Immunosenescence and vaccine failure in the elderly: strategies for improving response.

The immune system of the elderly is particularly susceptible to infectious diseases and displays reduced response to vaccination. The current vaccines, designed for young and adult individuals, proved less effective and less protective in old people. The world population is rapidly ageing, and consequently preventing infectious diseases in the elderly have become an important public health issue. To this end, it is necessary to develop novel vaccines especially suited to raising protective immunity in the ageing population. Approaches in this direction include high-dose vaccines, booster vaccinations, different immunisation routes, and use of new adjuvants. These approaches, still empirical, must be supported by intensive research to unravel the biological and molecular mechanisms underlying immunosenescence. Only this knowledge would allow us to design approaches to immune rejuvenation and more effective vaccines for protecting the elderly.

[1]  B. Blomberg,et al.  Aging Affects Human B Cell Responses , 2011, Journal of Clinical Immunology.

[2]  J. Ongrádi,et al.  Numerical alterations of ageing B lymphocyte subsets. , 2011, Acta physiologica Hungarica.

[3]  M. Salmon,et al.  Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging , 2009, The Journal of experimental medicine.

[4]  R. Rappuoli,et al.  Molecular and cellular signatures of human vaccine adjuvants , 2008, Proceedings of the National Academy of Sciences.

[5]  S. Reed,et al.  Use of defined TLR ligands as adjuvants within human vaccines , 2011, Immunological reviews.

[6]  Diana Boraschi,et al.  The Gracefully Aging Immune System , 2013, Science Translational Medicine.

[7]  K. Rothman,et al.  Effectiveness of Adjuvanted Influenza Vaccination in Elderly Subjects in Northern Italy , 2012, American journal of epidemiology.

[8]  M. Ventresca,et al.  The Polyfunctionality of Human Memory CD8+ T Cells Elicited by Acute and Chronic Virus Infections Is Not Influenced by Age , 2012, PLoS pathogens.

[9]  W. Keitel,et al.  Direct comparison of an inactivated subvirion influenza A virus subtype H5N1 vaccine administered by the intradermal and intramuscular routes. , 2012, The Journal of infectious diseases.

[10]  C. Verschoor,et al.  Blood CD33(+)HLA-DR(−) myeloid-derived suppressor cells are increased with age and a history of cancer , 2013, Journal of leukocyte biology.

[11]  P. Haley Species differences in the structure and function of the immune system. , 2003, Toxicology.

[12]  K. Schmader,et al.  Herpes zoster in older adults. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  D. Weiskopf,et al.  Biology of immune responses to vaccines in elderly persons. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  E. Ho,et al.  Aging is associated with altered dendritic cells subset distribution and impaired proinflammatory cytokine production , 2010, Experimental Gerontology.

[15]  F. de Looze,et al.  Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. , 2008, The Journal of infectious diseases.

[16]  E. Kovacs,et al.  In Vivo Ethanol Exposure Down-Regulates TLR2-, TLR4-, and TLR9-Mediated Macrophage Inflammatory Response by Limiting p38 and ERK1/2 Activation1 , 2005, The Journal of Immunology.

[17]  N. Jenny Inflammation in aging: cause, effect, or both? , 2012, Discovery medicine.

[18]  H. Basaga,et al.  Modulation of cell death in age-related diseases. , 2014, Current pharmaceutical design.

[19]  R. Vaughan,et al.  B-cell diversity decreases in old age and is correlated with poor health status , 2009, Aging cell.

[20]  K. Richardson,et al.  A Meta‐analysis of intradermal versus intramuscular influenza vaccines: Immunogenicity and Adverse Events , 2012, Influenza and other respiratory viruses.

[21]  R. Yung,et al.  Impaired dendritic cell function in aging leads to defective antitumor immunity. , 2008, Cancer research.

[22]  Janko Nikolich-Zugich,et al.  Immune memory and aging: an infinite or finite resource? , 2010, Current opinion in immunology.

[23]  B. Blomberg,et al.  Quantity, not quality, of antibody response decreased in the elderly. , 2011, The Journal of clinical investigation.

[24]  K. Pfeiffer,et al.  Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. , 2005, Vaccine.

[25]  Q. Zhuge,et al.  Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus , 2012, Aging.

[26]  Ruth R. Montgomery,et al.  Human innate immunosenescence: causes and consequences for immunity in old age. , 2009, Trends in immunology.

[27]  J. Ouslander,et al.  T cell subset-specific susceptibility to aging. , 2008, Clinical immunology.

[28]  Cécile Viboud,et al.  Antibody response to influenza vaccination in the elderly: a quantitative review. , 2006, Vaccine.

