Immunosenescence Modulation by Vaccination

  • Janet E. McElhaney


A decline in immune function is a hallmark of aging that leads to complicated illness from a variety of infectious diseases, cancer and other immune-mediated disorders, and may limit the ability to appropriately respond to vaccination. How vaccines might alter the senescent immune response and what are the immune correlates of protection will be addressed from the perspective of 1) stimulating a previously primed response as in the case of vaccines for seasonal influenza and herpes zoster, 2) priming the response to novel antigens such as pandemic influenza or other viruses, 3) vaccination against bacterial pathogens such as pneumococcus, and 4) altering the immune response to an endogenous protein as in the case of a vaccine against Alzheimer’s disease. In spite of the often limited efficacy of vaccines for older adults, influenza vaccination remains the only cost-saving medical intervention in this population. Thus, considerable opportunity exists to improve current vaccines and develop new vaccines as a preventive approach to a variety of diseases in older adults. Strategies for selecting appropriate immunologic targets for new vaccine development and evaluating how vaccines may alter the senescent immune response in terms of potential benefits and risks in the preclinical and clinical trial phases of vaccine development will be discussed.

Vaccination Correlates of protection Helper T-cells Cytotoxic T-lymphocytes Antibodies Cytokines Granzyme B Influenza Herpes zoster Pneumococcus Alzheimer’s disease 


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  1. 1.
    Thompson WW, Shay DK, Weintraub E et al (2004) Influenza-associated hospitalizations in the United States. JAMA 292:1333–1340PubMedGoogle Scholar
  2. 2.
    Thompson WW, Shay DK, Weintraub E et al (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179–186PubMedGoogle Scholar
  3. 3.
    Govaert TM, Sprenger MJ, Dinant GJ, Aretz K, Masurel N, Knottnerus JA (1994) Immune response to influenza vaccination of elderly people. A randomized double-blind placebocontrolled trial. Vaccine 12:1185–1189PubMedGoogle Scholar
  4. 4.
    Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T (1994) The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 331:778–784PubMedGoogle Scholar
  5. 5.
    Vu T, Farish S, Jenkins M, Kelly H (2002) A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community. Vaccine 20:1831–1836PubMedGoogle Scholar
  6. 6.
    Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M (2003) Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 348:1322–1332PubMedGoogle Scholar
  7. 7.
    Nichol KL (2003) The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 21:1769–1775PubMedGoogle Scholar
  8. 8.
    Virelizier JL, Postlethwaite R, Schild GC, Allison AC (1974) Antibody responses to antigenic determinants of influenza virus hemagglutinin. I. Thymus dependence of antibody formation and thymus independence of immunological memory. J Exp Med 140:1559–1570PubMedGoogle Scholar
  9. 9.
    Goodwin K, Viboud C, Simonsen L (2005) Antibody response to influenza vaccination in the elderly: A quantitative review. VaccineGoogle Scholar
  10. 10.
    de Bruijn IA, Remarque EJ, Beyer WE, le Cessie S, Masurel N, Ligthart GJ (1997) Annually repeated influenza vaccination improves humoral responses to several influenza virus strains in healthy elderly. Vaccine 15:1323–1329PubMedGoogle Scholar
  11. 11.
    de Bruijn IA, Remarque EJ, Jol-van der Zijde CM, van Tol MJ, Westendorp RG, Knook DL (1999) Quality and quantity of the humoral immune response in healthy elderly and young subjects after annually repeated influenza vaccination. J Infect Dis 179:31–36PubMedGoogle Scholar
  12. 12.
    Keitel WA, Cate TR, Couch RB (1988) Efficacy of sequential annual vaccination with inactivated influenza virus vaccine. Am J Epidemiol 127:353–364PubMedGoogle Scholar
  13. 13.
    Ahmed AE, Nicholson KG, Nguyen-Van-Tam JS (1995) Reduction in mortality associated with influenza vaccine during 1989–90 epidemic. Lancet 346:591–595PubMedGoogle Scholar
  14. 14.
    Voordouw AC, Sturkenboom MC, Dieleman JP et al (2004) Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. JAMA 292:2089–2095PubMedGoogle Scholar
  15. 15.
