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IMMUNOSENESCENCE and VACCINE FAILURE

IMMUNOSENESCENCE and VACCINE FAILURE. Jean-Pierre MICHEL et Pierre Olivier LANG Geneva Medical University & Hospitals. DISCLOSURE. I am NOT An immunologist A vaccine specialist A public health specialist I am simply A geriatrician. Burden of preventable infectious diseases (PIDs)

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IMMUNOSENESCENCE and VACCINE FAILURE

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  1. IMMUNOSENESCENCEand VACCINE FAILURE Jean-Pierre MICHEL et Pierre Olivier LANG Geneva Medical University & Hospitals

  2. DISCLOSURE I am NOT An immunologist A vaccine specialist A public health specialist I am simplyA geriatrician

  3. Burden of preventable infectious diseases (PIDs) • 2. Immunosenescence • 3. Roles of the homeostatic milieu • 4. Consequences of the age related changes in immune responses • 5. Strategy to address immunosenescence • 6. Take home messages

  4. Two thirds of the 2,000 Tetanus cases notified in Europe between 1999 and 2008 occur in people aged over 65 years ECDChttp://ecdc.europa.eu/en/publications/Publications/0910 20% of chronic cough in old adults are linked to an unrecognized Pertussis infection WHO position paper. Wkly Epidemiol Rec 2005;80:31-9 50% of the 8’000 Diphtheria casesnotified in Europe between 1999 and 2008concerned people over 45 y. WHO – CISID – htpp:/data.euro.who.int/cisid BURDEN ofINFECTIOUSDISEASES inthe OLD ADULTS (1) The incidence of postherpetic neuralgia increases with advancing age, reaching more than 50% in older patients with Herpes zoster SCHMADER K Clin Infect Dis 2001;32:1481-6

  5. Lower respiratory infections4th cause of deathin developed countries LIANG SY et al Clin Geriatr Med 2007; 23: 441-56 Streptococcuspneumoniae is the cause of 30% of community- acquired pneumonia http://www.who.int/vaccine_research/diseases/ari/en/index3.html Most influenza-related and pneumococcal disease deathsoccur in people aged 65 y.o. THOMPSON WW et al Jama 2003; 289: 179-86WHO Wkly Epidemiol Rec 2007;82:93-104 BURDEN ofINFECTIOUSDISEASES inthe OLD ADULTS (2) In the EU, the number of excess deaths associated with influenzais estimated between 40’000 and 220’000, depending of the seasonal variation TILLETT HE et al Lancet 1980; 1: 793-5

  6. To summarize the problem In the US, approximately1’000 to 3’000 childrendie eachyear ofvaccine preventablediseases Each year,approximately 50’000 to 70’000 US adults die ofvaccine preventable diseases BURDEN ofINFECTIOUSDISEASES inthe OLD ADULTS (3) POLAND GA, Vaccine 2010, in Press

  7. Importance of herd immunity European Centre for Disease Prevention and Control, 2008

  8. To summarize the problem In the US, approximately1’000 to 3’000 childrendie eachyear ofvaccine preventablediseases Each year,approximately 50’000 to 70’000 US adults die ofvaccine preventable diseases BURDEN ofINFECTIOUSDISEASES inthe OLD ADULTS (3) This imbalance is strikingand reflecting of a number of underlyingstructural, economic, cultural and political issues POLAND GA, Vaccine 2010, in Press

  9. Avoid mortality linked to preventable infectious diseases E.g. Influenza vaccine  all-cause mortality by 48–50% in community-dwelling older persons Reduce complications and hospitalisation E.g. Hospitalisations for influenza or pneumonia were  by 27% in community dwelling older influenza vaccinees Decrease antibiotic use E.g. Antibiotic prescriptions were  by 64% following influenza vaccination in a Canadian study Decrease antibiotic-resistant infections E.g. Pneumococcal conjugate vaccine  nasopharyngeal carriage of penicillin- resistant Streptococcus pneumoniae Cost effectiveness E.g. Herpes zoster vaccine  quality-adjusted life years compared with no vaccination in older persons Expected benefits of vaccinationin the ageing population NICHOL KL et al N Engl J Med 2007;357:1373-81; KWONG J et al Clin Infect Dis 2009;49:750-6; DAGAN R Clin Microb Infect 2009;15(Suppl 3):16-20, HORNBERGER J et al Ann Intern Med 2006;145:317-35

