandez JE, Mu Y, Hirst S, Villarreal L, Felgner PL, Crotty S. Vaccinia virus H3L envelope protein is a major target of neutralizing antibodies in humans and elicits protection against lethal challenge in mice. J Virol 2005;79:11724–33. doi:10.1128/JVI.79.18.11724-11733.2005.PubMedCrossRefGoogle Scholar
  9. 9.
    Davies DH, Molina DM, Wrammert J, Miller J, Hirst S, Mu Y, Pablo J, Unal B, Nakajima-Sasaki R, Liang X, Crotty S, Karem KL, Damon IK, Ahmed R, Villarreal L, Felgner PL. Proteome-wide analysis of the serological response to vaccinia and smallpox. Proteomics 2007;7:1678–86. doi:10.1002/pmic.200600926.PubMedCrossRefGoogle Scholar
  10. 10.
    Talbot PJ, Buchmeier MJ. Catabolism of homologous murine monoclonal hybridoma IgG antibodies in mice. Immunology 1987;60:485–9.PubMedGoogle Scholar
  11. 11.
    Vieira P, Rajewsky K. The half-lives of serum immunoglobulins in adult mice. Eur J Immunol 1988;18:313–6. doi:10.1002/eji.1830180221.PubMedCrossRefGoogle Scholar
  12. 12.
    Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A. Survival of long-lived plasma cells is independent of antigen. Int Immunol 1998;10:1703–11. doi:10.1093/intimm/10.11.1703.PubMedCrossRefGoogle Scholar
  13. 13.
    Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature 1997;388:133–4. doi:10.1038/40540.PubMedCrossRefGoogle Scholar
  14. 14.
    McMillan R, Longmire RL, Yelenosky R, Lang JE, Heath V, Craddock CG. Immunoglobulin synthesis by human lymphoid tissues: normal bone marrow as a major site of IgG production. J Immunol 1972;109:1386–94.PubMedGoogle Scholar
  15. 15.
    Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity 1998;8:363–72. doi:10.1016/S1074-7613(00)80541-5.PubMedCrossRefGoogle Scholar
  16. 16.
    Cassese G, Lindenau S, de Boer B, Arce S, Hauser A, Riemekasten G, Berek C, Hiepe F, Krenn V, Radbruch A, Manz RA. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur J Immunol 2001;31:2726–32. doi:10.1002/1521-4141(200109)31:9<2726::AID-IMMU2726>3.0.CO;2-H.PubMedCrossRefGoogle Scholar
  17. 17.
    Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, Dorner T, Hiepe F. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 2006;6:741–50. doi:10.1038/nri1886.PubMedCrossRefGoogle Scholar
  18. 18.
    Terstappen LW, Johnsen S, Segers-Nolten IM, Loken MR. Identification and characterization of plasma cells in normal human bone marrow by high-resolution flow cytometry. Blood 1990;76:1739–47.PubMedGoogle Scholar
  19. 19.
    Cooper EH. Production of lymphocytes and plasma cells in the rat following immunization with human serum albumin. Immunology 1961;4:219–31.PubMedGoogle Scholar
  20. 20.
    Levy M, Vieira P, Coutinho A, Freitas A. The majority of “natural” immunoglobulin-secreting cells are short-lived and the progeny of cycling lymphocytes. Eur J Immunol 1987;17:849–54. doi:10.1002/eji.1830170618.PubMedCrossRefGoogle Scholar
  21. 21.
    Makela O, Nossal GJ. Autoradiographic studies on the immune response. II. DNA synthesis amongst single antibody-producing cells. J Exp Med 1962;115:231–44. doi:10.1084/jem.115.1.231.PubMedCrossRefGoogle Scholar
  22. 22.
    Nossal GJ, Makela O. Autoradiographic studies on the immune response.I. The kinetics of plasma cell proliferation. J Exp Med 1962;115:209–30. doi:10.1084/jem.115.1.209.PubMedCrossRefGoogle Scholar
  23. 23.
    Schooley JC. Autoradiographic observations of plasma cell formation. J Immunol 1961;86:331–7.PubMedGoogle Scholar
  24. 24.
    Slifka MK, Ahmed R. Long-term humoral immunity against viruses: revisiting the issue of plasma cell longevity. Trends Microbiol 1996;4:394–400. doi:10.1016/0966-842X(96)10059-7.PubMedCrossRefGoogle Scholar
  25. 25.
    Bernasconi NL, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 2002;298:2199–202. doi:10.1126/science.1076071.PubMedCrossRefGoogle Scholar
  26. 26.
    Di Genova G, Roddick J, McNicholl F, Stevenson FK. Vaccination of human subjects expands both specific and bystander memory T cells but antibody production remains vaccine specific. Blood 2006;107:2806–13. doi:10.1182/blood-2005-08-3255.PubMedCrossRefGoogle Scholar
  27. 27.
    Nanan R, Heinrich D, Frosch M, Kreth HW. Acute and long-term effects of booster immunisation on frequencies of antigen-specific memory B-lymphocytes. Vaccine 2001;20:498–504. doi:10.1016/S0264-410X(01)00328-0.PubMedCrossRefGoogle Scholar
  28. 28.
    Odendahl M, Mei H, Hoyer BF, Jacobi AM, Hansen A, Muehlinghaus G, Berek C, Hiepe F, Manz R, Radbruch A, Dorner T. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 2005;105:1614–21. doi:10.1182/blood-2004-07-2507.PubMedCrossRefGoogle Scholar
  29. 29.