[29]  Ruth R. Montgomery,et al.  Age-Associated Decrease in TLR Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response , 2010, The Journal of Immunology.

[30]  Mark M. Davis,et al.  Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. , 2011, The Journal of clinical investigation.

[31]  K. Ladell,et al.  A T Cell-Inducing Influenza Vaccine for the Elderly: Safety and Immunogenicity of MVA-NP+M1 in Adults Aged over 50 Years , 2012, PloS one.

[32]  C. Franceschi Inflammaging as a major characteristic of old people: can it be prevented or cured? , 2007, Nutrition reviews.

[33]  E. Kovacs,et al.  The aging innate immune system. , 2005, Current opinion in immunology.

[34]  R. Couch,et al.  High doses of purified influenza A virus hemagglutinin significantly augment serum and nasal secretion antibody responses in healthy young adults , 1994, Journal of clinical microbiology.

[35]  Samit R. Joshi,et al.  Dysregulation of human Toll-like receptor function in aging , 2011, Ageing Research Reviews.

[36]  Jennifer P. Wang,et al.  Distinct Patterns of Dendritic Cell Cytokine Release Stimulated by Fungal β-Glucans and Toll-Like Receptor Agonists , 2009, Infection and Immunity.

[37]  Stefan Tümpel,et al.  The role of telomere shortening in somatic stem cells and tissue aging: lessons from telomerase model systems , 2012, Annals of the New York Academy of Sciences.

[38]  S. Kim,et al.  Intranasal immunization with recombinant PspA fused with a flagellin enhances cross-protective immunity against Streptococcus pneumoniae infection in mice. , 2011, Vaccine.

[39]  K. Nichol,et al.  Effectiveness of influenza vaccine in the community-dwelling elderly. , 2007, The New England journal of medicine.

[40]  Erin Burns,et al.  Estimates of deaths associated with seasonal influenza --- United States, 1976-2007. , 2010, MMWR. Morbidity and mortality weekly report.

[41]  W. Shieh,et al.  Increased MDSC Accumulation and Th2 Biased Response to Influenza A Virus Infection in the Absence of TLR7 in Mice , 2011, PloS one.

[42]  W. Parson,et al.  Naïve T Cells in the Elderly , 2006, Annals of the New York Academy of Sciences.

[43]  R. Effros Role of T lymphocyte replicative senescence in vaccine efficacy. , 2007, Vaccine.

[44]  A. Osterhaus,et al.  Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis. , 2002, Vaccine.

[45]  J. Beygo,et al.  Assessment of Antigen-Specific and Cross-Reactive Antibody Responses to an MF59-Adjuvanted A/H5N1 Prepandemic Influenza Vaccine in Adult and Elderly Subjects , 2012, Clinical and Vaccine Immunology.

[46]  C. Ewen,et al.  T Cell Responses Are Better Correlates of Vaccine Protection in the Elderly1 , 2006, The Journal of Immunology.

[47]  C. Weyand,et al.  Understanding immunosenescence to improve responses to vaccines , 2013, Nature Immunology.

[48]  Songbai Zheng,et al.  Senescent remodeling of the immune system and its contribution to the predisposition of the elderly to infections. , 2012, Chinese medical journal.

[49]  W. Blackwelder,et al.  Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine. , 2011, Vaccine.

[50]  R. Couch,et al.  Increasing doses of purified influenza virus hemagglutinin and subvirion vaccines enhance antibody responses in the elderly , 1996, Clinical and diagnostic laboratory immunology.

[51]  C. Bode,et al.  TLR-based immune adjuvants. , 2011, Vaccine.

[52]  B. Grubeck‐Loebenstein Changes in the aging immune system. , 1997, Biologicals : journal of the International Association of Biological Standardization.

[53]  W. Maloney,et al.  Stem cells and the aging hematopoietic system. , 2010, Current opinion in immunology.

[54]  G. Pawelec,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. , 2012, Vaccine.

[55]  C. Bonorino,et al.  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 , 2011, Mechanisms of Ageing and Development.

[56]  W. Weninger,et al.  Phenotype and functions of conventional dendritic cells are not compromised in aged mice , 2012, Immunology and cell biology.

[57]  Harry B. Greenberg,et al.  Influence of Prior Influenza Vaccination on Antibody and B-Cell Responses , 2008, PloS one.

[58]  C. Mandl,et al.  Vaccines for the twenty-first century society , 2012, Nature Reviews Immunology.

[59]  C. Mangione,et al.  Management of Cardiovascular Disease Risk Factors in Older Adults with Type 2 Diabetes Mellitus: 2002–2012 Literature Review , 2013, Journal of the American Geriatrics Society.

