Immunologic Research

, Volume 29, Issue 1–3, pp 113–124 | Cite as

Immunity to influenza

The challenges of protecting an aging population
  • Jacqueline M. Katz
  • Julie Plowden
  • Mary Renshaw-Hoelscher
  • Xiuhua Lu
  • Terrence M. Tumpey
  • Suryaprakash Sambhara
Immunology at Emory University


Influenz a viruses cause annual epidemics and occasional pandemics of acute respiratory disease. Improved vaccines that can overcome the decline in immune function with aging and/or can induce broader immunity to novel pandemic strains are a high priority. To design improved vaccines for the elderly, we need to better understand the effects of age on both innate and adaptive immunity. In a murine model, we have determined that defects in antigen-presenting cell (APC) expression of pattern-recognition molecules, costimulatory molecules, and cytokine production may play an important role in the reduced clonal expansion of T cells in aging. The use of immunomodulators such as adjuvants may overcome some of the defects of aging immunity and may also be, useful in the development of improved vaccines for avian influenza A subtypes that pose a pandemic threat. Several novel strategies including the use of ISCOM-formulated vaccines, mucosal delivery, or DNA vaccination provided cross-subtype protection that could provide an important component of immunity in the event of a pandemic.

Key words

Influenza virus Immune response Aging Pandemics 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Simonsen L, Fukuda K, Schonberger LB, Cox NJ: Impact of influenza epidemics on hospitalizations J Infect Dis 2000;181:831–837.PubMedCrossRefGoogle Scholar
  2. 2.
    Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Achonberger LB: Impact of influenza epidemics on mortality: introduction of a severity index. Am J Public Health 1997;87:1944–1950.PubMedCrossRefGoogle Scholar
  3. 3.
    Thompson WW, Shay DK, Weintraub A, Brammer L, Cox NJ, Anderson LJ, Fukuda K: Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179–186.PubMedCrossRefGoogle Scholar
  4. 4.
    Centers for Disease Control and Prevention, National Center for Health Statistics, Health United States 1998. US Department of Health and Human Services, CDC, 1998; DHHS publication, no. (PHS) 98–1232.Google Scholar
  5. 5.
    Centers for Disease Control and Prevention. Prevention and Control of Influenza-recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbid Mortal Wkly 2003;52:1–35.Google Scholar
  6. 6.
    Patriarca PA, Weber JA, Parker RA, et al.: Efficacy of influenza vaccine in nursing homes reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA 1985;253:1136–1139.PubMedCrossRefGoogle Scholar
  7. 7.
    Monto AS, Hornbuckle K, Ohmit SE: Influenza vaccine effectiveness among elderly nursing home residents: a cohort study. Am J Epidemiol 2001;154:15–60.CrossRefGoogle Scholar
  8. 8.
    Wright PF, Webster RG: Orthomyxoviruses. In Field's Virology, 4th ed. Knipe DM, Howley PM, eds.. Lippincott-Raven, Philadelphia, 2001, pp. 1533–1579.Google Scholar
  9. 9.
    Subbarao K, Katz JM: Avian influenza viruses infecting humans. Cell Mol Life Sci 2000;57:1770–1784.PubMedCrossRefGoogle Scholar
  10. 10.
    Centers for Disease Control and Prevention: Update: influenza activity: United States and Worldwide, 2002–03 season and composition of the 2003–04 influenza vaccine. Morbid Mortal Wkly 2003;52:516–521.Google Scholar
  11. 11.
    Treanor JJ, Wilkinson BE, Masseoud F, Hu-Primmer J, Battaglia R, O'Brien D, et al.: Safety and immuno-genicity of a recombinant hemagglutinin vaccine for H5 influenza in humans. Vaccine 2001;19:1732–1737.PubMedCrossRefGoogle Scholar
  12. 12.
    Nicholson KG, Colegate AE, Podda A, Stephenson I, Wood J, Ypma E, Zambon MC: Safety and antigenicity of non-adju vanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomized trial of two potential vaccines against H5N1 influenza. Lancet 2001;357:1937–1943.PubMedCrossRefGoogle Scholar