    Sakai A, Takikawa S, Thimme R, Meunier JC, Spangenberg HC, Govindarajan S, Farci P, Emerson SU, Chisari FV, Purcell RH, Bukh J. In vivo study of the HC-TN strain of hepatitis C virus recovered from a patient with fulminant hepatitis: RNA transcripts of a molecular clone (pHC-TN) are infectious in chimpanzees but not in Huh7.5 cells. J Virol 2007;81:7208–19. doi:10.1128/JVI.01774-06.PubMedCrossRefGoogle Scholar
  30. 30.
    Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C, Govindarajan S, Purcell RH, Chisari FV. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A 2002;99:15661–8. doi:10.1073/pnas.202608299.PubMedCrossRefGoogle Scholar
  31. 31.
    Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003;77:68–76. doi:10.1128/JVI.77.1.68-76.2003.PubMedCrossRefGoogle Scholar
  32. 32.
    Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996;272:1947–50. doi:10.1126/science.272.5270.1947.PubMedCrossRefGoogle Scholar
  33. 33.
    Tough DF, Sprent J. Bystander stimulation of T cells in vivo by cytokines. Vet Immunol Immunopathol 1998;63:123–9. doi:10.1016/S0165-2427(98)00088-9.PubMedCrossRefGoogle Scholar
  34. 34.
    Tough DF, Sun S, Sprent J. T cell stimulation in vivo by lipopolysaccharide (LPS). J Exp Med 1997;185:2089–94. doi:10.1084/jem.185.12.2089.PubMedCrossRefGoogle Scholar
  35. 35.
    Murali-Krishna K, Altman JD, Suresh M, Sourdive DJ, Zajac AJ, Miller JD, Slansky J, Ahmed R. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 1998;8:177–87. doi:10.1016/S1074-7613(00)80470-7.PubMedCrossRefGoogle Scholar
  36. 36.
    Terajima M, Cruz J, Raines G, Kilpatrick ED, Kennedy JS, Rothman AL, Ennis FA. Quantitation of CD8+ T cell responses to newly identified HLA-A*0201-restricted T cell epitopes conserved among vaccinia and variola (smallpox) viruses. J Exp Med 2003;197:927–32. doi:10.1084/jem.20022222.PubMedCrossRefGoogle Scholar
  37. 37.
    Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001;410:106–11. doi:10.1038/35065118.PubMedCrossRefGoogle Scholar
  38. 38.
    Barouch DH, Letvin NL. CD8+ cytotoxic T lymphocyte responses to lentiviruses and herpesviruses. Curr Opin Immunol 2001;13:479–82. doi:10.1016/S0952-7915(00)00244-2.PubMedCrossRefGoogle Scholar
  39. 39.
    Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O'Callaghan CA, Steven N, McMichael AJ, Rickinson AB. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med 1998;187:1395–402. doi:10.1084/jem.187.9.1395.PubMedCrossRefGoogle Scholar
  40. 40.
    Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RA. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997;186:1407–18. doi:10.1084/jem.186.9.1407.PubMedCrossRefGoogle Scholar
  41. 41.
    Lauer GM, Ouchi K, Chung RT, Nguyen TN, Day CL, Purkis DR, Reiser M, Kim AY, Lucas M, Klenerman P, Walker BD. Comprehensive analysis of CD8(+)-T-cell responses against hepatitis C virus reveals multiple unpredicted specificities. J Virol 2002;76:6104–13. doi:10.1128/JVI.76.12.6104-6113.2002.PubMedCrossRefGoogle Scholar
  42. 42.
    Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000;191:1499–512. doi:10.1084/jem.191.9.1499.PubMedCrossRefGoogle Scholar
  43. 43.
    McMichael AJ, Rowland-Jones SL. Cellular immune responses to HIV. Nature 2001;410:980–7. doi:10.1038/35073658.PubMedCrossRefGoogle Scholar
  44. 44.
    Roos MT, van Lier RA, Hamann D, Knol GJ, Verhoofstad I, van Baarle D, Miedema F, Schellekens PT. Changes in the composition of circulating CD8+ T cell subsets during acute epstein-barr and human immunodeficiency virus infections in humans. J Infect Dis 2000;182:451–8. doi:10.1086/315737.PubMedCrossRefGoogle Scholar
  45. 45.
    Tan LC, Gudgeon N, Annels NE, Hansasuta P, O'Callaghan CA, Rowland-Jones S, McMichael AJ, Rickinson AB, Callan MF. A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol 1999;162:1827–35.PubMedGoogle Scholar
  46. 46.
    Urbani S, Boni C, Missale G, Elia G, Cavallo C, Massari M, Raimondo G, Ferrari C. Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C. J Virol 2002;76:12423–34. doi:10.1128/JVI.76.24.12423-12434.2002.PubMedCrossRefGoogle Scholar
  47. 47.
    van Leeuwen EM, Gamadia LE, Baars PA, Remmerswaal EB, ten Berge IJ, van Lier RA. Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+ T cells. J Immunol 2002;169:5838–43.PubMedGoogle Scholar
  48. 48.
    Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 2002;8:379–85. doi:10.1038/nm0402-379.PubMedCrossRefGoogle Scholar
  49. 49.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–12. doi:10.1038/44385.PubMedCrossRefGoogle Scholar
  50. 50.
    Tomiyama H, Takata H, Matsuda T, Takiguchi M. Phenotypic classification of human CD8+ T cells reflecting their function: inverse correlation between quantitative expression of CD27 and cytotoxic effector function. Eur J Immunol 2004;34:999–1010. doi:10.1002/eji.200324478.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jens Wrammert
    • 1
  • Joe Miller
    • 1
  • Rama Akondy
    • 1
  • Rafi Ahmed
    • 1
  1. 1.Emory Vaccine CenterEmory UniversityAtlantaUSA

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