Impact of aging and cytomegalovirus on immunological response to influenza vaccination and infection

Frontiers in Immunology

Volumn 8, Issue JUL, 2017, Pages

  Merani, Shahzma ^a   Pawelec, Graham ^a,b   Kuchel, George A ^c   McElhaney, Janet E ^a  

^a HEALTH SCIENCES NORTH   (Canada)

^b UNIVERSITY OF TÜBINGEN   (Germany)

^c UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

Author keywords

Aging; Cytomegalovirus; Cytotoxic T lymphocyte; Elderly; Infection; Influenza; Older adult; Vaccination

Indexed keywords

ADJUVANT; ANTIVIRUS AGENT; B LYMPHOCYTE RECEPTOR; CD28 ANTIGEN; GAMMA INTERFERON; GRANZYME B; INFLUENZA VACCINE; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 21; INTERLEUKIN 6; TUMOR NECROSIS FACTOR;

ADAPTIVE IMMUNITY; AGING; ANTIBODY RESPONSE; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL FUNCTION; CELLULAR IMMUNITY; CLINICAL TRIAL (TOPIC); CYTOMEGALOVIRUS INFECTION; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; DRUG DESIGN; DRUG EFFICACY; ELDERLY CARE; HELPER CELL; HUMAN; IMMUNE RESPONSE; IMMUNOSENESCENCE; INFLUENZA; INFLUENZA VACCINATION; INNATE IMMUNITY; MACROPHAGE; MOLECULAR GENETICS; NONHUMAN; REVIEW;

EID: 85025470940     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2017.00784     Document Type: Review

References (221)

1. Haspot F, Lavault A, Sinzger C, Laib Sampaio K, Stierhof Y, Pilet P, et al. Human cytomegalovirus entry into dendritic cells occurs via a macropinocytosis-like pathway in a pH-independent and cholesterol-dependent manner. PLoS One (2012) 7(4):e34795. doi:10.1371/journal.pone.0034795
2. Antona D, Lepoutre A, Fonteneau L, Baudon C, Halftermeyer-Zhou F, LE Strat Y, et al. Seroprevalence of cytomegalovirus infection in France in 2010. Epidemiol Infect (2017) 145(7):1471-8. doi:10.1017/S0950268817000103
3. Vilibic-Cavlek T, Kolaric B, Beader N, Vrtar I, Tabain I, Mlinaric-Galinovic G. Seroepidemiology of cytomegalovirus infections in Croatia. Wien Klin Wochenschr (2016) 129(3-4):129-35. doi:10.1007/s00508-016-1069-7
4. Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis (2006) 43(9):1143-51. doi:10.1086/508173
5. Pawelec G, McElhaney JE, Aiello AE, Derhovanessian E. The impact of CMV infection on survival in older humans. Curr Opin Immunol (2012) 24(4):507-11. doi:10.1016/j.coi.2012.04.002
6. Pawelec G, Derhovanessian E. Role of CMV in immune senescence. Virus Res (2011) 157(2):175-9. doi:10.1016/j.virusres.2010.09.010
7. Schmaltz HN, Fried LP, Xue Q-L, Walston J, Leng SX, Semba RD. Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J Am Geriatr Soc (2005) 53(5):747-54. doi:10.1111/j.1532-5415.2005.53250.x
8. Wang GC, Kao WHL, Murakami P, Xue Q-L, Chiou RB, Detrick B, et al. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol (2010) 171(10):1144-52. doi:10.1093/aje/kwq062
9. Savva GM, Pachnio A, Kaul B, Morgan K, Huppert FA, Brayne C, et al. Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell (2013) 12(3):381-7. doi:10.1111/acel.12059
10. Moro-García MA, Alonso-Arias R, López-Vázquez A, Suárez-García FM, Solano-Jaurrieta JJ, Baltar J, et al. Relationship between functional ability in older people, immune system status, and intensity of response to CMV. Age (2012) 34(2):479-95. doi:10.1007/s11357-011-9240-6
11. Aiello AE, Haan MN, Pierce CM, Simanek AM, Liang J. Persistent infection, inflammation, and functional impairment in older Latinos. J Gerontol A Biol Sci Med Sci (2008) 63(6):610-8. doi:10.1093/gerona/63.6.610
12. Boxer R, Kleppinger A, Ahmad A, Annis K, Hager D, Kenny A. The 6-minute walk is associated with frailty and predicts mortality in older adults with heart failure. Congest Heart Fail (2010) 16(5):208-13. doi:10.1111/j.1751-7133.2010.00151.x
13. Wikby A, Johansson B, Olsson J, Löfgren S, Nilsson B-O, Ferguson F. Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol (2002) 37(2-3):445-53. doi:10.1016/S0531-5565(01)00212-1
14. Derhovanessian E, Larbi A, Pawelec G. Biomarkers of human immunosenescence: impact of cytomegalovirus infection. Curr Opin Immunol (2009) 21(4):440-5. doi:10.1016/j.coi.2009.05.012
15. Matheï C, Adriaensen W, Vaes B, Van Pottelbergh G, Wallemacq P, Degryse J. No relation between CMV infection and mortality in the oldest old: results from the BELFRAIL study. Age Ageing (2015) 44(1):130-5. doi:10.1093/ageing/afu094
16. Derhovanessian E, Maier AB, Hähnel K, McElhaney JE, Slagboom EP, Pawelec G. Latent infection with cytomegalovirus is associated with poor memory CD4 responses to influenza a core proteins in the elderly. J Immunol (2014) 193(7):3624-31. doi:10.4049/jimmunol.1303361
17. Najarro K, Nguyen H, Chen G, Xu M, Alcorta S, Yao X, et al. Telomere length as an indicator of the robustness of B-and T-cell response to influenza in older adults. J Infect Dis (2015) 212(8):1261-9. doi:10.1093/infdis/jiv202
18. Johnstone J, Parsons R, Botelho F, Millar J, McNeil S, Fulop T, et al. Immune biomarkers predictive of respiratory viral infection in elderly nursing home residents. PLoS One (2014) 9(10):e108481. doi:10.1371/journal.pone.0108481
19. Stowe RP, Kozlova EV, Yetman DL, Walling DM, Goodwin JS, Glaser R. Chronic herpesvirus reactivation occurs in aging. Exp Gerontol (2007) 42(6):563-70. doi:10.1016/j.exger.2007.01.005
20. Parry HM, Zuo J, Frumento G, Mirajkar N, Inman C, Edwards E, et al. Cytomegalovirus viral load within blood increases markedly in healthy people over the age of 70 years. Immun Ageing (2016) 13:1. doi:10.1186/s12979-015-0056-6
21. Wills MR, Poole E, Lau B, Krishna B, Sinclair JH. The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies? Cell Mol Immunol (2015) 12(2):128-38. doi:10.1038/cmi.2014.75
22. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA (2003) 289(2):1333-40. doi:10.1001/jama.289.2.179
