• 1
    World Population Prospects: The 2006 Revision and World Urbanization Prospects: The 2005 Revision, Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat [on-line]. Available at Accessed December 30, 2008.
  • 2
    High K. Immunizations in older adults. Clin Geriatr Med 2007;23:669685.
  • 3
    Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179186.
  • 4
    Vaccines and Immunizations. Centers for Disease Control and Prevention [on-line]. Available at Accessed May 15, 2009.
  • 5
    Poland GA, Schaffner W. Immunization guidelines for adult patients: An annual update and a challenge. Ann Intern Med 2009;150:5354.
  • 6
    Nichol KL, Nordin JD, Nelson DB et al. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med 2007;357:13731381.
  • 7
    Jackson ML, Nelson JC, Weiss NS et al. Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: A population-based, nested case-control study. Lancet 2008;372:398405.
  • 8
    Jackson LA, Jackson ML, Nelson JC et al. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol 2006;35:337344.
  • 9
    Falsey AR, Walsh EE, Francis CW et al. Response of C-reactive protein and serum amyloid A to influenza A infection in older adults. J Infect Dis 2001;183:995999.
  • 10
    Nichol KL, Nordin J, Mullooly J et al. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 2003;348:13221332.
  • 11
    Lamontagne F, Garant MP, Carvalho JC et al. Pneumococcal vaccination and risk of myocardial infarction. Can Med Assoc J 2008;179:773777.
  • 12
    Ferrucci L, Guralnik JM, Pahor M et al. Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled. JAMA 1997;277:728734.
  • 13
    Barker WH, Borisute H, Cox C. A study of the impact of influenza on the functional status of frail older people. Arch Intern Med 1998;158:645650.
  • 14
    Falsey AR, Hennessey PA, Formica MA et al. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:17491759.
  • 15
    High KP. Immunizations in older adults. Clin Geriatr Med 2007;3:669685.
  • 16
    Weinberger B, Herndler-Brandstetter D, Schwanninger A et al. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 2008;46:10781084.
  • 17
    Kovaiou RD, Herndler-Brandstetter D, Grubeck-Loebenstein B. Age-related changes in immunity: Implications for vaccination in the elderly. Expert Rev Mol Med 2007;9:117.
  • 18
    Kovaiou RD, Grubeck-Loebenstein B. Age-associated changes within CD4+T cells. Immunol Lett 2006;107:814.
  • 19
    van Duin D, Mohanty S, Thomas V et al. Age-associated defect in human TLR-1/2 function. J Immunol 2007;178:970975.
  • 20
    Stout-Delgado HW, Yang X, Walker WE et al. Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation. J Immunol 2008;181:67476756.
  • 21
    Takahashi K, Shibata T, Akashi-Takamura S et al. A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. J Exp Med 2007;204:29632976.
  • 22
    Haynes L, Swain SL. Why aging T cells fail: Implications for vaccination. Immunity 2006;24:663666.
  • 23
    Haynes L, Eaton SM. The effect of age on the cognate function of CD4+T cells. Immunol Rev 2005;205:220228.
  • 24
    Haynes L. How vaccines work on the background of the aging immune system. Exp Gerontol 2007;42:438440.
  • 25
    Cicin-Sain L, Messaoudi I, Park B et al. Dramatic increase in naïve T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A 2007;104:1996019965.
  • 26
    Nikolich-Zugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 2008;8:512522.
  • 27
    Carson PJ, Nichol KL, O'Brien J et al. Immune function and vaccine responses in healthy advanced elderly patients. Arch Intern Med 2000;160:20172024.
  • 28
    Goronzy JJ, Fulbright JW, Crowson CS et al. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 2001;75:1218212187.
  • 29
    Hakim FT, Memon SA, Cepeda R et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005;115:930939.
  • 30
    Naylor K, Li G, Vallejo AN et al. The influence of age on T cell generation and TCR diversity. J Immunol 2005;174:74467452.
  • 31
    Lee WW, Cui D, Czesnikiewicz-Guzik M et al. Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling. Rejuvenation Res 2008;11:10011011.
  • 32
    Czesnikiewicz-Guzik M, Lee WW, Cui D et al. T cell subset-specific susceptibility to aging. Clin Immunol 2008;127:107118.
  • 33
    Clambey ET, White J, Kappler JW et al. Identification of two major types of age-associated CD8 clonal expansions with highly divergent properties. Proc Natl Acad Sci U S A 2008;105:1299713002.
  • 34
    Paganelli R, Quinti I, Fagiolo U et al. Changes in circulating B cells and immunoglobulin classes and subclasses in a healthy aged population. Clin Exp Immunol 1992;90:351354.
  • 35
    Sansoni P, Vescovini R, Fagnoni F et al. The immune system in extreme longevity. Exp Gerontol 2008;43:6165.
  • 36
    Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol 2007;211:144156.
  • 37
    Son NH, Murray S, Yanovski J et al. Lineage specific telomere shortening and unaltered capacity for telomerase expression in human T and By lymphocytes with age. J Immunol 2000;165:11911196.