    Skowronski DM, Tweed SA, De Serres G Rapid decline of influenza vaccine-induced antibody in the elderly: is it real, is it relevant? J Infect Dis. In pressGoogle Scholar
  16. 16.
    Effros RB (2007) Role of T lymphocyte replicative senescence in vaccine efficacy. Vaccine 25:599–604PubMedGoogle Scholar
  17. 17.
    McElhaney JE, Xie D, Hager WD et al (2006) T cell responses are better correlates of vaccine protection in the elderly. J Immunol 176:6333–6339PubMedGoogle Scholar
  18. 18.
    Murasko DM, Bernstein ED, Gardner EM et al (2002) Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly. Exp Gerontol 37:427–439PubMedGoogle Scholar
  19. 19.
    Effros RB, Doherty PC, Gerhard W, Bennink J (1977) Generation of both cross-reactive and virus-specific T-cell populations after immunization with serologically distinct influenza A viruses. J Exp Med 145:557–568PubMedGoogle Scholar
  20. 20.
    Butchko GM, Armstrong RB, Ennis FA (1978) Specificity studies on the proliferative response of thymus-derived lymphocytes to influenza viruses. J Immunol 121:2381–2385PubMedGoogle Scholar
  21. 21.
    Russell SM, Liew FY (1979) T cells primed by influenza virion internal components can cooperate in the antibody response to haemagglutinin. Nature 280:147–148PubMedGoogle Scholar
  22. 22.
    Mitchell DM, Callard RE (1983) Fine specificity of the in vitro antibody response to influenza virus by human blood lymphocytes. J Immunol 131:1229–1233PubMedGoogle Scholar
  23. 23.
    Nguyen HH, Moldoveanu Z, Novak MJ et al (1999) Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8(+) cytotoxic T lymphocyte responses induced in mucosa-associated tissues. Virology 254:50–60PubMedGoogle Scholar
  24. 24.
    Benacerraf B (1981) Role of MHC gene products in immune regulation. Science 212:1229–1238PubMedGoogle Scholar
  25. 25.
    Hackett CJ, Eisenlohr LC (1990) Virus entry and antigen biosynthesis in the processing and presentation of class-II MHC-restricted T-cell determinants of influenza virus. Immunol Res 9:103–114PubMedGoogle Scholar
  26. 26.
    Ennis FA, Rook AH, Qi YH et al (1981) HLA restricted virus-specific cytotoxic T-lymphocyte responses to live and inactivated influenza vaccines. Lancet 2:887–891PubMedGoogle Scholar
  27. 27.
    Demotz S, Grey HM, Sette A (1990) The minimal number of class II MHC-antigen complexes needed for T cell activation. Science 249:1028–1030PubMedGoogle Scholar
  28. 28.
    Hackett CJ, Yewdell JW, Bennink JR, Wysocka M (1991) Class II MHC-restricted T cell determinants processed from either endosomes or the cytosol show similar requirements for host protein transport but different kinetics of presentation. J Immunol 146:2944–2951PubMedGoogle Scholar
  29. 29.
    Lamb CA, Yewdell JW, Bennink JR, Cresswell P (1991) Invariant chain targets HLA class II molecules to acidic endosomes containing internalized influenza virus. Proc Natl Acad Sci U S A 88:5998–6002PubMedGoogle Scholar
  30. 30.
    Askonas BA, Mullbacher A, Ashman RB (1982) Cytotoxic T-memory cells in virus infection and the specificity of helper T cells. Immunology 45:79–84PubMedGoogle Scholar
  31. 31.
    Hosaka Y, Sasao F, Yamanaka K, Bennink JR, Yewdell JW (1988) Recognition of noninfectious influenza virus by class I-restricted murine cytotoxic T lymphocytes. J Immunol 140:606–610PubMedGoogle Scholar
  32. 32.
    Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3:161–167PubMedGoogle Scholar
  33. 33.
    Huckriede A, Bungener L, Stegmann T et al (2005) The virosome concept for influenza vaccines. Vaccine 23 Suppl 1:S26-S38PubMedGoogle Scholar
  34. 34.
