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Aging and Disease    2012, Vol. 3 Issue (1) : 68-90     DOI:
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Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population
Adrian J. Reber, Tatiana Chirkova, Jin Hyang Kim, Weiping Cao, Renata Biber, David K. Shay, Suryaprakash Sambhara
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA
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Abstract  

Influenza is an important contributor to morbidity and mortality worldwide. Accumulation of genetic mutations termed antigenic drift, allows influenza viruses to inflict yearly epidemics that may result in 250,000 to 500,000 deaths annually. Over 90% of influenza-related deaths occur in the older adult population. This is at least in part a result of increasing dysregulation of the immune system with age, termed immunosenescence. This dysregulation results in reduced capacity to cope with infections and decreased responsiveness to vaccination. The older adult population is in dire need of improved vaccines capable of eliciting protective responses in the face of a waning immune system. This review focuses on the status of immunity, responses to influenza vaccination, and strategies that are currently being explored to elicit enhanced immune responses in this high risk population.

Keywords Aging      Influenza      Vaccination      Immune Response      Immunosenescence     
Corresponding Authors: Suryaprakash Sambhara   
Issue Date: 01 January 2012
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Adrian J. Reber
Tatiana Chirkova
Jin Hyang Kim
Weiping Cao
Renata Biber
David K. Shay
Suryaprakash Sambhara
Cite this article:   
Adrian J. Reber,Tatiana Chirkova,Jin Hyang Kim, et al. Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population[J]. Aging and Disease, 2012, 3(1): 68-90.
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http://www.aginganddisease.org/EN/     OR     http://www.aginganddisease.org/EN/Y2012/V3/I1/68
[1] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K(2003). Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA, 289:179-186
[2] 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, 352:1749-1759
[3] World Health Organization (WHO)Fact sheet no. No211. April 2009. [Available at: http://www.who.int/mediacentre/factsheets/fs211/en/index.html. Accessed May 25, 2011].
[4] Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, Fukuda K(2004). Influenza-associated hospitalizations in the United States. JAMA, 292:1333-1340
[5] Mullooly JP, Bridges CB, Thompson WW, Chen J, Weintraub E, Jackson LA, Black S, Shay DK(2007). Influenza- and RSV-associated hospitalizations among adults. Vaccine, 25:846-855
[6] Powers DC, Fries LF, Murphy BR, Thumar B, Clements ML(1991). In elderly persons live attenuated influenza A virus vaccines do not offer an advantage over inactivated virus vaccine in inducing serum or secretory antibodies or local immunologic memory. J Clin Microbiol, 29:498-505
[7] Treanor J, Dumyati G, O’Brien D, Riley MA, Riley G, Erb S, Betts R(1994). Evaluation of cold-adapted, reassortant influenza B virus vaccines in elderly and chronically ill adults. J Infect Dis, 169:402-407
[8] 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 placebo-controlled trial. Vaccine, 12:1185-1189
[9] Govaert TM, Thijs CT, Masurel N, Sprenger MJ, Dinant GJ, Knottnerus JA(1994). The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial. JAMA, 272:1661-1665
[10] Nichol KL(2005). Influenza vaccination in the elderly: impact on hospitalisation and mortality. Drugs Aging, 22:495-515
[11] Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V(2005). Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet, 366:1165-1174
[12] Jacobson RM, Targonski PV, Poland GA(2007). Meta-analyses in vaccinology. Vaccine, 25:3153-3159
[13] Simonsen L, Taylor RJ, Viboud C, Miller MA, Jackson LA(2007). Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis, 7:658-666
[14] Jackson ML, Nelson JC, Weiss NS, Neuzil KM, Barlow W, Jackson LA(2008). Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a population-based, nested case-control study. Lancet, 372:398-405
[15] Jansen AG, Sanders EA, Nichol KL, van Loon AM, Hoes AW, Hak E(2008). Decline in influenza-associated mortality among Dutch elderly following the introduction of a nationwide vaccination program. Vaccine, 26:5567-5574
[16] Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E(2007). Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med, 357:1373-1381
[17] 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, 348:1322-1332
[18] Fireman B, Lee J, Lewis N, Bembom O, van der Laan M, Baxter R(2009). Influenza vaccination and mortality: differentiating vaccine effects from bias. Am J Epidemiol, 170:650-656
[19] Baxter R, Ray GT, Fireman BH(2010). Effect of influenza vaccination on hospitalizations in persons aged 50 years and older. Vaccine, 28:7267-7272
[20] Gross PA(2002). Review: inactivated vaccines provide the greatest protection against influenza in healthy persons. ACP J Club, 136:103
[21] Edwards KM, Dupont WD, Westrich MK, Plummer WDJr, Palmer PS, Wright PF(1994). A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis, 169:68-76
[22] Keitel WA, Cate TR, Couch RB, Huggins LL, Hess KR(1997). Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period. Vaccine, 15:1114-1122
[23] Bridges CB, Thompson WW, Meltzer MI, Reeve GR, Talamonti WJ, Cox NJ, Lilac HA, Hall H, Klimov A, Fukuda K(2000). Effectiveness and cost-benefit of influenza vaccination of healthy working adults: A randomized controlled trial. JAMA, 284:1655-1663
[24] Goodwin K, Viboud C, Simonsen L(2006). Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine, 24:1159-1169
[25] Nordin J, Mullooly J, Poblete S, Strikas R, Petrucci R, Wei F, Rush B, Safirstein B, Wheeler D, Nichol KL(2001). Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans. J Infect Dis, 184:665-670
[26] Hobson D, Curry RL, Beare AS, Ward-Gardner A(1972). The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond)70:767-777
[27] Potter CW, Oxford JS(1979). Determinants of immunity to influenza infection in man. Br Med Bull, 35:69-75
[28] Beare AS, Hobson D, Reed SE, Tyrrell DA(1968). A comparison of live and killed influenza-virus vaccines. Report to the Medical Research Council’s Committee on Influenza and other Respiratory Virus Vaccines. Lancet, 2:418-422