23. Zimmerman RK, Lauderdale DS, Tan SM, Wagener DK. Prevalence of high-risk indications for influenza vaccine varies by age, race, and income. Vaccine (2010) 28(39):6470-7. doi:10.1016/j.vaccine.2010.07.037
24. Loerbroks A, Stock C, Bosch JA, Litaker DG, Apfelbacher CJ. Influenza vaccination coverage among high-risk groups in 11 European countries. Eur J Public Health (2012) 22(4):562-8. doi:10.1093/eurpub/ckr094
25. Thompson WW, Shay DK, Weintraub E. Influenza-associated hospitalizations in the United States. JAMA (2004) 292(11):1333-40. doi:10.1001/jama.292.11.1333
26. Ferrucci L, Guralnik JM, Pahor M, Corti M, Havlik RJ. Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled. JAMA (1997) 277(9):728-34. doi:10.1001/jama.1997.03540330050034
27. Monto AS, Ansaldi F, Aspinall R, McElhaney JE, Montaño LF, Nichol KL, et al. Influenza control in the 21st century: optimizing protection of older adults. Vaccine (2009) 27(37):5043-53. doi:10.1016/j.vaccine.2009.06.032
28. Finco O, Rappuoli R. Designing vaccines for the twenty-first century society. Front Immunol (2014) 5:12. doi:10.3389/fimmu.2014.00012
29. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med (1994) 331(12):778-84. doi:10.1056/NEJM199409223311206
30. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine (2006) 24(8):1159-69. doi:10.1016/j.vaccine.2005.08.105
31. Simonsen L, Taylor RJ, Viboud C, Miller MA, Jackson LA. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis (2007) 7(10):658-66. doi:10.1016/S1473-3099(07)70236-0
32. Andrew M, Shinde V, Ye L, Hatchette T, Haguinet F, Dos Santos G, et al. The importance of frailty in the assessment of trivalent inactivated influenza vaccine effectiveness against influenza-related hospitalization in elderly people. J Infect Dis (2017) (in press).
33. Mahbub S, Deburghgraeve CR, Kovacs EJ. Advanced age impairs macrophage polarization. J Interferon Cytokine Res (2012) 32(1):18-26. doi:10.1089/jir.2011.0058
34. Mohanty S, Joshi SR, Ueda I, Wilson J, Blevins TP, Siconolfi B, et al. Prolonged proinflammatory cytokine production in monocytes modulated by interleukin 10 after influenza vaccination in older adults. J Infect Dis (2015) 211(7):1174-84. doi:10.1093/infdis/jiu573
35. van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, et al. Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis (2007) 195(11):1590-7. doi:10.1086/516788
36. Cheung AKL, Gottlieb DJ, Plachter B, Pepperl-Klindworth S, Avdic S, Cunningham AL, et al. The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency. Blood (2009) 114(1):4128-37. doi:10.1182/blood-2008-12-197111
37. Chang WLW, Baumgarth N, Yu D, Barry PA. Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality. J Virol (2004) 78(16):8720-31. doi:10.1128/JVI.78.16.8720-8731.2004
38. Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, et al. Age-associated decrease in TLR Function in primary human dendritic cells predicts influenza vaccine response. J Immunol (2010) 184(5):2518-27. doi:10.4049/jimmunol.0901022
39. Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O'Fallon WM, Weyand CM. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol (2001) 75(24):12182-7. doi:10.1128/JVI.75.24.12182-12187.2001
40. Saurwein-Teissl M, Lung TL, Marx F, Gschösser C, Asch E, Blasko I, et al. 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 (2002) 168(11):5893-9. doi:10.4049/jimmunol.168.11.5893
41. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine. Vaccine (2015) 33(12):1433-9. doi:10.1016/j.vaccine.2015.01.071
42. Frasca D, Diaz A, Romero M, Landin AM, Phillips M, Lechner SC, et al. Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans. Vaccine (2010) 28(51):8077-84. doi:10.1016/j.vaccine.2010.10.023
43. Frasca D, Diaz A, Romero M, Phillips M, Mendez NV, Landin AM, et al. Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine. Int Immunol (2012) 24(3):175-82. doi:10.1093/intimm/dxr123
44. Khurana S, Frasca D, Blomberg B, Golding H. AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. PLoS Pathog (2012) 8(9):e1002920. doi:10.1371/journal.ppat.1002920
45. Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol (2008) 180(8):5283-90. doi:10.4049/jimmunol.180.8.5283
46. Sasaki S, Sullivan M, Narvaez CF, Holmes TH, Furman D, Zheng N-Y, et al. Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. J Clin Invest (2011) 121(8):3109-19. doi:10.1172/JCI57834
47. Pritz T, Lair J, Ban M, Keller M, Weinberger B, Krismer M, et al. Plasma cell numbers decrease in bone marrow of old patients. Eur J Immunol (2015) 45(3):738-46. doi:10.1002/eji.201444878
48. Frasca D, Diaz A, Romero M, Blomberg BB. The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations. Vaccine (2016) 34(25):2834-40. doi:10.1016/j.vaccine.2016.04.023
49. Andrews SF, Kaur K, Pauli NT, Huang M, Huang Y, Wilson PC. High preexisting serological antibody levels correlate with diversification of the influenza vaccine response. J Virol (2015) 89(6):3308-17. doi:10.1128/JVI.02871-14
50. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One (2011) 6(3):e17739. doi:10.1371/journal.pone.0017739
51. Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol (2012) 188(8):3734-44. doi:10.4049/jimmunol.1103246
52. Kaur K, Sullivan M, Wilson PC. Targeting B cell responses in universal influenza vaccine design. Trends Immunol (2011) 32(11):524-31. doi:10.1016/j.it.2011.08.007
53. Burlington DB, Clements ML, Meiklejohn G, Phelan M, Murphy BR. Hemagglutinin-specific antibody responses in immunoglobulin G, A, and M isotypes as measured by enzyme-linked immunosorbent assay after primary or secondary infection of humans with influenza A virus. Infect Immun (1983) 41(2):540-5.