    Bright RA, Carter DM, Daniluka S et al (2007) Influenza virus-like particles elicit broader immune responses than whole virion inactivated influenza virus or recombinant hemagglutinin. Vaccine 25:3871–3878PubMedGoogle Scholar
  35. 35.
    Puig-Barbera J, Diez-Domingo J, Perez Hoyos S, Belenguer Varea A, Gonzalez Vidal D (2004) Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Vaccine 23:283–289PubMedGoogle Scholar
  36. 36.
    Ray SJ, Franki SN, Pierce RH et al (2004) The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. Immunity 20:167–179PubMedGoogle Scholar
  37. 37.
    Liang S, Mozdzanowska K, Palladino G, Gerhard W (1994) Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity. J Immunol 152:1653–1661PubMedGoogle Scholar
  38. 38.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357PubMedGoogle Scholar
  39. 39.
    Scherle PA, Gerhard W (1988) Differential ability of B cells specific for external vs. internal influenza virus proteins to respond to help from influenza virus- specific T-cell clones in vivo. Proc Natl Acad Sci U S A 85:4446–4450PubMedGoogle Scholar
  40. 40.
    Palladino G, Scherle PA, Gerhard W (1991) Activity of CD4+ T-cell clones of type 1 and type 2 in generation of influenza virus-specific cytotoxic responses in vitro. J Virol 65:6071–6076PubMedGoogle Scholar
  41. 41.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1b and 6 but not transforming growth factor-b are essential for the differentiation of interleukin 17–producing human T helper cells. Nat Immunol 8:942–949PubMedGoogle Scholar
  42. 42.
    Laurence A, O’Shea JJ (2007) TH-17 differentiation: of mice and men. Nat Immunol 8:903–905PubMedGoogle Scholar
  43. 43.
    McElhaney JE, Gravenstein S, Upshaw CM, Hooton JW, Krause P, Drinka P (1998) Immune response to influenza vaccination in institutionalized elderly: effect on different T-cell subsets. Vaccine 16:403–409PubMedGoogle Scholar
  44. 44.
    McElhaney JE, Upshaw CM, Hooton JW, Lechelt KE, Meneilly GS (1998) Responses to influenza vaccination in different T-cell subsets: a comparison of healthy young and older adults. Vaccine 16:1742–1747PubMedGoogle Scholar
  45. 45.
    Bernstein E, Kaye D, Abrutyn E, Gross P, Dorfman M, Murasko DM (1999) Immune response to influenza vaccination in a large healthy elderly population. Vaccine 17:82–94PubMedGoogle Scholar
  46. 46.
    McElhaney JE, Gravenstein S, Upshaw CM et al (2001) Granzyme B: A marker of risk for influenza in institutionalized older adults. Vaccine. In PressGoogle Scholar
  47. 47.
    Gardner EM, Murasko DM (2002) Age-related changes in Type 1 and Type 2 cytokine production in humans. Biogerontology 3:271–290PubMedGoogle Scholar
  48. 48.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852PubMedGoogle Scholar
  49. 49.
    Khader SA, Bell GK, Pearl JE et al (2007) IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8:369–377PubMedGoogle Scholar
  50. 50.
    Acosta-Rodriguez EV, Rivino L, Geginat J et al (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8:639–646PubMedGoogle Scholar
  51. 51.
    Gottesman SR, Walford RL, Thorbecke GJ (1985) Proliferative and cytotoxic immune functions in aging mice. III. Exogenous interleukin-2 rich supernatant only partially restores alloreactivity in vitro. Mech Ageing Dev 31:103–113PubMedGoogle Scholar
  52. 52.
    Canonica GW, Ciprandi G, Caria M et al (1985) Defect of autologous mixed lymphocyte reaction and interleukin-2 in aged individuals. Mech Ageing Dev 32:205–212PubMedGoogle Scholar
  53. 53.
    Wiedmeier SE, Araneo BA, Huang K, Daynes RA (1991) Thymic modulation of IL-2 and IL-4 synthesis by peripheral T cells. Cell Immunol 135:501–518PubMedGoogle Scholar
  54. 54.
    Powers DC, Belshe RB (1993) Effect of age on cytotoxic T lymphocyte memory as well as serum and local antibody responses elicited by inactivated influenza virus vaccine. J Infect Dis 167:584–592PubMedGoogle Scholar
  55. 55.