[29] Beare AS, Tyrrell DA, Hobson D, Howells CH, Pereira MS, Pollock TM, Tyler LE(1969). Live influenza B vaccine in volunteers. A report to the Medical Research Council by their Committee on Influenza and Other Respiratory Virus Vaccines. J Hyg (Lond)67:1-11
[30] McElhaney JE, Xie D, Hager WD, Barry MB, Wang Y, Kleppinger A, Ewen C, Kane KP, Bleackley RC(2006). T cell responses are better correlates of vaccine protection in the elderly. J Immunol, 176:6333-6339
[31] McElhaney JE, Ewen C, Zhou X, Kane KP, Xie D, Hager WD, Barry MB, Kleppinger A, Wang Y, Bleackley RC(2009). Granzyme B: Correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine, 27:2418-2425
[32] Targonski PV, Jacobson RM, Poland GA(2007). Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine, 25:3066-3069
[33] Aspinall R, Del Giudice G, Effros RB, Grubeck-Loebenstein B, Sambhara S(2007). Challenges for vaccination in the elderly. Immun Ageing, 4:9
[34] Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S(2002). Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol, 20:621-667
[35] Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K(2000). Immunobiology of dendritic cells. Annu Rev Immunol, 18:767-811
[36] Banchereau J, Steinman RM(1998). Dendritic cells and the control of immunity. Nature, 392:245-252
[37] Shortman K, Liu YJ(2002). Mouse and human dendritic cell subtypes. Nat Rev Immunol, 2:151-161
[38] Colonna M, Krug A, Cella M(2002). Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol, 14:373-379
[39] Grolleau-Julius A, Garg MR, Mo R, Stoolman LL, Yung RL(2006). Effect of aging on bone marrow-derived murine CD11c+CD4-CD8alpha- dendritic cell function. J Gerontol A Biol Sci Med Sci, 61:1039-1047
[40] Tesar BM, Walker WE, Unternaehrer J, Joshi NS, Chandele A, Haynes L, Kaech S, Goldstein DR(2006). Murine [corrected] myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging. Aging Cell, 5:473-486
[41] Jing Y, Shaheen E, Drake RR, Chen N, Gravenstein S, Deng Y(2009). Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol, 70:777-784
[42] Agrawal A, Agrawal S, Cao JN, Su H, Osann K, Gupta S(2007). Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol, 178:6912-6922
[43] Della Bella S, Bierti L, Presicce P, Arienti R, Valenti M, Saresella M, Vergani C, Villa ML(2007). Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol, 122:220-228
[44] Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC(2010). Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol, 184:2518-2527
[45] Shodell M, Siegal FP(2002). Circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing. Scand J Immunol, 56:518-521
[46] Moretto MM, Lawlor EM, Khan IA(2008). Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J Immunol, 181:7977-7984
[47] Steger MM, Maczek C, Grubeck-Loebenstein B(1996). Morphologically and functionally intact dendritic cells can be derived from the peripheral blood of aged individuals. Clin Exp Immunol, 105:544-550
[48] Grewe M(2001). Chronological ageing and photoageing of dendritic cells. Clin Exp Dermatol, 26:608-612
[49] Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM(1998). Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest, 101:890-898
[50] Aprahamian T, Takemura Y, Goukassian D, Walsh K(2008). Ageing is associated with diminished apoptotic cell clearance in vivo. Clin Exp Immunol, 152:448-455
[51] Agrawal A, Tay J, Yang GE, Agrawal S, Gupta S(2010). Age-associated epigenetic modifications in human DNA increase its immunogenicity. Aging (Albany NY)2:93-100
[52] Agrawal A, Tay J, Ton S, Agrawal S, Gupta S(2009). Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA. J Immunol, 182:1138-1145
[53] Underhill DM, Ozinsky A(2002). Phagocytosis of microbes: complexity in action. Annu Rev Immunol, 20:825-852
[54] Zissel G, Schlaak M, Muller-Quernheim J(1999). Age-related decrease in accessory cell function of human alveolar macrophages. J Investig Med, 47:51-56
[55] Tasat DR, Mancuso R, O’Connor S, Molinari B(2003). Age-dependent change in reactive oxygen species and nitric oxide generation by rat alveolar macrophages. Aging Cell, 2:159-164
[56] Antonini JM, Roberts JR, Clarke RW, Yang HM, Barger MW, Ma JY, Weissman DN(2001). Effect of age on respiratory defense mechanisms: pulmonary bacterial clearance in Fischer 344 rats after intratracheal instillation of Listeria monocytogenes. Chest, 120:240-249
[57] Khare V, Sodhi A, Singh SM(1996). Effect of aging on the tumoricidal functions of murine peritoneal macrophages. Nat Immun, 15:285-294
[58] Videla LA, Tapia G, Fernandez V(2001). Influence of aging on Kupffer cell respiratory activity in relation to particle phagocytosis and oxidative stress parameters in mouse liver. Redox Rep, 6:155-159
[59] Martin G, Sewell RB, Yeomans ND, Morgan DJ, Smallwood RA(1994). Hepatic Kupffer cell function: the efficiency of uptake and intracellular degradation of 14C-labelled mitochondria is reduced in aged rats. Mech Ageing Dev, 73:157-168
[60] Kohut ML, Senchina DS, Madden KS, Martin AE, Felten DL, Moynihan JA(2004). Age effects on macrophage function vary by tissue site, nature of stimulant, and exercise behavior. Exp Gerontol, 39:1347-1360
[61] Murciano C, Yanez A, O’Connor JE, Gozalbo D, Gil ML(2008). Influence of aging on murine neutrophil and macrophage function against Candida albicans. FEMS Immunol Med Microbiol, 53:214-221
[62] Barbul A, Regan MC(1995). Immune involvement in wound healing. Otolaryngol Clin North Am, 28:955-968
[63] Swift ME, Burns AL, Gray KL, DiPietro LA(2001). Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol, 117:1027-1035
[64] Swift ME, Kleinman HK, DiPietro LA(1999). Impaired wound repair and delayed angiogenesis in aged mice. Lab Invest, 79:1479-1487
[65] Meydani SN, Meydani M, Verdon CP, Shapiro AA, Blumberg JB, Hayes KC(1986). Vitamin E supplementation suppresses prostaglandin E1(2) synthesis and enhances the immune response of aged mice. Mech Ageing Dev, 34:191-201
[66] Wu D, Meydani SN(2004). Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Brain Behav Immun, 18:487-494
[67] Kawai T, Akira S(2006). TLR signaling. Cell Death Differ, 13:816-825
[68] Kong KF, Delroux K, Wang X, Qian F, Arjona A, Malawista SE, Fikrig E, Montgomery RR(2008). Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J Virol, 82:7613-7623