54. Frasca D, Blomberg BB. Aging, cytomegalovirus (CMV) and influenza vaccine responses. Hum Vaccin Immunother (2016) 12(3):682-90. doi:10.1080/21645515.2015.1105413
55. Frasca D, Landin AM, Alvarez JP, Blackshear PJ, Riley RL, Blomberg BB. Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of E47 mRNA. J Immunol (2007) 179(2):918-27. doi:10.4049/jimmunol.179.2.918
56. Prösch S, Staak K, Stein J, Liebenthal C, Stamminger T, Volk H-D, et al. Stimulation of the human cytomegalovirus IE enhancer/promoter in HL-60 cells by TNFa is mediated via induction of NF-κB. Virology (1995) 208(1):197-206. doi:10.1006/viro.1995.1143
57. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. High TNF-a levels in resting B cells negatively correlate with their response. Exp Gerontol (2014) 54:116-22. doi:10.1016/j.exger.2014.01.004
58. Furman D, Jojic V, Sharma S, Shen-Orr S, Angel CJL, Onengut-Gumuscu S, et al. Cytomegalovirus infection improves immune responses to influenza. Sci Transl Med (2015) 7(281):281ra43. doi:10.1126/scitranslmed.aaa2293
59. McElhaney JE, Garneau H, Camous X, Dupuis G, Pawelec G, Baehl S, et al. Predictors of the antibody response to influenza vaccination in older adults with type 2 diabetes. BMJ Open Diabetes Res Care (2015) 3:1. doi:10.1136/bmjdrc-2015-000140
60. Trzonkowski P, Mysliwska J, Szmit E, Wickiewicz J, Lukaszuk K, Brydak LB, et al. Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination-an impact of immunosenescence. Vaccine (2003) 21(22-26):3826-36. doi:10.1016/S0264-410X(03)00309-8
61. Wald A, Selke S, Magaret A, Boeckh M. Impact of human cytomegalovirus (CMV) infection on immune response to pandemic 2009 H1N1 influenza vaccine in healthy adults. J Med Virol (2013) 85(9):1557-60. doi:10.1002/jmv.23642
62. den Elzen WPJ, Vossen ACMT, Cools HJM, Westendorp RGJ, Kroes ACM, Gussekloo J. Cytomegalovirus infection and responsiveness to influenza vaccination in elderly residents of long-term care facilities. Vaccine (2011) 29(29-30):4869-74. doi:10.1016/j.vaccine.2011.03.086
63. Haq K, Fulop T, Tedder G, Gentleman B, Garneau H, Meneilly GS, et al. Cytomegalovirus seropositivity predicts a decline in the T cell but not the antibody response to influenza in accinated older adults independent of type 2 diabetes status. J Gerontol A Biol Sci Med Sci (2016):glw216. doi:10.1093/gerona/glw216
64. Bragstad K, Emborg H, Fischer TK, Voldstedlund M, Gubbels S, Andersen B, et al. Low vaccine effectiveness against influenza A(H3N2) virus among elderly people in Denmark in 2012/13-a rapid epidemiological and virological assessment. Euro Surveill (2013) 18(6):11-7.
65. Remschmidt C, Rieck T, Bödeker B, Wichmann O. Application of the screening method to monitor influenza vaccine effectiveness among the elderly in Germany. BMC Infect Dis (2015) 15:137. doi:10.1186/s12879-015-0882-3
66. Höpping AM, McElhaney J, Fonville JM, Powers DC, Beyer WEP, Smith DJ. The confounded effects of age and exposure history in response to influenza vaccination. Vaccine (2016) 34(4):540-6. doi:10.1016/j.vaccine.2015.11.058
67. Boon ACM, deBeauchamp J, Krauss S, Rubrum A, Webb AD, Webster RG, et al. Cross-reactive neutralizing antibodies directed against pandemic H1N1 2009 virus are protective in a highly sensitive DBA/2 mouse influenza model. J Virol (2010) 84(15):7662-7. doi:10.1128/JVI.02444-09
68. Collerton J, Martin-Ruiz C, Davies K, Hilkens CM, Isaacs J, Kolenda C, et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech Ageing Dev (2012) 133(6):456-66. doi:10.1016/j.mad.2012.05.005
69. Reed RG, Greenberg RN, Segerstrom SC. Cytomegalovirus serostatus, inflammation, and antibody response to influenza vaccination in older adults: the moderating effect of beta blockade. Brain Behav Immun (2016) 61:14-20. doi:10.1016/j.bbi.2016.09.025
70. Holen E, Elsayed S. Effects of ß2 adrenoceptor agonists on T-cell subpopulations. APMIS (1998) 106(9):849-57. doi:10.1111/j.1699-0463.1998.tb00231.x
71. Black S, Nicolay U, Del Giudice G, Rappuoli R. Influence of statins on influenza vaccine response in elderly individuals. J Infect Dis (2016) 213(8):1224-8. doi:10.1093/infdis/jiv456
72. McLean HQ, Chow BDW, VanWormer JJ, King JP, Belongia EA. Effect of statin use on influenza vaccine effectiveness. J Infect Dis (2016) 214(8):11150-8. doi:10.1093/infdis/jiw335
73. Huemer HP. Possible immunosuppressive effects of drug exposure and environmental and nutritional effects on infection and vaccination. Mediators Inflamm (2015) 2015. doi:10.1155/2015/349176
74. Salami JA, Warraich H, Valero-Elizondo J, Spatz ES, Desai NR, Rana JS, et al. National trends in statin use and expenditures in the US adult population from 2002 to 2013: insights from the medical expenditure panel survey. JAMA Cardiol (2017) 2(1):56-65. doi:10.1001/jamacardio.2016.4700
75. Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA (2008) 300(24):2867-78. doi:10.1001/jama.2008.892
76. Wang C, Liu Y, Xu LT, Jackson KJL, Roskin KM, Pham TD, et al. Effects of aging, CMV infection, and EBV infection on human B cell repertoires. J Immunol (2014) 192(2):603-11. doi:10.4049/jimmunol.1301384
77. de Bourcy CF, Angel CJ, Vollmers C, Dekker CL, Davis MM, Quake SR. Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging. Proc Natl Acad Sci U S A (2017) 114(5):1105-10. doi:10.1073/pnas.1617959114
78. Sun J, Madan R, Karp CL, Braciale TJ. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med (2009) 15(3):277-84. doi:10.1038/nm.1929
79. Wahl A, McCoy W, Schafer F, Bardet W, Buchli R, Fremont DH, et al. T-cell tolerance for variability in an HLA class I-presented influenza a virus epitope. J Virol (2009) 83(18):9209-14. doi:10.1128/JVI.00932-09
80. McMichael AJ, Gotch FM, Noble GR, Beare PAS. Cytotoxic T-cell immunity to influenza. N Engl J Med (1983) 309:13-7. doi:10.1056/NEJM198307073090103
81. Hsu JP, Phoon MC, Koh GCH, Chen MIC, Lee VJ, Wu Y, et al. Comparison of neutralizing antibody and cell-mediated immune responses to pandemic H1N1 2009 influenza virus before and after H1N1 2009 influenza vaccination of elderly subjects and healthcare workers. Int J Infect Dis (2012) 16(8):e621-7. doi:10.1016/j.ijid.2012.04.010
82. Wilkinson TM, Li CKF, Chui CSC, Huang AKY, Perkins M, Liebner JC, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med (2012) 18(2):274-80. doi:10.1038/nm.2612
83. Schulz AR, Mälzer JN, Domingo C, Jürchott K, Grützkau A, Babel N, et al. Low thymic activity and dendritic cell numbers are associated with the immune response to primary viral infection in elderly humans. J Immunol (2015) 195(10):4699-711. doi:10.4049/jimmunol.1500598
84. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev (2005) 205(1):158-69. doi:10.1111/j.0105-2896.2005.00256.x
85. O'Bryan JM, Woda M, Co M, Mathew A, Rothman AL. Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections. Immun Ageing (2013) 10:37. doi:10.1186/1742-4933-10-37
86. Wertheimer AM, Bennett MS, Park B, Uhrlaub JL, Martinez C, Pulko V, et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J Immunol (2014) 192(5):2143-55. doi:10.4049/jimmunol.1301721
87. Novak EJ, Liu AW, Nepom GT, Kwok WW. MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen. J Clin Invest (1999) 104(12):R63-7. doi:10.1172/JCI8476
88. Marshall D, Sealy R, Sangster M, Coleclough C. Cells primed during influenza virus infection provide help for qualitatively distinct antibody responses to subsequent immunization. J Immunol (1999) 163(9):4673-82.
