Optimizing Response to Vaccination in the Elderly

  • Diana BoraschiEmail author
  • Rino Rappuoli
  • Giuseppe Del Giudice


The elderly population is generally “immunologically frail” and more susceptible to infectious diseases, making the need of preventive treatments (vaccination) a public health issue. However, normal vaccines that are effective in young and adult individuals are less immunogenic and less protective in the elderly, due to their impaired immune responsiveness. It is therefore necessary to design new vaccines especially suited to raise protective immunity in the elderly population. Among the several approaches recently undertaken in this direction, the case of influenza vaccination is exemplary and can be taken as paradigm of how a vaccine for the elderly is designed and developed. The approach includes higher antigen dosage, repeated challenges, different immunization routes, and use of strong adjuvants. Basically, a better knowledge of the anomalous immune responsiveness in the elderly remains the unrenounceable basis on which effective immunization strategies in immunologically frail populations should be based.


Respiratory Syncytial Virus Herpes Zoster Influenza Vaccine Influenza Vaccination Vaccine Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ansaldi F, Bacilieri S, Durando P et al (2008) Cross-protection by MF59-adjuvanted influenza vaccine: neutralizing and hemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses. Vaccine 26:1525–1529PubMedCrossRefGoogle Scholar
  2. Ansaldi F, Zancolli F, Durando P et al (2010) Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates. Vaccine 28:4123–4129PubMedCrossRefGoogle Scholar
  3. Aspinall R, Pido-Lopez J, Imami N et al (2007) Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination. Rejuvenation Res 10:5–17PubMedCrossRefGoogle Scholar
  4. Bachmann MF, Jennings GT (2011) Therapeutic vaccines for chronic diseases: successes and technical challenges. Philos Trans R Soc Lond B Biol Sci 366:2815–2822PubMedCrossRefGoogle Scholar
  5. Baldo V, Baldovin T, Pellegrini M et al (2010) Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol. doi: 10.1155/2010/517198 PubMedGoogle Scholar
  6. Beebe GW, Simon AH, Vivona S (1972) Long-term mortality follow-up of Army recruits who received adjuvant influenza virus vaccine in 1951–1953. Am J Epidemiol 95:337–346PubMedGoogle Scholar
  7. Belshe RB, Newman FK, Cannon J et al (2004) Serum antibody responses after intradermal vaccination against influenza. N Engl J Med 351:2286–2294PubMedCrossRefGoogle Scholar
  8. Belshe RB, Edwards KM, Vesikari T et al (2007a) Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 356:685–696PubMedCrossRefGoogle Scholar
  9. Belshe RB, Newman FK, Wilkins K et al (2007b) Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults. Vaccine 25:6755–6763PubMedCrossRefGoogle Scholar
  10. Ben-Yehuda A, Joseph A, Barenholz Y et al (2003a) Immunogenicity and safety of a novel IL-2-supplemented liposomal influenza vaccine (INFLUSOME-VAC) in nursing-home residents. Vaccine 21:3169–3178PubMedCrossRefGoogle Scholar
  11. Ben-Yehuda A, Joseph A, Zeira E et al (2003b) Immunogenicity and safety of a novel liposomal influenza subunit vaccine (INFLUSOME-VAC) in young adults. J Med Virol 69:560–567PubMedCrossRefGoogle Scholar
  12. Betts RF, Treanor JJ (2000) Approaches to improved influenza vaccination. Vaccine 18:1690–1695PubMedCrossRefGoogle Scholar
  13. Blank PR, Schwenkglenks M, Szucs TD (2008) Influenza vaccination coverage rates in five European countries during season 2006/07 and trends over six consecutive seasons. BMC Public Health 8:272PubMedCrossRefGoogle Scholar
  14. Brown H, Kasel JA, Freeman DM et al (1977) The immunizing effect of influenza A/New Jersey/76 (Hsw1N1) virus vaccine administered intradermally and intramuscularly to adults. J Infect Dis 136:S466–S471PubMedCrossRefGoogle Scholar
  15. Camilloni B, Neri M, Lepri E et al (2009) Cross-reactive antibodies in middle-aged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages. Vaccine 27:4099–4103PubMedCrossRefGoogle Scholar
  16. Centers for Disease Control and Prevention (2010) Estimates of deaths associated with seasonal influenza Unites States, 1976–2007. MMWR 59:1057–1062Google Scholar
  17. Crimmins EM, Finch CE (2006) Infection, inflammation, height, and longevity. Proc Natl Acad Sci U S A 103:498–503PubMedCrossRefGoogle Scholar
  18. de Bruijn IA, Nauta J, Cramer WC et al (2005) Clinical experience with inactivated, virosomal influenza vaccine. Vaccine 23(Suppl 1):S39–S49PubMedCrossRefGoogle Scholar
  19. de Bruijn IA, Nauta J, Gerez L et al (2006) The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad®) in elderly subjects. Vaccine 24:6629–6631PubMedCrossRefGoogle Scholar