[69] Agius E, Lacy KE, Vukmanovic-Stejic M, Jagger AL, Papageorgiou AP, Hall S, Reed JR, Curnow SJ, Fuentes-Duculan J, Buckley CD, Salmon M, Taams LS, Krueger J, Greenwood J, Klein N, Rustin MH, Akbar AN(2009). Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J Exp Med, 206:1929-1940
[70] 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, 169:4697-4701
[71] Boehmer ED, Meehan MJ, Cutro BT, Kovacs EJ(2005). Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway. Mech Ageing Dev, 126:1305-1313
[72] Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S(2004). Innate immunity in aging: impact on macrophage function. Aging Cell, 3:161-167
[73] Takeda K, Akira S(2004). TLR signaling pathways. Semin Immunol, 16:3-9
[74] Takeda K, Akira S(2005). Toll-like receptors in innate immunity. Int Immunol, 17:1-14
[75] Akira S, Takeda K(2004). Toll-like receptor signalling. Nat Rev Immunol, 4:499-511
[76] Chelvarajan RL, Liu Y, Popa D, Getchell ML, Getchell TV, Stromberg AJ, Bondada S(2006). Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages. J Leukoc Biol, 79:1314-1327
[77] Qian F, Wang X, Zhang L, Lin A, Zhao H, Fikrig E, Montgomery RR(2011). Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J Infect Dis, 203:1415-1424
[78] Dunston CR, Griffiths HR(2010). The effect of ageing on macrophage Toll-like receptor-mediated responses in the fight against pathogens. Clin Exp Immunol, 161:407-416
[79] Tortorella C, Simone O, Piazzolla G, Stella I, Cappiello V, Antonaci S(2006). Role of phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways in granulocyte macrophage-colony-stimulating factor failure to delay fas-induced neutrophil apoptosis in elderly humans. J Gerontol A Biol Sci Med Sci, 61:1111-1118
[80] Leger B, Derave W, De Bock K, Hespel P, Russell AP(2008). Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation. Rejuvenation Res, 11:163-175B
[81] Peralta S, Carrascosa JM, Gallardo N, Ros M, Arribas C(2002). Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction. Biochem Biophys Res Commun, 296:425-428
[82] Li Y, Howell EA, Lagoo AS, Kuchibhatla M, Pan H, Cohen HJ, Lagoo SA(2009). Differential gene expression of interleukin-1 receptor associated kinase-1 and interleukin-1 receptor associated kinase-M in peripheral blood mononuclear cells of young and aged rats following preconditioning with endotoxin. Shock, 31:55-63
[83] Cooper MA, Fehniger TA, Caligiuri MA(2001). The biology of human natural killer-cell subsets. Trends Immunol, 22:633-640
[84] Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA(2001). Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood, 97:3146-3151
[85] Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA(2006). Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing, 3:10
[86] Almeida-Oliveira A, Smith-Carvalho M, Porto LC, Cardoso-Oliveira J, Ribeiro Ados S, Falcao RR, Abdelhay E, Bouzas LF, Thuler LC, Ornellas MH, Diamond HR(2011). Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol, 72:319-329
[87] Mocchegiani E, Giacconi R, Cipriano C, Malavolta M(2009). NK and NKT cells in aging and longevity: role of zinc and metallothioneins. J Clin Immunol, 29:416-425
[88] Mariani E, Sgobbi S, Meneghetti A, Tadolini M, Tarozzi A, Sinoppi M, Cattini L, Facchini A(1996). Perforins in human cytolytic cells: the effect of age. Mech Ageing Dev, 92:195-209
[89] Kaszubowska L, Kaczor JJ, Hak L, Dettlaff-Pokora A, Szarynska M, Kmiec Z(2011). Sensitivity of natural killer cells to activation in the process of ageing is related to the oxidative and inflammatory status of the elderly. J Physiol Pharmacol, 62:101-109
[90] Krishnaraj R, Bhooma T(1996). Cytokine sensitivity of human NK cells during immunosenescence. 2 IL2-induced interferon gamma secretion. Immunol Lett, 50:59-63
[91] Fang M, Roscoe F, Sigal LJ(2010). Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J Exp Med, 207:2369-2381
[92] Mariani E, Neri S, Cattini L, Mocchegiani E, Malavolta M, Dedoussis GV, Kanoni S, Rink L, Jajte J, Facchini A(2008). Effect of zinc supplementation on plasma IL-6 and MCP-1 production and NK cell function in healthy elderly: interactive influence of +647 MT1a and -174 IL-6 polymorphic alleles. Exp Gerontol, 43:462-471
[93] Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R(1999). NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol, 34:253-265
[94] Dorfman JR, Raulet DH(1998). Acquisition of Ly49 receptor expression by developing natural killer cells. J Exp Med, 187:609-618
[95] Kutza J, Murasko DM(1994). Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-alpha. Cell Immunol, 155:195-204
[96] Lutz CT, Moore MB, Bradley S, Shelton BJ, Lutgendorf SK(2005). Reciprocal age related change in natural killer cell receptors for MHC class I. Mech Ageing Dev, 126:722-731
[97] Hayhoe RP, Henson SM, Akbar AN, Palmer DB(2010). Variation of human natural killer cell phenotypes with age: identification of a unique KLRG1-negative subset. Hum Immunol, 71:676-681
[98] Aspinall R, Andrew D(2000). Thymic involution in aging. J Clin Immunol, 20:250-256
[99] Linton PJ, Dorshkind K(2004). Age-related changes in lymphocyte development and function. Nat Immunol, 5:133-139
[100] Flores KG, Li J, Sempowski GD, Haynes BF, Hale LP(1999). Analysis of the human thymic perivascular space during aging. J Clin Invest, 104:1031-1039
[101] Andrew D, Aspinall R(2001). Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol, 166:1524-1530
[102] Henson SM, Snelgrove R, Hussell T, Wells DJ, Aspinall R(2005). An IL-7 fusion protein that shows increased thymopoietic ability. J Immunol, 175:4112-4118
[103] Aspinall R, Pido-Lopez J, Imami N, Henson SM, Ngom PT, Morre M, Niphuis H, Remarque E, Rosenwirth B, Heeney JL(2007). Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination. Rejuvenation Res, 10:5-17
[104] Rosenberg SA, Sportes C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL, Stetler-Stevenson M, Morton KE, Mavroukakis SA, Morre M, Buffet R, Mackall CL, Gress RE(2006). IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother, 29:313-319
[105] Ortman CL, Dittmar KA, Witte PL, Le PT(2002). Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol, 14:813-822
[106] Andrew D, Aspinall R(2002). Age-associated thymic atrophy is linked to a decline in IL-7 production. Exp Gerontol, 37:455-463