  10. Avoid mortality linked to preventable infectious diseases E.g. Influenza vaccine  all-cause mortality by 48–50% in community-dwelling older persons Reduce complications and hospitalisation E.g. Hospitalisations for influenza or pneumonia were  by 27% in community dwelling older influenza vaccinees Decrease antibiotic use E.g. Antibiotic prescriptions were  by 64% following influenza vaccination in a Canadian study Decrease antibiotic-resistant infections E.g. Pneumococcal conjugate vaccine  nasopharyngeal carriage of penicillin- resistant Streptococcus pneumoniae Cost effectiveness E.g. Herpes zoster vaccine  quality-adjusted life years compared with no vaccination in older persons Expected benefits of vaccinationin the ageing population Why vaccine coverage rate of old adults so low ? NICHOL KL et al N Engl J Med 2007;357:1373-81; KWONG J et al Clin Infect Dis 2009;49:750-6; DAGAN R Clin Microb Infect 2009;15(Suppl 3):16-20, HORNBERGER J et al Ann Intern Med 2006;145:317-35

  11. Burden of preventable infectious diseases (PIDs) • 2. Immunosenescence • 3. Roles of the homeostatic milieu • 4. Consequences of the age related changes in immune responses • 5. Strategy to address immunosenescence • 6. Take home messages

  12. Immunosenescence Definition A constellation of age-related changes to the immune system, resulting mainly in 1) greater susceptibility to infections 2) reduced response to vaccination Adapted from Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9

  13. The innate and adaptive immune responses Capture of Ag Ag Presentation to T cells IMMUNE RESPONSES Dendritic cells Innate Adaptive Cellular immunity (T cells) Neutrophils Nb = but  functions MacrophagesNb = but  functions Natural Killer cells  or  DCs= Nb  functions  IL6,  IL1,  TNF-α Adapted from Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9

  14. Ageing T-Cells Thymic involution( of central production of T-cells) Memory   Ratio of ----------------- Naives  senescent T cells  Memory CD45 RA- CD8 CD28 + Effector CD45 RA+ CD8 CD28 - Adapted from GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: 243-84

  15. Ageing T-Cells Thymic involution ( of central production of naive T-cells + shinkring of the peripheral T-cells pool) Memory   Ratio of ------------------------- for Cytotoxic and Helper T cells Naives 2. Significant shortening of telomeres length of the naive T Cells resistance to apoptosis PFISTER G et al Ann N Y Acad Sci. 2006;1067:152-7 • Reductionof the repertoire of the naive T cells receptors (TCR) • PFISTER G et al Ann N Y Acad Sci. 2006;1067:152-7 Based on TARGONSKI PV et al Vaccine 2007; 25: 3066-9

  16. Ageing T-Cells Thymic involution ( of central production of T-cells) Memory   Ratio of ------------------------- for Cytotoxic and Helper T cells Naives 2. Loss of expressionofCD28 cell surfacemarker EFFROS RB et al Exp Gerontol 1994; 29: 601-9 • Decrease of the telomeraseactivityateachreplication •  resistance to apoptosis • VALENZUELA HF et alClin Immunol 2002; 105: 117-25 153 community dwelling persons (65-98 y.o.) 10% with CD28- AB production by 24% GORONZY JJ et al J Virol 2001; 75: 12182-7

  17. Changes in cytokines production throughout life IL-2 IL-4 TFN- IL15 GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: 243-84 CHIU WK et al J Immunol 2006; 177: 7802-10

  18. The innate and adaptive immune responses Capture of Ag Ag Presentation to T cells IMMUNE RESPONSES Dendritic cells Innate Adaptive Cellular immunity (T cells) Neutrophils Nb = but  functions MacrophagesNb = but  functions Natural Killer cells  or  • DCs • Nb  functions Humoral immunity (B cells)  IL6,  IL1,  TNF-α Antibody production Adapted from Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9

  19. B-cell responses and ageing Large number of naive B-Cells (diverse specificity) Small number of memory B-cell clones Most bonescontainhaemotopoeiticbonemarrow, rich in B-cellprogenitors  Production of naive B-cells Accumulation of memory B-cells (limited specificity) Decreasedhaematopoieticbonemarrowwith fat depsosits and decreased B-cellprogenitors 19 Adapted from SIEGRIST CA and ASPINALL R. Nat Rev Immunol 2009;9:185-94

  20. B-cell responses and ageing Large number of naive B-Cells (diverse specificity) Small number of memory B-cell clones Most bones contain haemotopoeitic bone marrow, rich in B-cell progenitors  Production of naive B-cells Accumulation of memory B-cells (limited specificity) Decreased haematopoietic bone marrow with fat deposits and decreased B-cell progenitors 20 Adapted from SIEGRIST CA and ASPINALL R. Nat Rev Immunol 2009;9:185-94