[60]  G. Pawelec,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. , 2012, Vaccine.

[61]  H. Hughes,et al.  Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members. , 2009, Vaccine.

[62]  G. Castellani,et al.  Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans , 2007, Mechanisms of Ageing and Development.

[63]  S. Reed,et al.  GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. , 2012, The Journal of infectious diseases.

[64]  K. Ishii,et al.  Adjuvants in influenza vaccines. , 2012, Vaccine.

[65]  Nicholas S. Kelley,et al.  Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. , 2012, The Lancet. Infectious diseases.

[66]  Gonzalo G. Garcia,et al.  Age-Dependent Alterations in the Assembly of Signal Transduction Complexes at the Site of T Cell/APC Interaction1 , 2000, The Journal of Immunology.

[67]  J. Wilkinson,et al.  Macrophage migration inhibitory factor‐knockout mice are long lived and respond to caloric restriction , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[68]  C. de Waure,et al.  23-valent pneumococcal polysaccharide vaccine (PPV23) for the prevention of invasive pneumococcal diseases (IPDs) in the elderly: is it really effective? , 2012, Journal of preventive medicine and hygiene.

[69]  A. Agrawal,et al.  Dendritic cells and aging: consequences for autoimmunity , 2012, Expert review of clinical immunology.

[70]  B. Grubeck‐Loebenstein,et al.  Gain and Loss of T Cell Subsets in Old Age—Age-Related Reshaping of the T Cell Repertoire , 2011, Journal of Clinical Immunology.

[71]  C W Potter,et al.  Determinants of immunity to influenza infection in man. , 1979, British medical bulletin.

[72]  R. Gasparini,et al.  Comparison between a conventional subunit vaccine and the MF59-adjuvanted subunit influenza vaccine in the elderly: an evaluation of the safety, tolerability and immunogenicity. , 2009, Journal of preventive medicine and hygiene.

[73]  D. Weiskopf,et al.  Biology of Immune Responses to Vaccines in the Elderly , 2008 .

[74]  Jean A. Roayaei,et al.  Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel. , 2009, JAMA.

[75]  D. Su,et al.  Immunosenescence: a product of the environment? , 2013, Current opinion in immunology.

[76]  C. Castelo-Branco,et al.  The immune system and aging: a review , 2014, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[77]  Ronan N. Rouxel,et al.  Endogenously expressed matrix protein M1 and nucleoprotein of influenza A are efficiently presented by class I and class II major histocompatibility complexes. , 2011, The Journal of general virology.

[78]  M. Loeb,et al.  Vaccine herd effect , 2011, Scandinavian journal of infectious diseases.

[79]  C. Bonorino,et al.  Alterations in dendritic cell function in aged mice: potential implications for immunotherapy design , 2009, Biogerontology.

[80]  C. R. Dunston,et al.  The effect of ageing on macrophage Toll‐like receptor‐mediated responses in the fight against pathogens , 2010, Clinical and experimental immunology.

[81]  C. Diazgranados,et al.  High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season. , 2013, Vaccine.

[82]  C. Finch,et al.  Infection, inflammation, height, and longevity. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[83]  A. Sturm,et al.  The Intestinal Epithelial Barrier: Does It Become Impaired with Age? , 2009, Digestive Diseases.

[84]  Epigenetics: judge, jury and executioner of stem cell fate. , 2012, Epigenetics.

[85]  C. Baker,et al.  Group B streptococcal infections in elderly adults. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[86]  D. Weigent,et al.  Protein hormones and immunity , 2007, Brain, Behavior, and Immunity.

[87]  E. Wagner,et al.  Care for chronic diseases , 2002, BMJ : British Medical Journal.

[88]  D. Knook,et al.  Randomized controlled trial of seroresponses to double dose and booster influenza vaccination in frail elderly subjects * , 2001, Journal of medical virology.

[89]  B. Lesourd Nutritional factors and immunological ageing , 2006, Proceedings of the Nutrition Society.

[90]  G. van Zant,et al.  Concise Review: Hematopoietic Stem Cell Aging, Life Span, and Transplantation , 2012, Stem cells translational medicine.

[91]  M. Smithey,et al.  Age-associated alterations in CD8α+ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium , 2012, Aging cell.

[92]  M. Cetron,et al.  Advanced age a risk factor for illness temporally associated with yellow fever vaccination. , 2001, Emerging infectious diseases.

[93]  E. Montecino-Rodriguez,et al.  Causes, consequences, and reversal of immune system aging. , 2013, The Journal of clinical investigation.