[107] Aggarwal S, Gupta S(1998). Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax. J Immunol, 160:1627-1637
[108] Aggarwal S, Gupta S(1999). Increased activity of caspase 3 and caspase 8 in anti-Fas-induced apoptosis in lymphocytes from ageing humans. Clin Exp Immunol, 117:285-290
[109] Tsukamoto H, Huston GE, Dibble J, Duso DK, Swain SL(2010). Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J Immunol, 185:4535-4544
[110] Plowden J, Renshaw-Hoelscher M, Gangappa S, Engleman C, Katz JM, Sambhara S(2004). Impaired antigen-induced CD8+ T cell clonal expansion in aging is due to defects in antigen presenting cell function. Cell Immunol, 229:86-92
[111] Jiang J, Gross D, Elbaum P, Murasko DM(2007). Aging affects initiation and continuation of T cell proliferation. Mech Ageing Dev, 128:332-339
[112] Timm JA, Thoman ML(1999). Maturation of CD4+ lymphocytes in the aged microenvironment results in a memory-enriched population. J Immunol, 162:711-717
[113] Clise-Dwyer K, Huston GE, Buck AL, Duso DK, Swain SL(2007). Environmental and intrinsic factors lead to antigen unresponsiveness in CD4(+) recent thymic emigrants from aged mice. J Immunol, 178:1321-1331
[114] Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA(2002). Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol, 169:1984-1992
[115] Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA(2007). The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J Virol, 81:7759-7765
[116] Decman V, Laidlaw BJ, Dimenna LJ, Abdulla S, Mozdzanowska K, Erikson J, Ertl HC, Wherry EJ(2010). Cell-intrinsic defects in the proliferative response of antiviral memory CD8 T cells in aged mice upon secondary infection. J Immunol, 184:5151-5159
[117] Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ(2005). The influence of age on T cell generation and TCR diversity. J Immunol, 174:7446-7452
[118] Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA(2008). Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med, 205:711-723
[119] Rudd BD, Venturi V, Davenport MP, Nikolich-Zugich J(2011). Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J Immunol, 186:2056-2064
[120] Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schachter F(1998). CD28 expression in T cell aging and human longevity. Exp Gerontol, 33:267-282
[121] Spaulding C, Guo W, Effros RB(1999). Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol, 34:633-644
[122] Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV(1996). Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS, 10:F17-22
[123] Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M(2008). The immune system in extreme longevity. Exp Gerontol, 43:61-65
[124] Ouyang Q, Wagner WM, Wikby A, Walter S, Aubert G, Dodi AI, Travers P, Pawelec G(2003). Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J Clin Immunol, 23:247-257
[125] Schirmer M, Goldberger C, Wurzner R, Duftner C, Pfeiffer KP, Clausen J, Neumayr G, Falkenbach A(2002). Circulating cytotoxic CD8(+) CD28(−) T cells in ankylosing spondylitis. Arthritis Res, 4:71-76
[126] Tsukishiro T, Donnenberg AD, Whiteside TL(2003). Rapid turnover of the CD8(+)CD28(−) T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol Immunother, 52:599-607
[127] Pilch H, Hoehn H, Schmidt M, Steiner E, Tanner B, Seufert R, Maeurer M(2002). CD8+CD45RA+CD27-CD28-T-cell subset in PBL of cervical cancer patients representing CD8+T-cells being able to recognize cervical cancer associated antigens provided by HPV 16 E7. Zentralbl Gynakol, 124:406-412
[128] Cortesini R, LeMaoult J, Ciubotariu R, Cortesini NS(2001). CD8+CD28- T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol Rev, 182:201-206
[129] Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B(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, 168:5893-5899
[130] Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E(2002). Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology, 106:190-199
[131] Zhao L, Sun L, Wang H, Ma H, Liu G, Zhao Y(2007). Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice. J Leukoc Biol, 81:1386-1394
[132] Tsaknaridis L, Spencer L, Culbertson N, Hicks K, LaTocha D, Chou YK, Whitham RH, Bakke A, Jones RE, Offner H, Bourdette DN, Vandenbark AA(2003). Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res, 74:296-308
[133] Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, Gasser T, Stoltze L(2007). Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol, 188:117-127
[134] Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss PA(2005). The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol, 140:540-546
[135] Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, Plas DR, Hildeman DA(2011). A major role for Bim in regulatory T cell homeostasis. J Immunol, 186:156-163
[136] Trzonkowski P, Szmit E, Mysliwska J, Mysliwski A(2006). CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence. Clin Immunol, 119:307-316
[137] Bryl E, Witkowski JM(2004). Decreased proliferative capability of CD4(+) cells of elderly people is associated with faster loss of activation-related antigens and accumulation of regulatory T cells. Exp Gerontol, 39:587-595
[138] Chiu BC, Stolberg VR, Zhang H, Chensue SW(2007). Increased Foxp3(+) Treg cell activity reduces dendritic cell co-stimulatory molecule expression in aged mice. Mech Ageing Dev, 128:618-627
[139] Williams-Bey Y, Jiang J, Murasko DM(2011). Expansion of regulatory T cells in aged mice following influenza infection. Mech Ageing Dev, 132:163-170
[140] Cusi MG, Martorelli B, Di Genova G, Terrosi C, Campoccia G, Correale P(2010). Age related changes in T cell mediated immune response and effector memory to Respiratory Syncytial Virus (RSV) in healthy subjects. Immun Ageing, 7:14
[141] Tenorio AR, Spritzler J, Martinson J, Gichinga CN, Pollard RB, Lederman MM, Kalayjian RC, Landay AL(2009). The effect of aging on T-regulatory cell frequency in HIV infection. Clin Immunol, 130:298-303
[142] Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, Belkaid Y, Chougnet C(2008). Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol, 181:1835-1848
[143] 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, 75:12182-12187
[144] Garcia GG, Berger SB, Sadighi Akha AA, Miller RA(2005). Age-associated changes in glycosylation of CD43 and CD45 on mouse CD4 T cells. Eur J Immunol, 35:622-631