  21. Immunosenescence • Ageing •  • Changes in T and B cell populations •  number of naive cells • number of effector T and memory B and T cells  • Repertoire of immune functions Defects in cooperation between T and B cells  Impaired immune responses in the old adults In summary Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9

  22. However large longitudinal studies showed thatat the same age, old adults ARE NOT ALL immunosenescent STRANDHALL J Exp Gerontol 2007; 42: 753-61 & WIKBY A et al Biogerontol 2008; 9: 299-308

  23. Burden of preventable infectious diseases (PIDs) • 2. Immunosenescence • 3. Roles of the homeostatic milieu • 4. Consequences of the age related changes in immune responses • 5. Strategy to address immunosenescence • 6. Take home messages

  24. Malnutrition and immunity Micronutriment deficits  Vitamin E  Vitamin D  Vitamin B12  Selenium  Zinc  Immunodeficiency Protein energy malnutrition  Alteration of T cell responses • Delayed-type hypersensibility • IL2 production • T cell proliferation • Antibody response FATA FT et al Ann Int Med 1996; 124: 299-304 LESSOURD B Am J Clin Nutr 1997; 66: 478S-84S FULOP T et al Clin Infect Dis 2009;48:443-8

  25. Chronic diseases and Immunity High burden of chronic diseases Impaired immunity  Inadequate antibody response to vaccine FULOP T et al Clin Infect Dis 2009;48:443-8

  26. Other causes of vaccine failurein the old population ? IgG anti-CMV carrier Pre-vaccination chronic proinflammatory activity exacerbated by the vaccine 1) High cytokines profile:  IL10IL6TNFα 2) Low immunosupressive cortisol level Impaired immune response P TRZONKOWSKI et al Vaccine 2003; 21: 3826-36

  27. Burden of preventable infectious diseases (PIDs) • 2. Immunosenescence • 3. Roles of the homeostatic milieu • 4. Consequences of the age related changes in immune responses • 5. Strategy to address immunosenescence • 6. Take home messages

  28. Consequences of age related immune system changes Adapted fromB GRUBECK- LOEBENSTEIN Aging 2009; 21: 1-9

  29. Post FLU vaccine response inyoung (N = 913) and old adults (N = 4492) % % * * ** ** ** Seroconversion(% of subjects with 4-fold AB increase) Seroprotection(% of subjects with AB titres > 40) Meta-analysis of 50 surveys performed since 1986GOODWIN K et al Vaccine 2006; 24: 1159-69

  30. FLU vaccine response in elders < 75 y. (N = 1945) and > 75 y. (N= 2492) % % ** ** ** ** ** ** Seroconversion(% of subjects with 4-fold AB increase) Seroprotection(% of subjects with AB titres > 40) Meta-analysis of 50 surveys performed since 1986 GOODWIN K et al Vaccine 2006; 24: 1159-69

  31. Antibody responses of old adults to all 23 capsular polysaccharides after Pneumococcal vaccine N = 53, m.a = 71 y. RUBINS JB et al Inf Immunity 1999: 67: 5979-84

  32. Cumulative immune responses of old adults to 23 polysaccharides pneumococcal vaccine ( at least two fold increase in polysscharide – specific IgG) N = 53, m.a = 71 y. 80% 48% 3.7% RUBINS JB et al Inf Immunity 1999: 67: 5979-84

  33. Age-related antibody responses after Pneumococcal vaccination Immune Response to 23-v PnPS Elisa IgG GMC (g/ml) ROMERO-STEINER S Clin Inf Dis 1999; 29: 281-8

  34. Age-dependant persistence of antibody after tetanus vaccine HAINZ U et al Vaccine 2005; 23 : 2232-5

  35. Burden of preventable infectious diseases (PIDs) • 2. Immunosenescence • 3. Roles of the homeostatic milieu • 4. Consequences of the age related changes in immune responses • 5. Strategy to address immunosenescence andvaccine failure • 6. Take home messages

  36. Strategy to address immunosenescence • Promoting life long vaccine programmes • Filling the adult vaccine gap • Reminding vaccine boosters • Improving macro- and micro- nutritional status • Developing new vaccines designed for old population • Reversing immunosenescence • Establishing vaccine recommendations for the ageing population

  37. Vaccine programs for a better life Scientificknowledge Pregnancy How to improve their growth ? Children Are they healthy ? Scientificknowledge The target: old adults TIME How to improve it ? How good is their health? Very effective Precise guidelines Well accepted Herd immunity Acceptance: +/- Previous exposures to pathogens Immunosenescence Individual variations !!