89. Reiner SL, Sallusto F, Lanzavecchia A. Division of labor with a workforce of one: challenges in specifying effector and memory T cell fate. Science (2007) 317(5838):622-5. doi:10.1126/science.1143775
90. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science (2007) 317(5838):627-9. doi:10.1126/science.1142331
91. Wahl SM, Chen W. Transforming growth factor-ß-induced regulatory T cells referee inflammatory and autoimmune diseases. Arthritis Res Ther (2005) 7(2):62-8. doi:10.1186/ar1504
92. Mansfield AS, Nevala WK, Dronca RS, Leontovich AA, Shuster L, Markovic SN. Normal ageing is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes. Clin Exp Immunol (2012) 170(2):186-93. doi:10.1111/j.1365-2249.2012.04644.x
93. Hsu H-C, Scott DK, Mountz JD. Impaired apoptosis and immune senescence-cause or effect? Immunol Rev (2005) 205(1):130-46. doi:10.1111/j.0105-2896.2005.00270.x
94. Taylor SF, Cottey RJ, Zander DS, Bender BS. Influenza infection of beta 2-microglobulin-deficient (beta 2m-/-) mice reveals a loss of CD4+ T cell functions with aging. J Immunol (1997) 159(7):3453-9.
95. Graham M, Braciale V, Braciale T. Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med (1994) 180(4):1273-82. doi:10.1084/jem.180.4.1273
96. Schmitt N, Morita R, Bourdery L, Bentebibel SE, Zurawski SM, Banchereau J, et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity (2009) 31(1):158-69. doi:10.1016/j.immuni.2009.04.016
97. Ma CS, Suryani S, Avery DT, Chan A, Nanan R, Santner-Nanan B, et al. Early commitment of naive human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol Cell Biol (2009) 87:590-600. doi:10.1038/icb.2009.64
98. Agrawal A, Su H, Chen J, Osann K, Agrawal S, Gupta S. Increased IL-21 secretion by aged CD4+T cells is associated with prolonged STAT-4 activation and CMV seropositivity. Aging (2012) 4(9):648-59. doi:10.18632/aging.100490
99. Fröhlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science (2009) 324(5934):1576-80. doi:10.1126/science.1172815
100. Yi JS, Du M, Zajac AJ. A vital role for IL-21 in the control of a chronic viral infection. Science (2009) 324(5934):1572-6. doi:10.1126/science.1175194
101. Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science (2009) 324(5934):1569-72. doi:10.1126/science.1174182
102. Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang Z, Avanesyan L, et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest (2011) 121(3):1154-62. doi:10.1172/JCI44198
103. Dodd JS, Clark D, Muir R, Korpis C, Openshaw PJM. Endogenous IL-21 regulates pathogenic mucosal CD4 T-cell responses during enhanced RSV disease in mice. Mucosal Immunol (2013) 6(4):704-17. doi:10.1038/mi.2012.108
104. Boyden AW, Legge KL, Waldschmidt TJ. Pulmonary infection with influenza a virus induces site-specific germinal center and T follicular helper cell responses. PLoS One (2012) 7(7):e40733. doi:10.1371/journal.pone.0040733
105. Crotty S. A brief history of T cell help to B cells. Nat Rev Immunol (2015) 15(3):185-9. doi:10.1038/nri3803
106. Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4+ T cells in immunity to viruses. Nat Rev Immunol (2012) 12(2):136-48. doi:10.1038/nri3152
107. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med (2000) 192(11):1545-52. doi:10.1084/jem.192.11.1545
108. Ozaki K, Spolski R, Feng CG, Qi C-F, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science (2002) 298(5598):1630-4. doi:10.1126/science.1077002
109. Spensieri F, Borgogni E, Zedda L, Bardelli M, Buricchi F, Volpini G, et al. Human circulating influenza-CD4+ ICOS1+IL-21+ T cells expand after vaccination, exert helper function, and predict antibody responses. Proc Natl Acad Sci U S A (2013) 110(35):14330-5. doi:10.1073/pnas.1311998110
110. Bentebibel S-E, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med (2013) 5(176):176ra32. doi:10.1126/scitranslmed.3005191
111. Herati RS, Reuter MA, Dolfi DV, Mansfield KD, Aung H, Badwan OZ, et al. Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. J Immunol (2014) 193(7):3528-37. doi:10.4049/jimmunol.1302503
112. Parmigiani A, Alcaide ML, Freguja R, Pallikkuth S, Frasca D, Fischl MA, et al. Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation. PLoS One (2013) 8(11):e79816. doi:10.1371/journal.pone.0079816
113. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med (2005) 202(5):673-85. doi:10.1084/jem.20050882
114. Vescovini R, Biasini C, Fagnoni FF, Telera AR, Zanlari L, Pedrazzoni M, et al. Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects. J Immunol (2007) 179(6):4283-91. doi:10.4049/jimmunol.179.6.4283
115. Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavic I, Lucin P, et al. Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med (1998) 188(6):1047-54. doi:10.1084/jem.188.6.1047
116. Pera A, Campos C, López N, Hassouneh F, Alonso C, Tarazona R, et al. Immunosenescence: implications for response to infection and vaccination in older people. Maturitas (2015) 82(1):50-5. doi:10.1016/j.maturitas.2015.05.004
117. Waller ECP, Day E, Sissons JGP, Wills MR. Dynamics of T cell memory in human cytomegalovirus infection. Med Microbiol Immunol (2008) 197(2):83-98. doi:10.1007/s00430-008-0082-5
118. Almanzar G, Schwaiger S, Jenewein B, Keller M, Herndler-Brandstetter D, Würzner R, et al. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-Cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol (2005) 79(6):3675-83. doi:10.1128/JVI.79.6.3675-3683.2005
119. O'Hara GA, Welten SPM, Klenerman P, Arens R. Memory T cell inflation: understanding cause and effect. Trends Immunol (2012) 33(2):84-90. doi:10.1016/j.it.2011.11.005
120. Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, et al. The immune system in extreme longevity. Exp Gerontol (2008) 43(2):61-5. doi:10.1016/j.exger.2007.06.008