    Meyer KC (2001) The role of immunity in susceptibility to respiratory infection in the aging lung. Respir Physiol 128:23–31PubMedGoogle Scholar
  56. 56.
    Baumgarth N, Brown L, Jackson D, Kelso A (1994) Novel features of the respiratory tract T-cell response to influenza virus infection: lung T cells increase expression of gamma interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10. J Virol 68:7575–7581PubMedGoogle Scholar
  57. 57.
    Bot A, Smith KA, von Herrath M (2004) Molecular and cellular control of T1/T2 immunity at the interface between antimicrobial defense and immune pathology. DNA Cell Biol 23:341–350PubMedGoogle Scholar
  58. 58.
    Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169:4697–4701PubMedGoogle Scholar
  59. 59.
    Haynes L, Eaton SM, Burns EM, Rincon M, Swain SL (2004) Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J Immunol 172:5194–5199PubMedGoogle Scholar
  60. 60.
    Glaser R, Robles TF, Sheridan J, Malarkey WB, Kiecolt-Glaser JK (2003) Mild depressive symptoms are associated with amplified and prolonged inflammatory responses after influenza virus vaccination in older adults. Arch Gen Psychiatry 60:1009–1014PubMedGoogle Scholar
  61. 61.
    Kimura A, Naka T, Kishimoto T (2007) IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci U S AGoogle Scholar
  62. 62.
    Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedGoogle Scholar
  63. 63.
    McMichael AJ, Gotch FM, Noble GR, Beare PA (1983) Cytotoxic T-cell immunity to influenza. N Engl J Med 309:13–17PubMedGoogle Scholar
  64. 64.
    Pasternack MS, Eisen HN (1985) A novel serine esterase expressed by cytotoxic T lymphocytes. Nature 314:743–745PubMedGoogle Scholar
  65. 65.
    Bleackley RC, Lobe CG, Duggan B et al (1988) The isolation and characterization of a family of serine protease genes expressed in activated cytotoxic T lymphocytes. Immunol Rev 103:5–19PubMedGoogle Scholar
  66. 66.
    Jenne DE, Tschopp J (1988) Granzymes, a family of serine proteases released from granules of cytolytic T lymphocytes upon T cell receptor stimulation. Immunol Rev 103:53–71PubMedGoogle Scholar
  67. 67.
    Ito T, Gorman OT, Kawaoka Y, Bean WJ, Webster RG (1991) Evolutionary analysis of the influenza A virus M gene with comparison of the M1 and M2 proteins. J Virol 65:5491–5498PubMedGoogle Scholar
  68. 68.
    Rouvier E, Luciani MF, Golstein P (1993) Fas involvement in Ca(2+)-independent T cellmediated cytotoxicity. J Exp Med 177:195–200PubMedGoogle Scholar
  69. 69.
    Doherty PC, Topham DJ, Tripp RA, Cardin RD, Brooks JW, Stevenson PG (1997) Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev 159:105–117PubMedGoogle Scholar
  70. 70.
    McMichael AJ, Gotch FM, Dongworth DW, Clark A, Potter CW (1983) Declining T-cell immunity to influenza, 1977-82. Lancet 2:762–764PubMedGoogle Scholar
  71. 71.
    Gorse GJ, Belshe RB (1990) Enhancement of antiinfluenza A virus cytotoxicity following influenza A virus vaccination in older, chronically ill adults. J Clin Microbiol 28:2539–2550PubMedGoogle Scholar
  72. 72.
    Powers DC (1993) Influenza A virus-specific cytotoxic T lymphocyte activity declines with advancing age [see comments]. J Am Geriatr Soc 41:1–5PubMedGoogle Scholar
  73. 73.
    Mbawuike IN, Lange AR, Couch RB (1993) Diminished influenza A virus-specific MHC class I-restricted cytotoxic T lymphocyte activity among elderly persons. Viral Immunol 6:55–64PubMedGoogle Scholar
  74. 74.
    McElhaney JE (2005) The unmet need in the elderly: designing new influenza vaccines for older adults. Vaccine 23 Suppl 1:S10–S25PubMedGoogle Scholar
  75. 75.