[145] Sadighi Akha AA, Miller RA(2005). Signal transduction in the aging immune system. Curr Opin Immunol, 17:486-491
[146] Pereira LF, de Souza AP, Borges TJ, Bonorino C(2011). Impaired in vivo CD4+ T cell expansion and differentiation in aged mice is not solely due to T cell defects: decreased stimulation by aged dendritic cells. Mech Ageing Dev, 132:187-194
[147] Cao JN, Gollapudi S, Sharman EH, Jia Z, Gupta S(2010). Age-related alterations of gene expression patterns in human CD8+ T cells. Aging Cell, 9:19-31
[148] Fulop T, Larbi A, Wikby A, Mocchegiani E, Hirokawa K, Pawelec G(2005). Dysregulation of T-cell function in the elderly : scientific basis and clinical implications. Drugs Aging, 22:589-603
[149] Larbi A, Douziech N, Dupuis G, Khalil A, Pelletier H, Guerard KP, Fulop TJr(2004). Age-associated alterations in the recruitment of signal-transduction proteins to lipid rafts in human T lymphocytes. J Leukoc Biol, 75:373-381
[150] Hallgren HM, Buckley CE3rd, Gilbertsen VA, Yunis EJ(1973). Lymphocyte phytohemagglutinin responsiveness, immunoglobulins and autoantibodies in aging humans. J Immunol, 111:1101-1107
[151] Haynes L, Linton PJ, Eaton SM, Tonkonogy SL, Swain SL(1999). Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J Exp Med, 190:1013-1024
[152] Ouyang Q, Wagner WM, Wikby A, Remarque E, Pawelec G(2002). Compromised interferon gamma (IFN-gamma) production in the elderly to both acute and latent viral antigen stimulation: contribution to the immune risk phenotype?. Eur Cytokine Netw, 13:392-394
[153] Rink L, Cakman I, Kirchner H(1998). Altered cytokine production in the elderly. Mech Ageing Dev, 102:199-209
[154] 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, 172:5194-5199
[155] Linton PJ, Haynes L, Klinman NR, Swain SL(1996). Antigen-independent changes in naive CD4 T cells with aging. J Exp Med, 184:1891-1900
[156] Candore G, Di Lorenzo G, Melluso M, Cigna D, Colucci AT, Modica MA, Caruso C(1993). gamma-Interferon, interleukin-4 and interleukin-6 in vitro production in old subjects. Autoimmunity, 16:275-280
[157] al-Rayes H, Pachas W, Mirza N, Ahern DJ, Geha RS, Vercelli D(1992). IgE regulation and lymphokine patterns in aging humans. J Allergy Clin Immunol, 90:630-636
[158] Yen CJ, Lin SL, Huang KT, Lin RH(2000). Age-associated changes in interferon-gamma and interleukin-4 secretion by purified human CD4+ and CD8+ T cells. J Biomed Sci, 7:317-321
[159] Gardner EM, Murasko DM(2002). Age-related changes in Type 1 and Type 2 cytokine production in humans. Biogerontology, 3:271-290
[160] Ely KH, Roberts AD, Kohlmeier JE, Blackman MA, Woodland DL(2007). Aging and CD8+ T cell immunity to respiratory virus infections. Exp Gerontol, 42:427-431
[161] Toapanta FR, Ross TM(2009). Impaired immune responses in the lungs of aged mice following influenza infection. Respir Res, 10:112
[162] Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L(2004). Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med, 200:1613-1622
[163] 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, 16:1742-1747
[164] Xie D, McElhaney JE(2007). Lower GrB+ CD62Lhigh CD8 TCM effector lymphocyte response to influenza virus in older adults is associated with increased CD28null CD8 T lymphocytes. Mech Ageing Dev, 128:392-400
[165] Gupta S, Gollapudi S(2008). CD95-mediated apoptosis in naive, central and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp Gerontol, 43:266-274
[166] Smithey MJ, Renkema KR, Rudd BD, Nikolich-Zugich J(2011). Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. Eur J Immunol, 41:1352-1364
[167] Jiang J, Bennett AJ, Fisher E, Williams-Bey Y, Shen H, Murasko DM(2009). Limited expansion of virus-specific CD8 T cells in the aged environment. Mech Ageing Dev, 130:713-721
[168] Jiang J, Fisher E, Bennett AJ, Murasko DM(2010). Enhancement of virus-specific expansion of transgenic CD8 T cells in aged mice by dendritic cells. Mech Ageing Dev, 131:580-583
[169] Kronenberg M(2005). Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol, 23:877-900
[170] Faunce DE, Palmer JL, Paskowicz KK, Witte PL, Kovacs EJ(2005). CD1d-restricted NKT cells contribute to the age-associated decline of T cell immunity. J Immunol, 175:3102-3109
[171] Kawabata T, Kinoshita M, Inatsu A, Habu Y, Nakashima H, Shinomiya N, Seki S(2008). Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide. Hepatology, 48:1586-1597
[172] Zeng W, Maciejewski JP, Chen G, Risitano AM, Kirby M, Kajigaya S, Young NS(2002). Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol, 119:803-809
[173] Mocchegiani E, Malavolta M(2004). NK and NKT cell functions in immunosenescence. Aging Cell, 3:177-184
[174] Stout-Delgado HW, Du W, Shirali AC, Booth CJ, Goldstein DR(2009). Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe, 6:446-456
[175] Tesar BM, Du W, Shirali AC, Walker WE, Shen H, Goldstein DR(2009). Aging augments IL-17 T-cell alloimmune responses. Am J Transplant, 9:54-63
[176] Frasca D, Landin AM, Riley RL, Blomberg BB(2008). Mechanisms for decreased function of B cells in aged mice and humans. J Immunol, 180:2741-2746
[177] Ademokun A, Wu YC, Dunn-Walters D(2010). The ageing B cell population: composition and function. Biogerontology, 11:125-137
[178] Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J(2005). CD27(+) (memory) B cell decrease and apoptosis-resistant CD27(−) (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances. Int Immunol, 17:383-390
[179] Kruetzmann S, Rosado MM, Weber H, Germing U, Tournilhac O, Peter HH, Berner R, Peters A, Boehm T, Plebani A, Quinti I, Carsetti R(2003). Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med, 197:939-945
[180] Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K(2005). Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol, 175:3262-3267
[181] Powers DC(1994). Effect of age on serum immunoglobulin G subclass antibody responses to inactivated influenza virus vaccine. J Med Virol, 43:57-61
[182] Rossi MI, Yokota T, Medina KL, Garrett KP, Comp PC, Schipul AHJr, Kincade PW(2003). B lymphopoiesis is active throughout human life, but there are developmental age-related changes. Blood, 101:576-584
[183] McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH(2001). Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood, 98:2498-2507
[184] Mackay F, Schneider P, Rennert P, Browning J(2003). BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol, 21:231-264