121. Gamadia LE, Remmerswaal EBM, Weel JF, Bemelman F, van Lier RAW, Ten Berge IJM. Primary immune responses to human CMV: a critical role for IFN-γ-producing CD4+ T cells in protection against CMV disease. Blood (2003) 101(7):2686-92. doi:10.1182/blood-2002-08-2502
122. Gibson L, Piccinini G, Lilleri D, Revello MG, Wang Z, Markel S, et al. Human cytomegalovirus proteins pp65 and immediate early protein 1 are common targets for CD8+ T cell responses in children with congenital or postnatal human cytomegalovirus infection. J Immunol (2004) 172(4):2256-64. doi:10.4049/jimmunol.172.4.2256
123. Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB. Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol (2006) 177(1):450-8. doi:10.4049/jimmunol.177.1.450
124. Ouyang Q, Wikby A, Walter S, Aubert G, Dodi AI, Travers P, et al. Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J Clin Immunol (2003) 23(4):247-57. doi:10.1023/A:1024580531705
125. Franceschi C, Bonafè M, Valensin S. Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine (2000) 18(16):1717-20. doi:10.1016/S0264-410X(99)00513-7
126. Cicin-Šain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, et al. Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates. Proc Natl Acad Sci U S A (2007) 104(50):19960-5. doi:10.1073/pnas.0705905104
127. Ahmed M, Lanzer KG, Yager EJ, Adams PS, Johnson LL, Blackman MA. Clonal expansions and loss of receptor diversity in the naive CD8 T cell repertoire of aged mice. J Immunol (2009) 182(2):784-92. doi:10.4049/jimmunol.182.2.784
128. Tsukamoto H, Clise-Dwyer K, Huston GE, Duso DK, Buck AL, Johnson LL, et al. Age-associated increase in lifespan of naïve CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc Natl Acad Sci U S A (2009) 106(43):18333-8. doi:10.1073/pnas.0910139106
129. Kilpatrick RD, Rickabaugh T, Hultin LE, Hultin P, Hausner MA, Detels R, et al. Homeostasis of the naive CD4(+) T cell compartment during aging. J Immunol (2008) 180(3):1499-507. doi:10.4049/jimmunol.180.10.6437-a
130. Gil A, Yassai MB, Naumov YN, Selin LK. Narrowing of human influenza a virus-specific T cell receptor a and ß repertoires with increasing age. J Virol (2015) 89(8):4102-16. doi:10.1128/JVI.03020-14
131. van de Sandt CE, Kreijtz JHCM, Rimmelzwaan GF. Evasion of influenza a viruses from innate and adaptive immune responses. Viruses (2012) 4(9):1438-76. doi:10.3390/v4091438
132. Topham DJ, Tripp RA, Doherty PC. CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J Immunol (1997) 159(11):5197-200.
133. Brincks EL, Katewa A, Kucaba TA, Griffith TS, Legge KL. CD8 T cells utilize TRAIL to control influenza virus infection. J Immunol (2008) 181(7):4918-25. doi:10.4049/jimmunol.181.7.4918
134. Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, et al. Human and mouse granzyme a induce a proinflammatory cytokine response. Immunity (2008) 29(5):720-33. doi:10.1016/j.immuni.2008.08.014
135. Brown DM, Lampe AT, Workman AM. The differentiation and protective function of cytolytic CD4 T cells in influenza infection. Front Immunol (2016) 7:93. doi:10.3389/fimmu.2016.00093
136. Shahid Z, Kleppinger A, Gentleman B, Falsey AR, McElhaney JE. Clinical and immunologic predictors of influenza illness among vaccinated older adults. Vaccine (2010) 28(38):6145-51. doi:10.1016/j.vaccine.2010.07.036
137. Zhou X, McElhaney JE. Age-related changes in memory and effector T cells responding to influenza A/H3N2 and pandemic A/H1N1 strains in humans. Vaccine (2011) 29(11):6145-51. doi:10.1016/j.vaccine.2010.12.029
138. Lee JB, Oelke M, Ramachandra L, Canaday DH, Schneck JP. Decline of influenza-specific CD8+ T cell repertoire in healthy geriatric donors. Immun Ageing (2011) 8:1. doi:10.1186/1742-4933-8-6
139. McElhaney JE, Ewen C, Zhou X, Kane KP, Xie D, Hager WD, et al. Granzyme B: correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine (2009) 27(18):2418-24. doi:10.1016/j.vaccine.2009.01.136
140. McElhaney JE, Xie D, Hager WD, Barry MB, Wang Y, Kleppinger A, et al. T cell responses are better correlates of vaccine protection in the elderly. J Immunol (2006) 176(1):6333-9. doi:10.4049/jimmunol.176.10.6333
141. Nowacki TM, Kuerten S, Zhang W, Shive CL, Kreher CR, Boehm BO, et al. Granzyme B production distinguishes recently activated CD8(+) memory cells from resting memory cells. Cell Immunol (2007) 247(1):36-48. doi:10.1016/j.cellimm.2007.07.004
142. Brown DM, Dilzer AM, Meents DL, Swain SL. CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol (2006) 177(5):2888-98. doi:10.4049/jimmunol.177.5.2888
143. Brown DM, Lee S, Garcia-Hernandez M, Swain SL. Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol (2012) 86(12):6792-803. doi:10.1128/JVI.07172-11
144. Strutt TM, McKinstry KK, Kuang Y, Bradley LM, Swain SL. Memory CD4(+) T-cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors. Proc Natl Acad Sci U S A (2012) 109(38):E2551-60. doi:10.1073/pnas.1205894109
145. McKinstry KK, Strutt TM, Buck A, Curtis JD, Dibble JP, Huston G, et al. IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high dose challenge. J Immunol (2009) 182(12):7353-63. doi:10.4049/jimmunol.0900657
146. Sun K, Torres L, Metzger DW. A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection. J Virol (2010) 84(10):5007-14. doi:10.1128/JVI.02408-09
147. McElhaney JE, Zhou X, Talbot HK, Soethout E, Bleackley RC, Granville DJ, et al. The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine (2012) 30(12):2060-7. doi:10.1016/j.vaccine.2012.01.015
148. Hiebert PR, Boivin WA, Abraham T, Pazooki S, Zhao H, Granville DJ. Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice. Exp Gerontol (2011) 46(6):489-99. doi:10.1016/j.exger.2011.02.004
149. Afonina IS, Tynan GA, Logue SE, Cullen SP, Bots M, Lüthi AU, et al. Granzyme B-dependent proteolysis acts as a switch to enhance the pro-inflammatory activity of IL-1a. Mol Cell (2011) 44(2):265-78. doi:10.1016/j.molcel.2011.07.037