    McElhaney JE, Gravenstein S, Krause P, Hooton JW, Upshaw CM, Drinka P (1998) Assessment of markers of the cell-mediated immune response after influenza virus infection in frail older adults. Clin Diagn Lab Immunol 5:840–844PubMedGoogle Scholar
  76. 76.
    Darmon AJ, Nicholson DW, Bleackley RC (1995) Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377:446–448PubMedGoogle Scholar
  77. 77.
    Johnson BJ, Costelloe EO, Fitzpatrick DR et al (2003) Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virusinfected mice. Proc Natl Acad Sci U S A 100:2657–2662 Epub 2003 Feb 24PubMedGoogle Scholar
  78. 78.
    Lawrence CW, Ream RM, Braciale TJ (2005) Frequency, specificity, and sites of expansion of CD8+ T cells during primary pulmonary influenza virus infection. J Immunol 174:5332–5340PubMedGoogle Scholar
  79. 79.
    Jenkins MR, Kedzierska K, Doherty PC, Turner SJ (2007) Heterogeneity of effector phenotype for acute phase and memory influenza A virus-specific CTL. J Immunol 179:64–70PubMedGoogle Scholar
  80. 80.
    McElhaney JE, Pinkoski MJ, Upshaw CM, Bleackley RC (1996) The cell-mediated cytotoxic response to influenza vaccination using an assay for granzyme B activity. J Immunol Methods 190:11–20PubMedGoogle Scholar
  81. 81.
    Ewen C, Kane KP, Shostak I et al (2003) A novel cytotoxicity assay to evaluate antigenspecific CTL responses using a colorimetric substrate for Granzyme B. J Immunol Methods 276:89–101PubMedGoogle Scholar
  82. 82.
    Boon AC, Fringuelli E, Graus YM et al (2002) Influenza A virus specific T cell immunity in humans during aging. Virology 299:100–108PubMedGoogle Scholar
  83. 83.
    McElhaney JE, Meneilly GS, Beattie BL et al (1992) The effect of influenza vaccination on IL2 production in healthy elderly: implications for current vaccination practices. J Gerontol 47:M3–M8PubMedGoogle Scholar
  84. 84.
    McElhaney JE, Meneilly GS, Lechelt KE, Bleackley RC (1994) Split-virus influenza vaccines: do they provide adequate immunity in the elderly? J Gerontol 49:M37–M43PubMedGoogle Scholar
  85. 85.
    McElhaney JE, Meneilly GS, Pinkoski MJ, Lechelt KE, Bleackley RC (1995) Vaccinerelated determinants of the interleukin-2 response to influenza vaccination in healthy young and elderly adults. Vaccine 13:6–10PubMedGoogle Scholar
  86. 86.
    Gravenstein S, Drinka P, Duthie EH et al (1994) Efficacy of an influenza hemagglutinindiphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak. J Am Geriatr Soc 42:245–251PubMedGoogle Scholar
  87. 87.
    McElhaney JE, Herre JM, Lawson ML, Cole SK, Burke BL, Hooton JW (2004) Effect of congestive heart failure on humoral and ex vivo cellular immune responses to influenza vaccination in older adults. Vaccine 22:681–688PubMedGoogle Scholar
  88. 88.
    McElhaney JE, Hooton JW, Hooton N, Bleackley RC (2005) Comparison of single versus booster dose of influenza vaccination on humoral and cellular immune responses in older adults. Vaccine 23:3294–3300PubMedGoogle Scholar
  89. 89.
    Gorse GJ, O’Connor TZ, Young SL et al (2003) Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study. Vaccine 21:2133–2144PubMedGoogle Scholar
  90. 90.
    Gorse GJ, O’Connor TZ, Newman FK et al (2004) Immunity to influenza in older adults with chronic obstructive pulmonary disease. J Infect Dis 190:11–19 Epub 2004 May 26PubMedGoogle Scholar
  91. 91.
    Kang I, Hong MS, Nolasco H et al (2004) Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. J Immunol 173:673–681PubMedGoogle Scholar
  92. 92.