[185] Mackay F, Ambrose C(2003). The TNF family members BAFF and APRIL: the growing complexity. Cytokine Growth Factor Rev, 14:311-324
[186] Jin R, Kaneko H, Suzuki H, Arai T, Teramoto T, Fukao T, Kondo N(2008). Age-related changes in BAFF and APRIL profiles and upregulation of BAFF and APRIL expression in patients with primary antibody deficiency. Int J Mol Med, 21:233-238
[187] MacLennan I, Vinuesa C(2002). Dendritic cells, BAFF, and APRIL: innate players in adaptive antibody responses. Immunity, 17:235-238
[188] Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M, Ohteki T(2011). Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity, 34:247-257
[189] Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, Nilsson BO, Wikby A, Kipling D, Dunn-Walters DK(2009). B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell, 8:18-25
[190] Weksler ME(2000). Changes in the B-cell repertoire with age. Vaccine, 18:1624-1628
[191] Weksler ME, Szabo P(2000). The effect of age on the B-cell repertoire. J Clin Immunol, 20:240-249
[192] Hu A, Ehleiter D, Ben-Yehuda A, Schwab R, Russo C, Szabo P, Weksler ME(1993). Effect of age on the expressed B cell repertoire: role of B cell subsets. Int Immunol, 5:1035-1039
[193] Delassus S, Gey A, Darche S, Cumano A, Roth C, Kourilsky P(1995). PCR-based analysis of the murine immunoglobulin heavy-chain repertoire. J Immunol Methods, 184:219-229
[194] Tonegawa S(1983). Somatic generation of antibody diversity. Nature, 302:575-581
[195] VanDyk L, Meek K(1992). Assembly of IgH CDR3: mechanism, regulation, and influence on antibody diversity. Int Rev Immunol, 8:123-133
[196] van Dijk-Hard I, Soderstrom I, Feld S, Holmberg D, Lundkvist I(1997). Age-related impaired affinity maturation and differential D-JH gene usage in human VH6-expressing B lymphocytes from healthy individuals. Eur J Immunol, 27:1381-1386
[197] Wang X, Stollar BD(1999). Immunoglobulin VH gene expression in human aging. Clin Immunol, 93:132-142
[198] Hijmans W, Radl J, Bottazzo GF, Doniach D(1984). Autoantibodies in highly aged humans. Mech Ageing Dev, 26:83-89
[199] Whisler RL, Grants IS(1993). Age-related alterations in the activation and expression of phosphotyrosine kinases and protein kinase C (PKC) among human B cells. Mech Ageing Dev, 71:31-46
[200] Zheng B, Han S, Takahashi Y, Kelsoe G(1997). Immunosenescence and germinal center reaction. Immunol Rev, 160:63-77
[201] Sayegh CE, Quong MW, Agata Y, Murre C(2003). E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat Immunol, 4:586-593
[202] Frasca D, Van der Put E, Riley RL, Blomberg BB(2004). Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J Immunol, 172:2155-2162
[203] Nussenzweig MC, Alt FW(2004). Antibody diversity: one enzyme to rule them all. Nat Med, 10:1304-1305
[204] Frasca D, Van der Put E, Landin AM, Gong D, Riley RL, Blomberg BB(2005). RNA stability of the E2A-encoded transcription factor E47 is lower in splenic activated B cells from aged mice. J Immunol, 175:6633-6644
[205] Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, Blomberg BB(2008). Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol, 180:5283-5290
[206] LeMaoult J, Szabo P, Weksler ME(1997). Effect of age on humoral immunity, selection of the B-cell repertoire and B-cell development. Immunol Rev, 160:115-126
[207] Caraux A, Klein B, Paiva B, Bret C, Schmitz A, Fuhler GM, Bos NA, Johnsen HE, Orfao A, Perez-Andres M(2010). Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138- and CD138+ plasma cells. Haematologica, 95:1016-1020
[208] Siegrist CA, Aspinall R(2009). B-cell responses to vaccination at the extremes of age. Nat Rev Immunol, 9:185-194
[209] U.S. Census BureauInternational Data Base (IDB). [Available at: http://www.census.gov/ipc/www/idb/informationGateway.php. Accessed May 20, 2011].
[210] Hoelscher M, Gangappa S, Zhong W, Jayashankar L, Sambhara S(2008). Vaccines against epidemic and pandemic influenza. Expert Opin Drug Deliv, 5:1139-1157
[211] Katz JM, Plowden J, Renshaw-Hoelscher M, Lu X, Tumpey TM, Sambhara S(2004). Immunity to influenza: the challenges of protecting an aging population. Immunol Res, 29:113-124
[212] Sambhara S, McElhaney JE(2009). Immunosenescence and influenza vaccine efficacy. Curr Top Microbiol Immunol, 333:413-429
[213] Sambhara S, Kurichh A, Miranda R, James O, Underdown B, Klein M, Tartaglia J, Burt D(2001). Severe impairment of primary but not memory responses to influenza viral antigens in aged mice: costimulation in vivo partially reverses impaired primary immune responses. Cell Immunol, 210:1-4
[214] Ferko B, Kittel C, Romanova J, Sereinig S, Katinger H, Egorov A(2006). Live attenuated influenza virus expressing human interleukin-2 reveals increased immunogenic potential in young and aged hosts. J Virol, 80:11621-11627
[215] Sambhara S, Kurichh A, Miranda R, Tamane A, Arpino R, James O, McGuinness U, Kandil A, Underdown B, Klein M, Burt D(1998). Enhanced immune responses and resistance against infection in aged mice conferred by Flu-ISCOMs vaccine correlate with up-regulation of costimulatory molecule CD86. Vaccine, 16:1698-1704
[216] Sambhara S, Woods S, Arpino R, Kurichh A, Tamane A, Bengtsson KL, Morein B, Underdown B, Klein M, Burt D(1997). Influenza (H1N1)-ISCOMs enhance immune responses and protection in aged mice. Mech Ageing Dev, 96:157-169
[217] O’Hagan DT, Wack A, Podda A(2007). MF59 is a safe and potent vaccine adjuvant for flu vaccines in humans: what did we learn during its development?. Clin Pharmacol Ther, 82:740-744
[218] Baras B, Bouveret N, Devaster JM, Fries L, Gillard P, Sanger R, Hanon E(2008). A vaccine manufacturer’s approach to address medical needs related to seasonal and pandemic influenza viruses. Influenza Other Respi Viruses, 2:251-260
[219] Novartis Pharmaceuticals Canada, Inc. Health Canada approves Fluad, new influenza vaccine for seniors[Available at: http://www.novartis.ca/downloads/en/News/FLUAD_Release_Feb2010_eng.pdf. Accessed July 19, 2011].
[220] Health CanadaHealth Canada has authorized the sale of Arepanrix H1N1 based on limited clinical testing in humans under the provision of an Interim Order (IO) issued on October 13, 2009. [Available at: http://hc-sc.gc.ca/dhp-mps/prodpharma/legislation/interimorders-arretesurgence/prodinfo-vaccin-eng.php. Accessed July 19, 2011].