[94]  A. Hill,et al.  Potent CD8+ T-Cell Immunogenicity in Humans of a Novel Heterosubtypic Influenza A Vaccine, MVA−NP+M1 , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[95]  J. Treanor,et al.  Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). , 2011, Vaccine.

[96]  E. De Gregorio,et al.  The mechanism of action of MF59 - an innately attractive adjuvant formulation. , 2012, Vaccine.

[97]  A. DeFranco,et al.  Contribution of Toll‐like receptor signaling to germinal center antibody responses , 2012, Immunological reviews.

[98]  C. Weyand,et al.  Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age , 2012, Proceedings of the National Academy of Sciences.

[99]  E. Hoster,et al.  Booster vaccination in the elderly: their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers. , 2006, Vaccine.

[100]  F. Ansaldi,et al.  Adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine , 2011, Human vaccines.

[101]  A. Procopio,et al.  Toll like receptor signaling in “inflammaging”: microRNA as new players , 2013, Immunity & Ageing.

[102]  Leon Flicker,et al.  Body Mass Index and Survival in Men and Women Aged 70 to 75 , 2010, Journal of the American Geriatrics Society.

[103]  J. Cambier,et al.  Ageing, autoimmunity and arthritis: Senescence of the B cell compartment – implications for humoral immunity , 2004, Arthritis research & therapy.

[104]  O. Lesur,et al.  Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. , 2012, Seminars in immunology.

[105]  Potent CD8+ T-Cell Immunogenicity in Humans of a Novel Heterosubtypic Influenza A Vaccine, MVA−NP+M1 , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[106]  L. Friedland,et al.  Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix(®)): results of two randomized trials. , 2012, Vaccine.

[107]  F. Ansaldi,et al.  Head-to-head comparison of an intradermal and a virosome influenza vaccine in patients over the age of 60 , 2013, Human vaccines & immunotherapeutics.

[108]  M. Loeb,et al.  Aging, frailty and age-related diseases , 2010, Biogerontology.

[109]  J. Tew,et al.  Activation of B cells by antigens on follicular dendritic cells. , 2010, Trends in immunology.

[110]  Samit R. Joshi,et al.  Aging of the innate immune system. , 2010, Current opinion in immunology.

[111]  Karl-Heinz Krause,et al.  Ageing and infection. , 2002, The Lancet. Infectious diseases.

[112]  R. Belshe,et al.  The Efficacy of Live Attenuated and Inactivated Influenza Vaccines in Children as a Function of Time Postvaccination , 2010, The Pediatric infectious disease journal.

[113]  Stephanie L. Dickinson,et al.  Efficacy of live attenuated influenza vaccine in children: A meta-analysis of nine randomized clinical trials. , 2009, Vaccine.

[114]  Michele Pellegrini,et al.  Immunogenicity of Three Different Influenza Vaccines against Homologous and Heterologous Strains in Nursing Home Elderly Residents , 2010, Clinical & developmental immunology.

[115]  M. Levin Immune senescence and vaccines to prevent herpes zoster in older persons. , 2012, Current opinion in immunology.

[116]  D. Fuchs,et al.  Recall Responses to Tetanus and Diphtheria Vaccination Are Frequently Insufficient in Elderly Persons , 2013, PloS one.

[117]  Yu-Ting Wu,et al.  Oxidative stress response elicited by mitochondrial dysfunction: Implication in the pathophysiology of aging , 2013, Experimental biology and medicine.

[118]  Jincun Zhao,et al.  Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. , 2011, The Journal of clinical investigation.

[119]  M. Singh,et al.  MF59: A Safe and Potent Adjuvant for Human Use , 2006 .

[120]  N. Chen,et al.  Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. , 2009, Human immunology.

[121]  I. Kang,et al.  Age-Associated Change in the Frequency of Memory CD4+ T Cells Impairs Long Term CD4+ T Cell Responses to Influenza Vaccine1 , 2004, The Journal of Immunology.

[122]  C. Hughes,et al.  Of Mice and Not Men: Differences between Mouse and Human Immunology , 2004, The Journal of Immunology.

[123]  J. Noh,et al.  Immunogenicity and Safety of the Influenza A/H1N1 2009 Inactivated Split-Virus Vaccine in Young and Older Adults: MF59-Adjuvanted Vaccine versus Nonadjuvanted Vaccine , 2011, Clinical and Vaccine Immunology.

[124]  Mark M Davis,et al.  A prescription for human immunology. , 2008, Immunity.

[125]  J. Treanor,et al.  Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response. , 2012, Vaccine.