  20. De Villiers PJT, Steele AD, Hiemstra LA et al (2009) Efficacy and safety of a live attenuated influenza vaccine in adults 60 years of age and older. Vaccine 28:228–234PubMedCrossRefGoogle Scholar
  21. Del Giudice G, Hilbert AK, Bugarini R et al (2006) An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine 24:3063–3065PubMedCrossRefGoogle Scholar
  22. Dupuis M, Murphy TJ, Higgins D et al (1998) Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol 186:18–27PubMedCrossRefGoogle Scholar
  23. Dupuis M, Denis-Mize K, LaBarbara A et al (2001) Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis. Eur J Immunol 31:2910–2918PubMedCrossRefGoogle Scholar
  24. Edwards MS, Baker CJ (2005) Group B streptococcal infections in elderly adults. Clin Infect Dis 41:839–847PubMedCrossRefGoogle Scholar
  25. Ellebedy AH, Lupfer C, Ghoneim HE et al (2011) Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC)in the adjuvant effect of MF59. Proc Natl Acad Sci U S A 108:2927–2932PubMedCrossRefGoogle Scholar
  26. Falsey AR (2007) Respiratory syncytial virus in adults. Semin Respir Crit Care Med 28:171–181PubMedCrossRefGoogle Scholar
  27. Flicker L, McCaul KA, Hankey GJ et al (2010) Body mass index and survival in men and women aged 70 to 75. J Am Geriatr Soc 58:234–241PubMedCrossRefGoogle Scholar
  28. Franceschi C (2007) Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev 65:S173–S176PubMedCrossRefGoogle Scholar
  29. Fujihashi K, Kiyono H (2009) Mucosal immunosenescence: new developments and vaccines to control infectious diseases. Trends Immunol 30:334–343PubMedCrossRefGoogle Scholar
  30. Galli G, Medini D, Borgogni E et al (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 106:3877–3882PubMedCrossRefGoogle Scholar
  31. Gavazzi G, Krause KH (2002) Ageing and infection. Lancet Infect Dis 2:659–666PubMedCrossRefGoogle Scholar
  32. Gibson KL, Wu YC, Barnett Y et al (2009) B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8:18–25PubMedCrossRefGoogle Scholar
  33. Goodwin K, Viboud C, Simonsen L (2006) Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24:1159–1169PubMedCrossRefGoogle Scholar
  34. Goronzy J, Li G, Yu M et al (2012) Signaling pathways in aged T cells – A reflection of T cell differentiation, cell senescence and host environment. Semin Immunol 24(5):365–372PubMedCrossRefGoogle Scholar
  35. Govaert TM, Thijs CT, Masurel N et al (1994) The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial. JAMA 272:1662–1665CrossRefGoogle Scholar
  36. Halperin W, Weiss WI, Altman R et al (1979) A comparison of the intradermal and subcutaneous routes of influenza vaccination with A/New Jersey/76 (Swine flu) and A/Victoria/75: report of a study and review of the literature. Am J Public Health 69:1247–1250PubMedCrossRefGoogle Scholar
  37. Herbert FA, Larke RP, Markstad EL (1979) Comparison of responses to influenza A/New Jersey/76-A/Victoria/75 virus vaccine administered intradermally or subcutaneously to adults with chronic respiratory disease. J Infect Dis 140:234–238PubMedCrossRefGoogle Scholar
  38. Herndler-Brandstetter D, Landgraf K, Tzankov A et al (2012) The impact of aging on memory T cell phenotype and function in the human bone marrow. J Leukoc Biol 91:197–205PubMedCrossRefGoogle Scholar
  39. Holland D, Booy R, De Looze F et al (2008) Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 198:650–658PubMedCrossRefGoogle Scholar
  40. Huckriede A, Bungener L, Stegmann T et al (2005) The virosome concept for influenza vaccines. Vaccine 23(Suppl 1):S26–S38PubMedCrossRefGoogle Scholar
  41. Johnson SA, Cambier JC (2004) Ageing, autoimmunity and arthritis: senescence of the B cell compartment. Implications for humoral immunity. Arthritis Res Ther 6:131–139PubMedCrossRefGoogle Scholar
  42. Keitel WA, Couch RB, Cate TR et al (1994) High doses of purified influenza A virus hemagglutinin significantly augment serum and nasal secretion antibody responses in healthy young adults. J Clin Microbiol 32:2468–2473PubMedGoogle Scholar
  43. Keitel WA, Cate TR, Atmar RL et al (1996) Increasing doses of purified influenza virus hemagglutinin and subvirion vaccines enhance antibody responses in the elderly. Clin Diagn Lab Immunol 3:507–510PubMedGoogle Scholar
  44. Kenney RT, Frech SA, Muenz LR et al (2004) Dose sparing with intradermal injection of influenza vaccine. N Engl J Med 351:2295–2301PubMedCrossRefGoogle Scholar
  45. Launay O, Grabar S, Bloch F et al (2008) Effect of sublingual administration of IFN-α on the immune response to influenza vaccination in institutionalized elderly individuals. Vaccine 26:4073–4079PubMedCrossRefGoogle Scholar
  46. Legrand J, Vergu E, Flahault A (2006) Real-time monitoring of the influenza vaccine field effectiveness. Vaccine 24:6605–6611PubMedCrossRefGoogle Scholar