  • 38
    Weng N-P. Telomere and the adaptive immunity. Mech Ageing Dev 2008;129:6066.
  • 39
    Weng N-P. Aging of the immune system: How much can the adaptive immunity adapt? Immunity 2006;24:495499.
  • 40
    Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179186.
  • 41
    Jefferson TO, Rivetti D, Di Pietrantonj C et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2007; (2):CD001269.
  • 42
    Aspinall R, Del Giudice G, Effros RB et al. Challenges for vaccination in the elderly. Immun Ageing 2007;4:9.
  • 43
    Simonsen L, Reichert TA, Viboud C et al. Impact of influenza vaccination on seasonal mortality in the US elderly population. Arch Intern Med 2005;165:265272.
  • 44
    Shapiro ED, Berg AT, Austrian R et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991;325:14531460.
  • 45
    Törling J, Hedlund J, Konradsen HB et al. Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons previously treated for pneumonia. Vaccine 2003;22:96103.
  • 46
    Forrester HL, Jahnigen DW, LaForce FM. Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med 1987;83:425430.
  • 47
    Sims RV, Steinmann WC, McConville JH et al. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988;108:653657.
  • 48
    Butler JC, Breiman RF, Campbell JF et al. Pneumococcal polysaccharide vaccine efficacy: An evaluation of current recommendations. JAMA 1993;270:18261831.
  • 49
    Farr BM, Johnston BL, Cobb DK et al. Preventing pneumococcal bacteremia in patients at risk: Results of a matched case-control study. Arch Intern Med 1995;155:23362340.
  • 50
    Andrews RM, Counahan ML, Hogg GG et al. Effectiveness of a publicly funded pneumococcal vaccination program against invasive pneumococcal disease among the elderly in Victoria, Australia. Vaccine 2004;23:132138.
  • 51
    Dominguez A, Salleras L, Fedson DS et al. Effectiveness of pneumococcal vaccination for elderly people in Catalonia, Spain: A case-control study. Clin Infect Dis 2005;40:12501257.
  • 52
    de Roux A, Schmöle-Thoma B, Siber GR et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: Conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis 2008;46:10151023.
  • 53
    Moberley SA, Holden J, Tatham DP et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev 2008;(1):CD000422.
  • 54
    Melegaro A, Edmunds WJ. The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the elderly: A comparison of meta-analyses. Eur J Epidemiol 2004;19:353363.
  • 55
    Jackson LA, Janoff EN. Pneumococcal vaccination of elderly adults: New paradigms for protection. Clin Infect Dis 2008;47:13281338.
  • 56
    Hak E, Sanders EA, Verheij TJ et al. Rationale and design of CAPITA: A RCT of 13-valent conjugated pneumococcal vaccine efficacy among older adults. Neth J Med 2008;66:378383.
  • 57
    Guris D, Jumaan AO, Mascola L et al. Changing varicella epidemiology in active surveillance sites—United States, 1995–2005. J Infect Dis 2008;197 (Suppl 2):S71S75 and CDC, unpublished data.
  • 58
    Levin MJ, Oxman MN, Zhang JH et al. Veterans affairs cooperative studies program shingles prevention study investigators. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis 2008;197:825835.
  • 59
    Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999–2004. Emerg Infect Dis 2007;13:14171419.
  • 60
    Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis 1998;26:10271034.
  • 61
    Kyne L, Warny M, Qamar A et al. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;357:189193.
  • 62
    Aboudola S, Kotloff KL, Kyne L et al. Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A. Infect Immun 2003;71:16081610.
  • 63
    Phares CR, Lynfield R, Farley MM et al. Active bacterial core surveillance/emerging infections program network. Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005. JAMA 2008;299:20562065.
  • 64
    Baker CJ, Paoletti LC, Rench MA et al. Immune response of healthy women to 2 different group B streptococcal type V capsular polysaccharide-protein conjugate vaccines. J Infect Dis 2004;189:11031112.
  • 65
    Palazzi DL, Rench MA, Edwards MS et al. Use of type V group B streptococcal conjugate vaccine in adults 65–85 years old. J Infect Dis 2004;190:558564.
  • 66
    Elixhauser A, Steiner C. Infections with Methicillin-Resistant Staphylococcus aureus (MRSA) in U.S. hospitals, 1993–2005 [on-line]. Available at Accessed November 10, 2009.
  • 67
    Furuya EY, Cook HA, Lee MH et al. Community-associated methicillin-resistant Staphylococcus aureus prevalence: How common is it? A methodological comparison of prevalence ascertainment. Am J Infect Control 2007;35:359366.
  • 68
    Maira-Litrán T, Kropec A, Goldmann DA et al. Comparative opsonic and protective activities of Staphylococcus aureus conjugate vaccines containing native or deacetylated Staphylococcal Poly-N-acetyl-beta-(1-6)-glucosamine. Infect Immun 2005;73:67526762. Erratum in: Infect Immun 2005;73:7789.