  13. 13.
    Simorsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K: Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53–60.Google Scholar
  14. 14.
    Nicholson KG, Kent J, Hammersley V, Cancio E: Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden. Br Med J 1997;315:1060.Google Scholar
  15. 15.
    Crossley KB, Peterson PK. Infections in the elderly. In Principles and Practice of Infectious Diseases 5th ed. Mandell GL, Bennett JE, Dolin R, eds. Churchill Livingstone. Philadelphia, 2000, pp. 3164–3169.Google Scholar
  16. 16.
    Meyer KC: The role of immunity in susceptibility to respiratory infection in the gaing lung. Respir Physiol 2001;128:23.PubMedCrossRefGoogle Scholar
  17. 17.
    Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M: Immunosenescence and infectious diseases. Microbes Infect 2001:3:851–857.PubMedCrossRefGoogle Scholar
  18. 18.
    Miller RA: The aging immune system: primer and prospectus. Science 1996;273:70–74.PubMedCrossRefGoogle Scholar
  19. 19.
    Claeys S, de Belder T, Holtappels G, Gevnert P, Verhasselt B, van Cauwenberge P, Bachert C: Human betadefensins and toll-like receptors in the upper airway. Allergy 2003:58:748–753.PubMedCrossRefGoogle Scholar
  20. 20.
    Hoffman JA, Kafatos FC, Janeway CA, Ezekowitz RA: Phylogenetic perspectives in innate immunity. Science 1999;284:1313–1318.CrossRefGoogle Scholar
  21. 21.
    Akira S, Takeda K, Kaisho T: Toll-like receptors:critical proteins linking innate and adaptive immunity. Nature Immunol 2001;2:675–680.CrossRefGoogle Scholar
  22. 22.
    Alexopoulou LA, Holt C, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-κB by toll-like receptor 3. Nature 2001;41:732–738.CrossRefGoogle Scholar
  23. 23.
    Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al.: Small anti-viral compunds activate immune cells via the TLR7 My D88-dependent signaling pathway. Nature Immunol 2002;3:196–200.CrossRefGoogle Scholar
  24. 24.
    Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S: Impaired Toll-like receptor expression and function in aging. J Immunol 2002;169:4697–4701.PubMedGoogle Scholar
  25. 25.
    Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, et al. T cells and aging, January 2002 update. Front. Biosci 2002;7:56–183.Google Scholar
  26. 26.
    Effros RB, Cai Z, Linton PJ: CD8 T cells and aging. Crit Rev Immunol 2003;23:61–80.CrossRefGoogle Scholar
  27. 27.
    Sambhara S, Kurichh A, Miranda R, James O, Underdown B, Klein M, et al.: Severe impairment of primary but not memory responses to influenza viral antigens in aged mice. Co-stimulation in vivo partially reverses impaired primary immune responses. Cellular Immunol 2001;210:1–4.CrossRefGoogle Scholar
  28. 28.
    Grubeck-Loebenstein B: Changes in the aging immune system. Biologicals 1997;25:205–208.PubMedCrossRefGoogle Scholar
  29. 29.
    Effros RB, Walford RL: The effect of age on the antigen-presenting mechanism in limiting dilution precursor cell frequency analysis. Cell Immunol 1994;88:53–539.Google Scholar
  30. 30.
    Davenport FM, Hennessy AV, Askin FB: Lack of adjuvant effect of AIPO4 on purified in fluenza hemagglutinin in man. J Immunol 1968;100:1139–1140.PubMedGoogle Scholar
  31. 31.
    Minutello M, Senatore F, Cecchinelli G, Bianchi M, Andreani T, Podda A, Crovari, P: Safety and immunogenicity of an inactivated subunit in fluenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine 1999;17:99–104.PubMedCrossRefGoogle Scholar
  32. 32.
    De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, et al.: Safety and immunogenicity of MF-59-adjuvanted influenza vaccine in the elderly. Vaccine 1999;17:3094–3101.PubMedCrossRefGoogle Scholar
  33. 33.
    Katz JM, Lu X, Todd CW, Newman MJ: A nonionic block co-polymer adjuvant (CRL1005) enhances the immunogenicity and efficacy of inactivated influenza vaccine in young and aged mice. Vaccine 2000;18:2177–2187.PubMedCrossRefGoogle Scholar
  34. 34.