    Franceschi C, Monti D, Sansoni P, Cossarizza A (1995) The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 16:12–16PubMedGoogle Scholar
  93. 93.
    Ferguson FG, Wikby A, Maxson P, Olsson J, Johansson B (1995) Immune parametes in a longitudinal study of a very old poplulation of Swedish people: a comparison between survivors and non-survivors. J Gerontol A Biol Sci Med Sci 50:B378–B382PubMedGoogle Scholar
  94. 94.
    Effros RB (1997) Loss of CD28 expression on T lymphocytes: a marker of replicative senescence. Dev Comp Immunol 21:471–478PubMedGoogle Scholar
  95. 95.
    Effros RB, Dagarag M, Valenzuela HF (2003) In vitro senescence of immune cells. Exp Gerontol 38:1243–1249PubMedGoogle Scholar
  96. 96.
    Effros RB, Boucher N, Porter V et al (1994) Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 29:601–609PubMedGoogle Scholar
  97. 97.
    Engwerda CR, Handwerger BS, Fox BS (1994) Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol 152:3740–3747PubMedGoogle Scholar
  98. 98.
    Effros RB (2003) Genetic alterations in the ageing immune system: impact on infection and cancer. Mech Ageing Dev 124:71–77PubMedGoogle Scholar
  99. 99.
    Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O’Fallon WM, Weyand CM (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75:12182–12187PubMedGoogle Scholar
  100. 100.
    Saurwein-Teissl M, Lung TL, Marx F et al (2002) Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168:5893–5899PubMedGoogle Scholar
  101. 101.
    Xie D, McElhaney JE (2007) Lower GrB+CD62Lhigh CD8 TCM effector lymphocyte response to influenza virus in old adults is associated with increased CD28null CD8 T lymphocytes. Mech Ageing Dev 128:392–400PubMedGoogle Scholar
  102. 102.
    Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G (2007) Role of persistent CMV infection in configuring T cell immunity in the elderly. Immun Ageing 4:2PubMedGoogle Scholar
  103. 103.
    Vescovini R, Biasini C, Fagnoni FF et al (2007) Massive Load of Functional Effector CD4+ and CD8+ T Cells against Cytomegalovirus in Very Old Subjects. J Immunol 179:4283–4291PubMedGoogle Scholar
  104. 104.
    Hope-Simpson RE (1965) The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 58:9–20PubMedGoogle Scholar
  105. 105.
    Schmader K (2001) Herpes zoster in older adults. Clin Infect Dis 32:1481–1486 Epub 2001 Apr 17PubMedGoogle Scholar
  106. 106.
    Brisson M, Edmunds WJ, Law B et al (2001) Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect 127:305–314PubMedGoogle Scholar
  107. 107.
    Feder HM, Jr., Hoss DM (2004) Herpes zoster in otherwise healthy children. Pediatr Infect Dis J 23:451–457 quiz 458–460PubMedGoogle Scholar
  108. 108.
    Cunningham AL, Dworkin RH (2000) The management of post-herpetic neuralgia. Bmj 321:778–779PubMedGoogle Scholar
  109. 109.
    Thomas SL, Hall AJ (2004) What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 4:26–33PubMedGoogle Scholar
  110. 110.
    Cohrs RJ, Gilden DH, Mahalingam R (2004) Varicella zoster virus latency, neurological disease and experimental models: an update. Front Biosci 9:751–762PubMedGoogle Scholar
  111. 111.
    Baiker A, Fabel K, Cozzio A et al (2004) Varicella-zoster virus infection of human neural cells in vivo. Proc Natl Acad Sci U S A 101:10792–10797PubMedGoogle Scholar
  112. 112.
    Arvin AM, Moffat JF, Redman R (1996) Varicella-zoster virus: aspects of pathogenesis and host response to natural infection and varicella vaccine. Adv Virus Res 46:263–309PubMedGoogle Scholar
  113. 113.
    Wallace DL, Zhang Y, Ghattas H et al (2004) Direct measurement of T cell subset kinetics in vivo in elderly men and women. J Immunol 173:1787–1794PubMedGoogle Scholar
  114. 114.
    Oxman MN, Levin MJ, Johnson GR et al (2005) A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271–2284PubMedGoogle Scholar
  115. 115.