[221] Schultze V, D’Agosto V, Wack A, Novicki D, Zorn J, Hennig R(2008). Safety of MF59 adjuvant. Vaccine, 26:3209-3222
[222] Podda A(2001). The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine, 19:2673-2680
[223] O’Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G(2011). MF59 adjuvant: the best insurance against influenza strain diversity. Expert Rev Vaccines, 10:447-462
[224] Parodi V, de Florentiis D, Martini M, Ansaldi F(2011). Inactivated influenza vaccines: recent progress and implications for the elderly. Drugs Aging, 28:93-106
[225] De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, Senatore F, Verweij P, Fritzell B, Podda A(1999). Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine, 17:3094-3101
[226] Minutello M, Senatore F, Cecchinelli G, Bianchi M, Andreani T, Podda A, Crovari P(1999). Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine, 17:99-104
[227] Gasparini R, Pozzi T, Montomoli E, Fragapane E, Senatore F, Minutello M, Podda A(2001). Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects. Eur J Epidemiol, 17:135-140
[228] Galli G, Hancock K, Hoschler K, DeVos J, Praus M, Bardelli M, Malzone C, Castellino F, Gentile C, McNally T, Del Giudice G, Banzhoff A, Brauer V, Montomoli E, Zambon M, Katz J, Nicholson K, Stephenson I(2009). Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc Natl Acad Sci U S A, 106:7962-7967
[229] Fragapane E, Gasparini R, Schioppa F, Laghi-Pasini F, Montomoli E, Banzhoff A(2010). A heterologous MF59-adjuvanted H5N1 prepandemic influenza booster vaccine induces a robust, cross-reactive immune response in adults and the elderly. Clin Vaccine Immunol, 17:1817-1819
[230] Galli G, Medini D, Borgogni E, Zedda L, Bardelli M, Malzone C, Nuti S, Tavarini S, Sammicheli C, Hilbert AK, Brauer V, Banzhoff A, Rappuoli R, Del Giudice G, Castellino F(2009). Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proc Natl Acad Sci U S A, 106:3877-3882
[231] Wack A, Baudner BC, Hilbert AK, Manini I, Nuti S, Tavarini S, Scheffczik H, Ugozzoli M, Singh M, Kazzaz J, Montomoli E, Del Giudice G, Rappuoli R, O’Hagan DT(2008). Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice. Vaccine, 26:552-561
[232] Higgins DA, Carlson JR, Van Nest G(1996). MF59 adjuvant enhances the immunogenicity of influenza vaccine in both young and old mice. Vaccine, 14:478-484
[233] Clinical Trials.gov, trial registered as NCT 00382187. [Available at: http://clinicaltrials.gov. Accessed May 18, 2011].
[234] Wang M, Lamberth K, Harndahl M, Roder G, Stryhn A, Larsen MV, Nielsen M, Lundegaard C, Tang ST, Dziegiel MH, Rosenkvist J, Pedersen AE, Buus S, Claesson MH, Lund O(2007). CTL epitopes for influenza A including the H5N1 bird flu; genome-, pathogen-, and HLA-wide screening. Vaccine, 25:2823-2831
[235] Jameson J, Cruz J, Terajima M, Ennis FA(1999). Human CD8+ and CD4+ T lymphocyte memory to influenza A viruses of swine and avian species. J Immunol, 162:7578-7583
[236] Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, O’Hagan D, Rappuoli R, De Gregorio E(2008). Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci U S A, 105:10501-10506
[237] Seubert A, Monaci E, Pizza M, O’Hagan DT, Wack A(2008). The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol, 180:5402-5412
[238] Dupuis M, Denis-Mize K, LaBarbara A, Peters W, Charo IF, McDonald DM, Ott G(2001). Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis. Eur J Immunol, 31:2910-2918
[239] Dupuis M, Murphy TJ, Higgins D, Ugozzoli M, van Nest G, Ott G, McDonald DM(1998). Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol, 186:18-27
[240] Leroux-Roels I, Borkowski A, Vanwolleghem T, Drame M, Clement F, Hons E, Devaster JM, Leroux-Roels G(2007). Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet, 370:580-589
[241] Moris P, van der Most R, Leroux-Roels I, Clement F, Drame M, Hanon E, Leroux-Roels GG, Van Mechelen M(2011). H5N1 Influenza Vaccine Formulated with AS03(A) Induces Strong Cross-Reactive and Polyfunctional CD4 T-Cell Responses. J Clin Immunol, 31:443-454
[242] Leroux-Roels I, Roman F, Forgus S, Maes C, De Boever F, Drame M, Gillard P, van der Most R, Van Mechelen M, Hanon E, Leroux-Roels G(2010). Priming with AS03 A-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: an open non-randomised extension of a double-blind randomised primary study. Vaccine, 28:849-857
[243] Heijmans S, De Meulemeester M, Reynders P, Giet D, Demanet E, Devresse PY, Icardi G, Drame M, Roman F, Gillard P(2011). Immunogenicity profile of a 3.75-mug hemagglutinin pandemic rH5N1 split virion AS03A-adjuvanted vaccine in elderly persons: a randomized trial. J Infect Dis, 203:1054-1062
[244] Roman F, Vaman T, Kafeja F, Hanon E, Van Damme P(2010). AS03(A)-Adjuvanted influenza A (H1N1) 2009 vaccine for adults up to 85 years of age. Clin Infect Dis, 51:668-677
[245] Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, Planty C, Elouahabi A, Harvengt P, Carlsen H, Kielland A, Chomez P, Garcon N, Van Mechelen M(2011). Adjuvant System AS03 containing alpha-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine, 29:2461-2473
[246] Couch RB, Winokur P, Brady R, Belshe R, Chen WH, Cate TR, Sigurdardottir B, Hoeper A, Graham IL, Edelman R, He F, Nino D, Capellan J, Ruben FL(2007). Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine, 25:7656-7663
[247] Keitel WA, Atmar RL, Cate TR, Petersen NJ, Greenberg SB, Ruben F, Couch RB(2006). Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med, 166:1121-1127
[248] Palache AM, Beyer WE, Sprenger MJ, Masurel N, de Jonge S, Vardy A, Charpentier B, Noury J, van Beek WC, Borst RJ(1993). Antibody response after influenza immunization with various vaccine doses: a double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers. Vaccine, 11:3-9
[249] Chen WH, Cross AS, Edelman R, Sztein MB, Blackwelder WC, Pasetti MF(2011). Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine. Vaccine, 29:2865-2873
[250] Sullivan SJ, Jacobson R, Poland GA(2010). Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine. Expert Rev Vaccines, 9:1127-1133
[251] U.S. Food and Drug Administration (FDA)News and Events. December 23, 2009. [Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm195483.htm. Accessed May 10, 2011].