  • 69
    Kelly-Quintos C, Cavacini LA, Posner MR et al. Characterization of the opsonic and protective activity against Staphylococcus aureus of fully human monoclonal antibodies specific for the bacterial surface polysaccharide poly-N-acetylglucosamine. Infect Immun 2006;74:27422750.
  • 70
    Kuklin NA, Clark DJ, Secore S et al. A novel Staphylococcus aureus vaccine: Iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model. Infect Immun 2006;74:22152223.
  • 71
    Schoenbaum SC, Mostow SR, Dowdle WR et al. Studies with inactivated influenza vaccines purified by zonal centrifugation: 2. Efficacy. Bull WHO 1969;41:531535.
  • 72
    Keitel WA, Atmar RL, Cate TR et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med 2006;166:11211127.
  • 73
    Powers DC, Smith GE, Anderson EL et al. Influenza A virus vaccines containing purified recombinant H3 hemagglutinin are well tolerated and induce protective immune responses in healthy adults. J Infect Dis 1995;171:15951599.
  • 74
    Lakey DL, Treanor JJ, Betts RF et al. Recombinant baculovirus influenza A hemagglutinin vaccines are well tolerated and immunogenic in healthy adults. J Infect Dis 1996;174:838841.
  • 75
    Treanor JJ, Betts RF, Smith GE et al. Evaluation of a recombinant hemagglutinin expressed in insect cells as an influenza vaccine in young and elderly adults. J Infect Dis 1996;173:14671470.
  • 76
    Treanor JJ, Schiff GM, Couch RB et al. Dose-related safety and immunogenicity of a trivalent baculovirus-expressed influenza-virus hemagglutinin vaccine in elderly adults. J Infect Dis 2006;193:12231228.
  • 77
    Treanor JJ, Schiff GM, Hayden FG et al. Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine: A randomized controlled trial. JAMA 2007;297:15771582.
  • 78
    Haynes L., Eaton SM. The effect of age on the cognate function of CD4+T cells. Immunol Rev 2005;205:220228.
  • 79
    Eaton SM, Burns EM, Kusser K et al. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med 2004;200:16131622.
  • 80
    Haynes L, Eaton SM, Burns EM et al. Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J Immunol 2004;172:51945199.
  • 81
    Renshaw M, Rockwell J, Engleman C et al. Cutting edge: Impaired Toll-like receptor expression and function in aging. J Immunol 2002;169:46974701.
  • 82
    Sharma S, Dominguez AL, Hoelzinger DB et al. CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: The implications for vaccinations in the aged. Cancer Immunol Immunother 2008;57:549561.
  • 83
    Maletto BA, Rópolo AS, Liscovsky MV et al. CpG oligodeoxynucleotides functions as an effective adjuvant in aged BALB/c mice. Clin Immunol 2005;117:251261.
  • 84
    Subramanian S, Divya Shree AN. Enhanced Th2 immunity after DNA prime-protein boost immunization with amyloid beta (1-42) plus CpG oligodeoxynucleotides in aged rats. Neurosci Lett 2008;436:219222.
  • 85
    Sen G, Chen Q, Snapper CM. Immunization of aged mice with a pneumococcal conjugate vaccine combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective immunoglobulin G antipolysaccharide responses and specific CD4+-T-cell priming to young adult levels. Infect Immun 2006;74:21772186.
  • 86
    Manning BM, Enioutina EY, Visic DM et al. CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice. Exp Gerontol 2001;37:107126.
  • 87
    Alignani D, Maletto B, Liscovsky M et al. Orally administered OVA/CpG-ODN induces specific mucosal and systemic immune response in young and aged mice. J Leukoc Biol 2005;77:898905.
  • 88
    Speiser DE, Liénard D, Rufer N et al. Rapid and strong human CD8+T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 2005;115:739746.
  • 89
    Cooper CL, Davis HL, Angel JB et al. CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 2005;19:14731479.
  • 90
    Fisman DN, Agrawal D, Leder K. The effect of age on immunologic response to recombinant hepatitis B vaccine: A meta-analysis. Clin Infect Dis 2002;35:13681375.
  • 91
    Kataoka K, McGhee JR, Kobayashi R et al. Nasal Flt3 ligand cDNA elicits CD11c+CD8+dendritic cells for enhanced mucosal immunity. J Immunol 2004;172:36123619.
  • 92
    Krieg AM, Yi AK, Matson S et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995;374:546549.
  • 93
    Clambey ET, White J, Kappler JW et al. Identification of two major types of age-associated CD8 clonal expansions with highly divergent properties. Proc Natl Acad Sci U S A 2008;105:1299713002.
  • 94
    Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439:682687.
  • 95
    Velu V, Titanji K, Zhu B et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2009;458:206210.
  • 96
    Nikolich-Zugich J. High specificity, not degeneracy, allows T cell alloresponses. Nat Immunol 2007;8:335337.