    Levin MJ, Smith JG, Kaufhold RM et al (2003) Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-hose VZV vaccine. J Infect Dis 2003188:1336–1344 Epub 2003 Oct 17Google Scholar
  116. 116.
    Smith JG, Levin M, Vessey R et al (2003) Measurement of cell-mediated immunity with a Varicella-Zoster Virus-specific interferon-gamma ELISPOT assay: responses in an elderly population receiving a booster immunization. J Med Virol 70 Suppl 1:S38–S41PubMedGoogle Scholar
  117. 117.
    Falsey AR (2007) Respiratory syncytial virus infection in adults. Semin Respir Crit Care Med 28:171–181PubMedGoogle Scholar
  118. 118.
    Mullooly JP, Bridges CB, Thompson WW et al (2007) Influenza- and RSV-associated hospitalizations among adults. Vaccine 25:846–855PubMedGoogle Scholar
  119. 119.
    Falsey AR, Treanor JJ, Betts RF, Walsh EE (1992) Viral respiratory infections in the institutionalized elderly: clinical and epidemiologic findings. J Am Geriatr Soc 40:115–119PubMedGoogle Scholar
  120. 120.
    Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE (2005) Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352:1749–1759PubMedGoogle Scholar
  121. 121.
    Walsh EE, Peterson DR, Falsey AR (2004) Risk factors for severe respiratory syncytial virus infection in elderly persons. J Infect Dis 189:233–238PubMedGoogle Scholar
  122. 122.
    Walsh EE, Falsey AR (2004) Age related differences in humoral immune response to respiratory syncytial virus infection in adults. J Med Virol 73:295–299PubMedGoogle Scholar
  123. 123.
    Zhang Y, Wang Y, Gilmore X, Xu K, Wyde PR, Mbawuike IN (2002) An aged mouse model for RSV infection and diminished CD8(+) CTL responses. Exp Biol Med (Maywood) 227:133–140Google Scholar
  124. 124.
    Looney RJ, Falsey AR, Walsh E, Campbell D (2002) Effect of aging on cytokine production in response to respiratory syncytial virus infection. J Infect Dis 185:682–685PubMedGoogle Scholar
  125. 125.
    Wald TG, Miller BA, Shult P, Drinka P, Langer L, Gravenstein S (1995) Can respiratory syncytial virus and influenza A be distinguished clinically in institutionalized older persons? J Am Geriatr Soc 43:170–174PubMedGoogle Scholar
  126. 126.
    Chen Q, Liang WN, Liu GF et al (2005) Case fatality rate of severe acute respiratory syndromes in Beijing. Biomed Environ Sci 18:220–226PubMedGoogle Scholar
  127. 127.
    Nash D, Mostashari F, Fine A et al (2001) The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 344:1807–1814PubMedGoogle Scholar
  128. 128.
    Casau NC (2005) Perspective on HIV infection and aging: emerging research on the horizon. Clin Infect Dis 41:855–863PubMedGoogle Scholar
  129. 129.
    Effros RB (2004) From Hayflick to Walford: the role of T cell replicative senescence in human aging. Exp Gerontol 39:885–890PubMedGoogle Scholar
  130. 130.
    van Baarle D, Tsegaye A, Miedema F, Akbar A (2005) Significance of senescence for virusspecific memory T cell responses: rapid ageing during chronic stimulation of the immune system. Immunol Lett 97:19–29PubMedGoogle Scholar
  131. 131.
    Effros RB (2007) Telomerase induction in T cells: a cure for aging and disease? Exp Gerontol 42:416–420PubMedGoogle Scholar
  132. 132.
    Fedson DS (1992) Clinical practice and public policy for influenza and pneumococcal vaccination of the elderly. Clin Geriatr Med 8:183–199PubMedGoogle Scholar
  133. 133.
    Sisk JE, Moskowitz AJ, Whang W et al (1997) Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA 278:1333–1339PubMedGoogle Scholar
  134. 134.
    Rubins JB, Alter M, Loch J, Janoff EN (1999) Determination of antibody responses of elderly adults to all 23 capsular polysaccharides after pneumococcal vaccination. Infect Immun 67:5979–5984PubMedGoogle Scholar
  135. 135.