[252] Centers for Disease Control and Prevention2010). Licensure of a high-dose inactivated influenza vaccine for persons aged > or = 65 years (Fluzone High-Dose) and guidance for use – United States, 2010. MMWR Morb Mortal Wkly Rep, 59:485-486
[253] Huckriede A, Bungener L, Stegmann T, Daemen T, Medema J, Palache AM, Wilschut J(2005). The virosome concept for influenza vaccines. Vaccine, 23(Suppl 1):S26-38
[254] Stegmann T, Morselt HW, Booy FP, van Breemen JF, Scherph of G, Wilschut J(1987). Functional reconstitution of influenza virus envelopes. EMBO J, 6:2651-2659
[255] Bungener L, Huckriede A, de Mare A, de Vries-Idema J, Wilschut J, Daemen T(2005). Virosome-mediated delivery of protein antigens in vivo: efficient induction of class I MHC-restricted cytotoxic T lymphocyte activity. Vaccine, 23:1232-1241
[256] Calcagnile S, Zuccotti GV(2010). The virosomal adjuvanted influenza vaccine. Expert Opin Biol Ther, 10:191-200
[257] de Bruijn IA, Nauta J, Gerez L, Palache AM(2004). Virosomal influenza vaccine: a safe and effective influenza vaccine with high efficacy in elderly and subjects with low pre-vaccination antibody titers. Virus Res, 103:139-145
[258] Holm KJ, Goa KL(1999). Liposomal influenza vaccine. BioDrugs, 11:137-144
[259] Kunzi V, Dornseiff M, Horwath J, Hartmann K(2009). Safe vaccination of children with a virosomal adjuvanted influenza vaccine. Vaccine, 27:1261-1265
[260] Amendola A, Boschini A, Colzani D, Anselmi G, Oltolina A, Zucconi R, Begnini M, Besana S, Tanzi E, Zanetti AR(2001). Influenza vaccination of HIV-1-positive and HIV-1-negative former intravenous drug users. J Med Virol, 65:644-648
[261] de Bruijn I, Meyer I, Gerez L, Nauta J, Giezeman K, Palache B(2007). Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Vaccine, 26:119-127
[262] Conne P, Gauthey L, Vernet P, Althaus B, Que JU, Finkel B, Gluck R, Cryz SJJr(1997). Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients. Vaccine, 15:1675-1679
[263] Pregliasco F, Mensi C, Serpilli W, Speccher L, Masella P, Belloni A(2001). Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly. Aging (Milano)13:38-43
[264] Baldo V, Baldovin T, Pellegrini M, Angiolelli G, Majori S, Floreani A, Busana MC, Bertoncello C, Trivello R(2010). Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol, 2010:517198
[265] Ruf BR, Colberg K, Frick M, Preusche A(2004). Open, randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an MF59-adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly. Infection, 32:191-198
[266] Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM(2004). Dose sparing with intradermal injection of influenza vaccine. N Engl J Med, 351:2295-2301
[267] Ueno H, Klechevsky E, Schmitt N, Ni L, Flamar AL, Zurawski S, Zurawski G, Palucka K, Banchereau J, Oh S(2011). Targeting human dendritic cell subsets for improved vaccines. Semin Immunol, 23:21-27
[268] Palucka K, Banchereau J, Mellman I(2010). Designing vaccines based on biology of human dendritic cell subsets. Immunity, 33:464-478
[269] Bos JD, Kapsenberg ML(1993). The skin immune system: progress in cutaneous biology. Immunol Today, 14:75-78
[270] Frech SA, Kenney RT, Spyr CA, Lazar H, Viret JF, Herzog C, Gluck R, Glenn GM(2005). Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch. Vaccine, 23:946-950
[271] Beran J, Ambrozaitis A, Laiskonis A, Mickuviene N, Bacart P, Calozet Y, Demanet E, Heijmans S, Van Belle P, Weber F, Salamand C(2009). Intradermal influenza vaccination of healthy adults using a new microinjection system: a 3-year randomised controlled safety and immunogenicity trial. BMC Med, 7:13
[272] Amorij JP, Hinrichs W, Frijlink HW, Wilschut JC, Huckriede A(2010). Needle-free influenza vaccination. Lancet Infect Dis, 10:699-711
[273] Ansaldi F, Durando P, Icardi G(2011). Intradermal influenza vaccine and new devices: a promising chance for vaccine improvement. Expert Opin Biol Ther, 11:415-427
[274] Holland D, Booy R, De Looze F, Eizenberg P, McDonald J, Karrasch J, McKeirnan M, Salem H, Mills G, Reid J, Weber F, Saville M(2008). Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis, 198:650-658
[275] Arnou R, Icardi G, De Decker M, Ambrozaitis A, Kazek MP, Weber F, Van Damme P(2009). Intradermal influenza vaccine for older adults: a randomized controlled multicenter phase III study. Vaccine, 27:7304-7312
[276] Chi RC, Rock MT, Neuzil KM(2010). Immunogenicity and safety of intradermal influenza vaccination in healthy older adults. Clin Infect Dis, 50:1331-1338
[277] European Medicines AgencyIntanza influenza vaccine (split virion, inactivated). [Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000957/human_med_000842.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124. Accessed
[278] Sanofi Pasteur. Sanofi Pasteur introduces new option for flu vaccination - tiny needle, same effectiveness as traditional flu shots. [Available at: http://www.sanofipasteur.com/sanofi-pasteur2/front/index.jsp?siteCode=SP_CORP&codeRubrique=34&codePage=PAG_34_PR11. Accessed July 21, 2011].
[279] U.S. Food and Drug AdministrationMay92011Approval Letter - Fluzone Intradermal. [Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm255160.htm. Accessed July 21, 2011].
[280] Van Damme P, Arnou R, Kafeja F, Fiquet A, Richard P, Thomas S, Meghlaoui G, Samson SI, Ledesma E(2010). Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study. BMC Infect Dis, 10:134
[281] Maue AC, Eaton SM, Lanthier PA, Sweet KB, Blumerman SL, Haynes L(2009). Proinflammatory adjuvants enhance the cognate helper activity of aged CD4 T cells. J Immunol, 182:6129-6135
[282] McElhaney JE(2011). Influenza vaccine responses in older adults. Ageing Res Rev, 10:379-388
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