150. Granville DJ. Granzymes in disease: bench to bedside. Cell Death Differ (2010) 17(4):565-6. doi:10.1038/cdd.2009.218
151. McLeod JD. Apoptotic capability in ageing T cells. Mech Ageing Dev (2001) 121(1-3):151-9. doi:10.1016/S0047-6374(00)00206-2
152. Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, et al. 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 (1994) 29(6):601-9. doi:10.1016/0531-5565(94)90073-6
153. Nociari MM, Telford W, Russo C. Postthymic development of CD28-CD8+ T cell subset: age-associated expansion and shift from memory to naive phenotype. J Immunol (1999) 162(6):3327-35.
154. Xie D, McElhaney JE. Lower GrB+CD62L(high) CD8 T(CM) effector lymphocyte response to influenza virus in older adults is associated with increased CD28(null) CD8 T lymphocytes. Mech Ageing Dev (2007) 128(5-6):392-400. doi:10.1016/j.mad.2007.05.001
155. Tortorella C, Loria MP, Piazzolla G, Schulze-Koops H, Lipsky PE, Jirillo E, et al. Age-related impairment of T cell proliferative responses related to the decline of CD28+ T cell subsets. Arch Gerontol Geriatr (1997) 26(1):55-70. doi:10.1016/S0167-4943(97)00033-2
156. Di Benedetto S, Derhovanessian E, Steinhagen-Thiessen E, Goldeck D, Muller L, Pawelec G. Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. Biogerontology (2015) 16(5):631-43. doi:10.1007/s10522-015-9563-2
157. van der Heiden M, van Zelm MC, Bartol SJW, de Rond LGH, Berbers GAM, Boots AMH, et al. Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females. Sci Rep (2016) 6:26892. doi:10.1038/srep26892
158. Derhovanessian E, Theeten H, Hähnel K, Van Damme P, Cools N, Pawelec G. Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Vaccine (2013) 31(4):685-90. doi:10.1016/j.vaccine.2012.11.041
159. Derhovanessian E, Maier AB, Hähnel K, Beck R, de Craen AJM, Slagboom EP, et al. Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. J Gen Virol (2011) 92(12):2746-56. doi:10.1099/vir.0.036004-0
160. Libri V, Azevedo RI, Jackson SE, Di Mitri D, Lachmann R, Fuhrmann S, et al. Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4(+) CD45RA(+) CD27(-) T cells: the potential involvement of interleukin-7 in this process. Immunology (2011) 132(3):326-39. doi:10.1111/j.1365-2567.2010.03386.x
161. Derhovanessian E, Maier AB, Hähnel K, Zelba H, de Craen AJM, Roelofs H, et al. Lower proportion of naïve peripheral CD8+ T cells and an unopposed pro-inflammatory response to human cytomegalovirus proteins in vitro are associated with longer survival in very elderly people. Age (2013) 35(4):1387-99. doi:10.1007/s11357-012-9425-7
162. Wang Y, Zhang J, Qiao F, Zhu J, Yin F, Han H. Correlation between T lymphocyte subsets in peripheral blood lymphocytes and 2-year all-cause mortality in an apparently healthy elderly Chinese cohort. Chin Med J (Engl) (2012) 125(6):1121-6.
163. Huppert FA, Pinto EM, Morgan K, Brayne C. Survival in a population sample is predicted by proportions of lymphocyte subsets. Mech Ageing Dev (2003) 124(4):449-51. doi:10.1016/S0047-6374(03)00021-6
164. Olsson J, Wikby A, Johansson B, Löfgren S, Nilsson B-O, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev (2001) 121(1-3):157-201. doi:10.1016/S0047-6374(00)00210-4
165. Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, et al. Expansion of cytotoxic CD8+ CD28-T cells in healthy ageing people, including centenarians. Immunology (1996) 88(4):501-7. doi:10.1046/j.1365-2567.1996.d01-689.x
166. Wack A, Cossarizza A, Heltai S, Barbieri D, D'Addato S, Fransceschi C, et al. Age-related modifications of the human alphabeta T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets. Int Immunol (1998) 10(9):1281-8. doi:10.1093/intimm/10.9.1281
167. Posnett DN, Edinger JW, Manavalan JS, Irwin C, Marodon G. Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28-cytotoxic effector clones. Int Immunol (1999) 11(2):229-41. doi:10.1093/intimm/11.2.229
168. Hadrup SR, Strindhall J, Køllgaard T, Seremet T, Johansson B, Pawelec G, et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol (2006) 176(4):2645-53. doi:10.4049/jimmunol.176.4.2645
169. Strindhall J, Ernerudh J, Mörner A, Waalen K, Löfgren S, Matussek A, et al. Humoral response to influenza vaccination in relation to pre-vaccination antibody titres, vaccination history, cytomegalovirus serostatus and CD4/CD8 ratio. Infect Dis (2016) 48(6):436-42. doi:10.3109/23744235.2015.1135252
170. Johnstone J, Parsons R, Botelho F, Millar J, McNeil S, Fulop T, et al. T-cell phenotypes predictive of frailty and mortality in elderly nursing home residents. J Am Geriatr Soc (2017) 65(1):153-9. doi:10.1111/jgs.14507
171. Taubenberger JK, Kash JC. Influenza virus evolution, host adaptation and pandemic formation. Cell Host Microbe (2010) 7(6):440-51. doi:10.1016/j.chom.2010.05.009
172. Heiny AT, Miotto O, Srinivasan KN, Khan AM, Zhang GL, Brusic V, et al. Evolutionarily conserved protein sequences of influenza A viruses, avian and human, as vaccine targets. PLoS One (2007) 2(11):e1190. doi:10.1371/journal.pone.0001190
173. Effros RB. Role of T lymphocyte replicative senescence in vaccine efficacy. Vaccine (2007) 25(4):599-604. doi:10.1016/j.vaccine.2006.08.032
174. Ohmit SE, Victor JC, Rotthoff JR, Teich ER, Truscon RK, Baum LL, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med (2006) 355(24):2513-22. doi:10.1056/NEJMoa061850
175. Sasaki S, He X-S, Holmes TH, Dekker CL, Kemble GW, Arvin AM, et al. Influence of prior influenza vaccination on antibody and B-cell responses. PLoS One (2008) 3(8):e2975. doi:10.1371/journal.pone.0002975
176. Camilloni B, Nunzi E, Basileo M, Iorio AM. Antibody responses after influenza vaccination in elderly people: useful information from a 27-year study (from 1988-1989 to 2014-2015). In: Baddour M, editor. The Steps Forward in Diagnosing and Controlling Influenza. InTech (2016).
177. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet (2012) 12(1):36-44. doi:10.1016/S1473-3099(11)70295-X
178. Slütter B, Pewe LL, Lauer P, Harty JT. Rapid boosting of cross-reactive memory CD8 T-cells broadens the protective capacity of the Flumist(®) vaccine. J Immunol (2013) 190(8):3854-8. doi:10.4049/jimmunol.1202790
179. DiazGranados C, Dunning A, Jordanov E, Landolfi V, Denis M, Talbot H. High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season. Vaccine (2013) 31(6):861-6. doi:10.1016/j.vaccine.2012.12.013
180. Falsey A, Treanor J, Tornieporth N, Capellan J, Gorse G. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis (2009) 200(2):172-80. doi:10.1086/599790
181. Pilkinton MA, Nicholas KJ, Warren CM, Smith RM, Yoder SM, Talbot HK, et al. Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion. Vaccine (2017) 35(2):329-36. doi:10.1016/j.vaccine.2016.11.059
182. Kim JH, Talbot HK, Mishina M, Zhu Y, Chen J, Cao W, et al. High-dose influenza vaccine favors acute plasmablast responses rather than long-term cellular responses. Vaccine (2016) 34(38):4594-601. doi:10.1016/j.vaccine.2016.07.018
183. Chen WH, Cross AS, Edelman R, Sztein MB, Blackwelder WC, Pasetti MF. Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine. Vaccine (2011) 29(16):2865-73. doi:10.1016/j.vaccine.2011.02.017
184. DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med (2014) 371(7):635-45. doi:10.1056/NEJMoa1315727
185. Coler RN, Baldwin SL, Shaverdian N, Bertholet S, Reed SJ, Raman VS, et al. A synthetic adjuvant to enhance and expand immune responses to influenza vaccines. PLoS One (2010) 5(10):e13677. doi:10.1371/journal.pone.0013677
186. Behzad H, Huckriede ALW, Haynes L, Gentleman B, Coyle K, Wilschut JC, et al. GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J Infect Dis (2011) 205(3):466-73. doi:10.1093/infdis/jir769
187. Coler RN, Bertholet S, Moutaftsi M, Guderian JA, Windish HP, Baldwin SL, et al. Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant. PLoS One (2011) 6(1):e16333. doi:10.1371/journal.pone.0016333
188. Janssen N, Derhovanessian E, Demuth I, Arnaout F, Steinhagen-Thiessen E, Pawelec G. Responses of dendritic cells to TLR-4 stimulation are maintained in the elderly and resist the effects of CMV infection seen in the young. J Gerontol A Biol Sci Med Sci (2016) 71(9):1117-23. doi:10.1093/gerona/glv119
189. Lambe T, Carey JB, Li Y, Spencer AJ, van Laarhoven A, Mullarkey CE, et al. Immunity against heterosubtypic influenza virus induced by adenovirus and MVA expressing nucleoprotein and matrix protein-1. Sci Rep (2013) 3:1443. doi:10.1038/srep01443
190. Epstein SL, Tumpey TM, Misplon JA, Lo C-Y, Cooper LA, Subbarao K, et al. DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice. Emerg Infect Dis (2002) 8(8):796-801. doi:10.3201/eid0808.010476
191. Doucet J-D, Forget M-A, Grange C, Rouxel RN, Arbour N, von Messling V, et al. Endogenously expressed matrix protein M1 and nucleoprotein of influenza A are efficiently presented by class I and class II major histocompatibility complexes. J Gen Virol (2011) 92(5):1162-71. doi:10.1099/vir.0.029777-0
192. Minor DP. Assaying the potency of influenza vaccines. Vaccines (Basel) (2015) 3(1):90-104. doi:10.3390/vaccines3010090
193. Brito LA, Chan M, Shaw CA, Hekele A, Carsillo T, Schaefer M, et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol Ther (2014) 22(12):2118-29. doi:10.1038/mt.2014.133
194. Bogers WM, Oostermeijer H, Mooij P, Koopman G, Verschoor EJ, Davis D, et al. Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV Type 1 envelope with a cationic nanoemulsion. J Infect Dis (2015) 211(6):647-55. doi:10.1093/infdis/jiu522
195. Edwards DK, Jasny E, Yoon H, Horscroft N, Schanen B, Geter T, et al. Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response. J Transl Med (2017) 15(1):798-801. doi:10.1186/s12967-016-1111-6
196. Petsch B, Schnee M, Vogel AB, Lange E, Hoffmann B, Voss D, et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol (2012) 30(12):1210-6. doi:10.1038/nbt.2436
197. Hekele A, Bertholet S, Archer J, Gibson DG, Palladino G, Brito LA, et al. Rapidly produced SAM(®) vaccine against H7N9 influenza is immunogenic in mice. Emerg Microbes Infect (2013) 2(8):e52. doi:10.1038/emi.2013.54
198. Brazzoli M, Magini D, Bonci A, Buccato S, Giovani C, Kratzer R, et al. Induction of broad-based immunity and protective efficacy by self-amplifying mRNA vaccines encoding influenza virus hemagglutinin. J Virol (2016) 90(1):332-44. doi:10.1128/JVI.01786-15
199. Berthoud TK, Hamill M, Lillie PJ, Hwenda L, Collins KA, Ewer KJ, et al. Potent CD8(+) T-cell immunogenicity in humans of a novel heterosubtypic influenza A vaccine, MVA-NP+M1. Clin Infect Dis (2011) 52(1):1-7. doi:10.1093/cid/ciq015
200. Antrobus RD, Lillie PJ, Berthoud TK, Spencer AJ, McLaren JE, Ladell K, et al. A T cell-inducing influenza vaccine for the elderly: safety and immunogenicity of MVA-NP+M1 in adults aged over 50 years. PLoS One (2012) 7(10):e48322. doi:10.1371/journal.pone.0048322