    Kolibab K, Smithson SL, Shriner AK et al (2005) Immune response to pneumococcal polysaccharides 4 and 14 in elderly and young adults. I. Antibody concentrations, avidity and functional activity. Immun Ageing 2:10PubMedGoogle Scholar
  136. 136.
    Musher DM, Groover JE, Rowland JM et al (1993) Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin Infect Dis 17:66–73PubMedGoogle Scholar
  137. 137.
    Bruyn GA (1992) Pneumococcal immunisation and the healthy elderly. Lancet 340:1418PubMedGoogle Scholar
  138. 138.
    Sankilampi U, Honkanen PO, Bloigu A, Herva E, Leinonen M (1996) Antibody response to pneumococcal capsular polysaccharide vaccine in the elderly. J Infect Dis 173:387–393PubMedGoogle Scholar
  139. 139.
    Perry FE, Catterall JR (1994) The pneumococcus: host-organism interactions and their implications for immunotherapy and immunoprophylaxis. Thorax 49:946–950PubMedGoogle Scholar
  140. 140.
    Khan AQ, Lees A, Snapper CM (2004) Differential regulation of IgG anti-capsular polysaccharide and antiprotein responses to intact Streptococcus pneumoniae in the presence of cognate CD4+ T cell help. J Immunol 172:532–539PubMedGoogle Scholar
  141. 141.
    Kemp K, Bruunsgaard H, Skinhoj P, Klarlund Pedersen B (2002) Pneumococcal infections in humans are associated with increased apoptosis and trafficking of type 1 cytokine-producing T cells. Infect Immun 70:5019–5025PubMedGoogle Scholar
  142. 142.
    Robinson KA, Baughman W, Rothrock G et al (2001) Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998: Opportunities for prevention in the conjugate vaccine era. JAMA 285:1729–1735PubMedGoogle Scholar
  143. 143.
    Arva E, Andersson B (1999) Induction of phagocyte-stimulating and Th1-promoting cytokines by in vitro stimulation of human peripheral blood mononuclear cells with Streptococcus pneumoniae. Scand J Immunol 49:417–423PubMedGoogle Scholar
  144. 144.
    Van Der Poll T, Marchant A, Keogh CV, Goldman M, Lowry SF (1996) Interleukin 10 impairs host defense in murine pneumococcal pneumonia. J Infect Dis 174:994–1000PubMedGoogle Scholar
  145. 145.
    Khan AQ, Shen Y, Wu ZQ, Wynn TA, Snapper CM (2002) Endogenous pro- and anti-inflammatory cytokines differentially regulate an in vivo humoral response to Streptococcus pneumoniae. Infect Immun 70:749–761PubMedGoogle Scholar
  146. 146.
    Modlin RL, Nutman TB (1993) Type 2 cytokines and negative immune regulation in human infections. Curr Opin Immunol 5:511–517PubMedGoogle Scholar
  147. 147.
    Sun K, Salmon SL, Lotz SA, Metzger DW (2007) Interleukin-12 promotes gamma interferondependent neutrophil recruitment in the lung and improves protection against respiratory Streptococcus pneumoniae infection. Infect Immun 75:1196–1202PubMedGoogle Scholar
  148. 148.
    Sun K, Metzger DW (2008) Inhibition of pulmonary antibacterial defense by interferongamma during recovery from influenza infection. Nat Med 14:558–564PubMedGoogle Scholar
  149. 149.
    Patton RL, Kalback WM, Esh CL et al (2006) Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am J Pathol 169:1048–1063PubMedGoogle Scholar
  150. 150.
    Monsonego A, Weiner HL (2003) Immunotherapeutic approaches to Alzheimer’s disease. Science 302:834–838PubMedGoogle Scholar
  151. 151.
    Monsonego A, Zota V, Karni A et al (2003) Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 112:415–422PubMedGoogle Scholar
  152. 152.
    Greenberg SM, Bacskai BJ, Hyman BT (2003) Alzheimer disease’s double-edged vaccine. Nat Med 9:389–390PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Janet E. McElhaney
    • 1
  1. 1.9B ProvidenceSt. Paul’s HospitalVancouver, BC

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