    deJong JC, Claas EC, Osterhaus AD, Webster RG, Lim WL: A pandemic waming. Nature 1997;389:554.PubMedCrossRefGoogle Scholar
  35. 35.
    Claas EC, Osterhaus AD, van Beek R, de Jong JC, Rimmelzwaan GF, Senne DA, et al.: Human influenza H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 1998;351:472–477.PubMedCrossRefGoogle Scholar
  36. 36.
    Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, et al.: Characterization of anavian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 1998;279:393–396.PubMedCrossRefGoogle Scholar
  37. 37.
    Guo YJ, Li JW, Cheng I, Wang M, Zhou Y, Li XH, et al.: Discovery of humans infected by avian influenza A (H9N2) virus. Chinese J Exp Clin Virol, 1999;15:105–108.Google Scholar
  38. 38.
    Lin YP, Shaw M, Gregory V, Cameron K, Lim W, Klimov A, et al.: Avian-to-human-transmission of H9N2 subtype influenza A viruses: Relationship between H9N2 and H5N1 human isolates. Proc Natl Acad Sci USA 2000;97:9654–9548.PubMedCrossRefGoogle Scholar
  39. 39.
    Gao P, Watanabe S, Ito T, Goto H, Wells K, McGregor M, et al.: Biological heterogeneity, including systemic replication in mice, of H5N1 influenza A virus isolates from humans in Hong Kong. J Virol, 1999;73:3184–3189.PubMedGoogle Scholar
  40. 40.
    Lu X, Tumpey TM, Morken T, Zaki SR, Cox NJ, Katz JM: A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans. J Virol 1999;73:5903–5911.PubMedGoogle Scholar
  41. 41.
    Tumpey TM, Lu X, Morken T, Zaki SR, Katz JM: Depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza A (H5N1) virus isolated from humans. J Virol 2000;74:6105–6116.PubMedCrossRefGoogle Scholar
  42. 42.
    Cheung CY, Poon LLM, Lau AS, Luk W, Lau YL, Shortridge KF, et al.: Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002;360:1831–1837.PubMedCrossRefGoogle Scholar
  43. 43.
    Seo SH, Hoffmann E, Webster RG: Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 2002;8:950–954.PubMedCrossRefGoogle Scholar
  44. 44.
    Zitzow LA, Rowe T, Morken T, Shieh W-J, Zaki S, Katz JM: Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J Virol 2002;76:4420–4429.PubMedCrossRefGoogle Scholar
  45. 45.
    Gerdil C: The annual production cycle for influenza vaccine. Vaccine 2003;21:1776–1779.PubMedCrossRefGoogle Scholar
  46. 46.
    Schulman JL, Kilbourne ED: Induction of partial specific heterotypic immunity in mice by a single infection with influenza A virus. J Bacteriol 1965;89:170–177.PubMedGoogle Scholar
  47. 47.
    Liang S, Mozdzanowska K, Pallandino G, Gerhard W: Heterosubtypic immunity to influenza type A virus in mice. J Immunol 1994;152:1653–1661.PubMedGoogle Scholar
  48. 48.
    Sonoguchi T, Naito H, Hara M, Takeuchi Y, Fukumi H: Cross-subtype protection in humans during sequential overlapping and/or concurrent epidemics caused by H3N2 and H1N1 virus infections. J Infect Dis 1985;151:81–88.PubMedGoogle Scholar
  49. 49.
    Sambhara S, Kurichh A, Miranda R, Tumpey T, Rowe T, Renshaw M, et al.: Heterosubtypic immunity against human Influenza A viruses including recently emerged avian H5 and H9 viruses induced by Flu-ISCOM vaccine in mice requires both CTL and macrophage function. Cell Immunol 2001;211:143–153.PubMedCrossRefGoogle Scholar
  50. 50.
    Tumpey T, Renshaw M, Clements JD, Katz JM: Mucosal delivery of inactivated influenza vaccine induces B cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection. J Virol 2001;75:5141–5150.PubMedCrossRefGoogle Scholar
  51. 51.
    Epstein SL, Tumpey TM, Misplon JA, Lo CY, Cooper LA, Subbarao K, et al.: DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice. Emerg Infect Dis 2002;8:796–801.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Jacqueline M. Katz
    • 1
  • Julie Plowden
    • 1
  • Mary Renshaw-Hoelscher
    • 1
  • Xiuhua Lu
    • 1
  • Terrence M. Tumpey
    • 1
  • Suryaprakash Sambhara
    • 1
  1. 1.Influenza Branch, Division of Viral and Rickettsial DiseasesCenters for Disease Control and PreventionAtlanta

Personalised recommendations