  38. Rate of VT- IPD before and after introduction of PCV7 USA 1998-2003 MMWR, Sept 16, 2005 / 54(36);893-897 Infant immunity may indirectly protect the elderly Reduced incidence of Invasive Pneumococcal Disease (IPD-VT) in the elderly after introduction of PCV7 in infants

  39. Japanese school vaccination program with TIV reduced mortality in the Community 14 12 10 8 6 4 2 0 P&I* Mortality Rate P&I = Pneumonia & Influenza mortality rate Excess Deaths From Pneumonia and Influenza (per 100,000 Population) 1987: Parents allowed to refuse vaccination 1994: Program discontinued 1962: Program to vaccinate school children with inactivated influenza vaccine begins 1990 1974 1978 1970 1950 1966 1986 1998 1982 1962 1994 1954 1958 REICHERT TA et al N Engl J Med 2001; 344: 889-96

  40. Strategy to address immunosenescence • Promoting life long vaccine programs • Filling the adult vaccine gap • Reminding vaccine boosters • Improving macro- and micro- nutritional status • Developing new vaccines designed for old population • Reversing immunosenescence • Establishing vaccine recommendations for the ageing population

  41. Vaccine programs for a better life Scientificknowledge Pregnancy How to improve their growth ? Children Scientificknowledge Are they healthy ? Midlife adults How to improve it ? Scientificknowledge How good is their health ? The target: old adults TIME How to improve it ? How good is their health? Very effective Precise guidelines Well accepted Continuity ofthe vaccine program !!HEALTHY AGEING Clinicalrecommendationsfor the ageing andaged adultsPart ofPREVENTIVEMEDICINE ! ?

  42. Influenza vaccination andrisk of primary cardiac arrest Population-based case-control study 342 cases of Primary cardiac arrest(registered from 1988 to 1994 in the Washington area) Demographically similar controls (N = 549)Spouses of subjects were interviewed Influenza vaccination seemed to be associated with a reduced risk ofprimary cardiac arrestOR = 0.51 [0.33- 0.79] SISCOVICK DS et al Am J Epidemiol 2000; 152: 674-7

  43. Coronary Artery Disease (CAD) and Influenza vaccine Randomized, controlled trial301 patients hospitalized for CAD(myocardial infarction or planned angiography/stenting)  After one year RR of cardiovascular mortality = 0.25 [0.07-0.86] in vaccinated compared with NOT vaccinated  After two years Same tendency(but samples were too small to show any significant difference) GURFINKEL EP et al Tex Heart Inst 2004; 25: 25-31 and GURFINKEL EP et al Tex Heart Inst2004; 31: 28-32

  44. Coronary Artery Disease (CAD)and Influenza vaccine Randomized. double blind, placebo controlled study with a 12 month-follow-up 658 optimally treated CAD patients (72% of men; mean age = 59.9  10.3 y.)  3 end points in 2 population groups (Vaccinated vs. Non Vaccinated)  • Cardiovascular death + myocardial infarction + coronary revascularization: HR: 0.54 [0.24-1.21] (P =0.13) • Coronary ischemic event: HR: 0.54 [0.29-0.99] (P =0.047) Does Influenza vaccine significantly improve the clinical course of CAD patients? CISZEWSKI A et al Eur Heart J 2008; 29: 1350-8

  45. Influenza vaccination assecondary prevention of Cardio Vascular Diseases (CVD) The American Heart Association and American College of CardiologyrecommendInfluenza vaccine (TIV intra muscular)as part of « secondary » preventionin persons with coronary and other atherosclerotic diseases DAVIS MM et al JACC 2006; 48: 1498-502

  46. INFLUENZA (Seasonal Flu)

  47. Flu Vaccine coverage rate in the 65+ population 2006/2007 2014 WHO goal = 75% 2006 WHO goal = 50% * Source: TNS survey 2006/7 Data in file

  48. Flu Vaccine coverage rate in the population < 65 at risk 2014 WHO goal = 75% 2006 WHO goal = 50% * Source: TNS survey 2006/7 Data in file

  49. Flu Vaccine coverage rate in the health care workers(HCWs) HERD IMMUNITY ! * Source: TNS survey 2006/7 Data in file

  50. Strategy to address immunosenescence • Promoting life long vaccine programmes • Filling the adult vaccine gap • Reminding vaccine boosters • Improving macro- and micro- nutritional status • Developing new vaccines designed for old population • Reversing immunosenescence • Establishing vaccine recommendations for the ageing population

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