  47. Li G, Yu M, Lee W-W et al (2012) Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med 18:1518–1524PubMedCrossRefGoogle Scholar
  48. Mosca F, Tritto E, Muzzi A et al (2008) Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci USA 105:10501–10506PubMedCrossRefGoogle Scholar
  49. Nichol KL, Nordin JD, Nelson DB et al (2007) Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med 357:1373–1381PubMedCrossRefGoogle Scholar
  50. Nikolich-Zugich J, Rudd BD (2010) Immune memory and aging: an infinite or finite resource? Curr Opin Immunol 22:535–540PubMedCrossRefGoogle Scholar
  51. Ohmit SE, Victor JC, Rotthoff JR et al (2006) Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 355:2513–2522PubMedCrossRefGoogle Scholar
  52. Panda A, Arjona A, Sapey E et al (2009) Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 30:325–333PubMedCrossRefGoogle Scholar
  53. Panda A, Qian F, Mohanty S et al (2010) Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol 184:2518–2527PubMedCrossRefGoogle Scholar
  54. Pellegrini M, Nicolay U, Lindert K et al (2009) MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine 27:6959–6965PubMedCrossRefGoogle Scholar
  55. Podda A, Del Giudice G, O’Hagan DT (2005) Chapter 9. MF59: a safe and potent adjuvant for human use. In: Schijns V, O’Hagan DT (eds) Immunopotentiators in modern medicines. Elsevier Press, AmsterdamGoogle Scholar
  56. Potter CW, Oxford JS (1979) Determinants of immunity to influenza in man. Br Med Bull 35:69–75PubMedGoogle Scholar
  57. Puig-Barberà J, Díez-Domingo J, Varea AB et al (2007) Effectiveness of the MF59TM-adjuvanted subunit influenza vaccine in preventing hospitalizations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. Vaccine 25:7313–7321PubMedCrossRefGoogle Scholar
  58. Rappuoli R, Mandl CW, Black S et al (2011) Vaccines for the twenty-first century society. Nat Rev Immunol 11:865–872PubMedGoogle Scholar
  59. Schmader K (2001) Herpes zoster in older adults. Clin Infect Dis 32:1481–1486PubMedCrossRefGoogle Scholar
  60. Seubert A, Monaci E, Pizza M et al (2008) The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol 180:5402–5412PubMedGoogle Scholar
  61. Seubert A, Calabro S, Santini L et al (2011) Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc Natl Acad Sci U S A 108:11169–11174PubMedCrossRefGoogle Scholar
  62. Shaw AC, Joshi S, Greenwood H et al (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513PubMedCrossRefGoogle Scholar
  63. Stephenson I, Nicholson KG, Hoschler K et al (2008) Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1. N Engl J Med 359:1631–1633PubMedCrossRefGoogle Scholar
  64. Treanor JJ, Mattison HR, Dumyati G et al (1992) Protective efficacy of combined live intranasal and inactivated influenza A virus vaccines in the elderly. Ann Intern Med 117:625–633PubMedCrossRefGoogle Scholar
  65. Treanor JJ, Campbell JD, Zangwill KM et al (2006) Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 354:1343–1351PubMedCrossRefGoogle Scholar
  66. United Nations, Department of Economic and Social Affairs, Population Division (2002) World population ageing 1950–2050. United Nations Publishing. Accessed 19 May 2009
  67. Van Damme P, Arnou R, Kafeja F et al (2010) Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomized comparative study. BMC Infect Dis 10:134PubMedCrossRefGoogle Scholar
  68. Vogel FR, Caillet C, Kusters IC et al (2009) Emulsion-based adjuvants for influenza vaccines. Expert Rev Vaccines 8:483–492PubMedCrossRefGoogle Scholar
  69. Wagner EH, Groves T (2002) Care for chronic diseases. Br Med J 325:913–914CrossRefGoogle Scholar
  70. Weinberger B, Herndler-Brandstetter D, Schwanninger A et al (2008) Biology of the immune response to vaccines in elderly persons. Clin Infect Dis 46:1078–1084PubMedCrossRefGoogle Scholar
  71. Wisniewski T, Konietzko U (2008) Amyloid-beta immunisation for Alzheimer’s disease. Lancet Neurol 7:805–811PubMedCrossRefGoogle Scholar
  72. World Bank (2004) World development indicators 2004. World Bank, Washington DCCrossRefGoogle Scholar
  73. World Health Organization (2005) Expert consultation on rabies. World Health Organ Tech Rep Ser 931:1–88Google Scholar
  74. Yu M, Li G, Lee W-W et al (2012) Signal inhibition by the Dual-Specific Phosphatase 4 impairs T cell-dependent B cell responses with age. Proc Natl Acad Sci U S A 109:E879–E888PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Diana Boraschi
    • 1
    Email author
  • Rino Rappuoli
    • 2
  • Giuseppe Del Giudice
    • 2
  1. 1.Lab Innate Immunity and CytokinesNational Research CouncilPisaItaly
  2. 2.Research Center, Novartis Vaccines and DiagnosticsSienaItaly

Personalised recommendations