201. Peng B, Wang LR, Gómez-Román VR, Davis-Warren A, Montefiori DC, Kalyanaraman VS, et al. Replicating rather than nonreplicating adenovirus-human immunodeficiency virus recombinant vaccines are better at eliciting potent cellular immunity and priming high-titer antibodies. J Virol (2005) 79(16):10200-9. doi:10.1128/JVI.79.16.10200-10209.2005
202. Bodewes R, de Mutsert G, van der Klis FRM, Ventresca M, Wilks S, Smith DJ, et al. Prevalence of antibodies against seasonal influenza A and B viruses in children in Netherlands. Clin Vaccine Immunol (2011) 18(3):469-76. doi:10.1128/CVI.00396-10
203. Gras S, Kedzierski L, Valkenburg SA, Laurie K, Liu YC, Denholm JT, et al. Cross-reactive CD8(+) T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses. Proc Natl Acad Sci U S A (2010) 107(28):12599-604. doi:10.1073/pnas.1007270107
204. Webster RG. Immunity to influenza in the elderly. Vaccine (2000) 18(16):1686-9. doi:10.1016/S0264-410X(99)00507-1
205. Agrati C, Gioia C, Lalle E, Cimini E, Castilletti C, Armignacco O, et al. Association of profoundly impaired immune competence in H1N1v-infected patients with a severe or fatal clinical course. J Infect Dis (2010) 202(5):681-9. doi:10.1086/655469
206. Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med (2003) 9(9):1121-7. doi:10.1038/nm917
207. Hammarlund E, Lewis MW, Carter SV, Amanna I, Hansen SG, Strelow LI, et al. Multiple diagnostic techniques identify previously vaccinated individuals with protective immunity against monkeypox. Nat Med (2005) 11(9):1005-11. doi:10.1038/nm1273
208. Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci U S A (2003) 100(25):15053-8. doi:10.1073/pnas.2433717100
209. Valkenburg SA, Venturi V, Dang THY, Bird NL, Doherty PC, Turner SJ, et al. Early priming minimizes the age-related immune compromise of CD8(+) T cell diversity and function. PLoS Pathog (2012) 8(2):e1002544. doi:10.1371/journal.ppat.1002544
210. Kissling E, Nunes B, Robertson C, Valenciano M, Reuss A, Larrauri A, et al. I-MOVE multicentre case-control study 2010/11 to 2014/15: is there within-season waning of influenza type/subtype vaccine effectiveness with increasing time since vaccination? Euro Surveill (2016) 21:16. doi:10.2807/1560-7917.ES.2016.21.16.30201
211. Cordero E, Roca-Oporto C, Bulnes-Ramos A, Aydillo T, Gavaldà J, Moreno A, et al. Two doses of inactivated influenza vaccine improve immune response in solid organ transplant recipients: results of TRANSGRIPE 1-2, a randomized controlled clinical trial. Clin Infect Dis (2017) 64(7):829-38. doi:10.1093/cid/ciw855
212. Oxford JS, Al-Jabri AA, Lambkin R, Palache AM, Fleming DM. Non-responders to egg grown influenza vaccine seroconvert after booster immunization with MDCK cell grown vaccine. Vaccine (2003) 21(21-22):2743-6. doi:10.1016/S0264-410X(03)00214-7
213. McElhaney JE, Hooton JW, Hooton N, Bleackley RC. Comparison of single versus booster dose of influenza vaccination on humoral and cellular immune responses in older adults. Vaccine (2005) 23(25):3294-300. doi:10.1016/j.vaccine.2005.01.080
214. Hoft DF, Lottenbach K, Goll JB, Hill H, Winokur PL, Patel SM, et al. Priming vaccination with influenza virus H5 hemagglutinin antigen significantly increases the duration of T cell responses induced by a heterologous H5 booster vaccination. J Infect Dis (2016) 214(7):1020-9. doi:10.1093/infdis/jiw310
215. Sijmons S, Thys K, Mbong Ngwese M, Van Damme E, Dvorak J, Van Loock M, et al. High-throughput analysis of human cytomegalovirus genome diversity highlights the widespread occurrence of gene-disrupting mutations and pervasive recombination. J Virol (2015) 89(15):7673-95. doi:10.1128/JVI.00578-15
216. Ross SA, Novak Z, Pati S, Patro RK, Blumenthal J, Danthuluri VR, et al. Mixed infection and strain diversity in congenital cytomegalovirus infection. J Infect Dis (2011) 204(7):1003-7. doi:10.1093/infdis/jir457
217. Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang M-L, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med (2009) 360(12):1191-9. doi:10.1056/NEJMoa0804749
218. Schleiss MR, Bierle CJ, Swanson EC, McVoy MA, Wang JB, Al-Mahdi Z, et al. Vaccination with a live attenuated cytomegalovirus devoid of a protein kinase R inhibitory gene results in reduced maternal viremia and improved pregnancy outcome in a guinea pig congenital infection model. J Virol (2015) 89(19):9727-38. doi:10.1128/JVI.01419-15
219. Mori T, Kanda Y, Takenaka K, Okamoto S, Kato J, Kanda J, et al. Safety of ASP0113, a cytomegalovirus DNA vaccine, in recipients undergoing allogeneic hematopoietic cell transplantation: an open-label phase 2 trial. Int J Hematol (2017) 105(2):206-12. doi:10.1007/s12185-016-2110-3
220. Dropulic LK, Cohen JI. Update on new antivirals under development for the treatment of double-stranded DNA virus infections. Clin Pharmacol Ther (2010) 88(5):610-9. doi:10.1038/clpt.2010.178
221. Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother (2010) 54(3):1290-7. doi:10.1128/AAC.01596-09