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IMMUNOSENESCENCE and VACCINE FAILURE Jean-Pierre MICHEL et Pierre Olivier LANG Geneva Medical University & Hospitals.

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Presentation on theme: "IMMUNOSENESCENCE and VACCINE FAILURE Jean-Pierre MICHEL et Pierre Olivier LANG Geneva Medical University & Hospitals."— Presentation transcript:

1 IMMUNOSENESCENCE and 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 simply A geriatrician

3 1. 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 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: % of chronic cough in old adults are linked to an unrecognized Pertussis infection WHO position paper. Wkly Epidemiol Rec 2005;80: % of the 8’000 Diphtheria cases notified in Europe between 1999 and 2008 concerned people over 45 y. WHO – CISID – htpp:/data.euro.who.int/cisid Two thirds of the 2,000 Tetanus cases notified in Europe between 1999 and 2008 occur in people aged over 65 years ECDC BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (1)

5 In the EU, the number of excess deaths associated with influenza is estimated between 40’000 and 220’000, depending of the seasonal variation TILLETT HE et al Lancet 1980; 1: Streptococcus pneumoniae is the cause of 30% of community- acquired pneumonia research/diseases/ari/en/index3.html Most influenza-related and pneumococcal disease deaths occur in people aged 65 y.o. THOMPSON WW et al Jama 2003; 289: WHO Wkly Epidemiol Rec 2007;82: Lower respiratory infections 4th cause of death in developed countries LIANG SY et al Clin Geriatr Med 2007; 23: BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (2)

6 In the US, approximately 1’000 to 3’000 children die each year of vaccine preventable diseases Each year, approximately 50’000 to 70’000 US adults die of vaccine preventable diseases To summarize the problem BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (3) POLAND GA, Vaccine 2010, in Press

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

8 In the US, approximately 1’000 to 3’000 children die each year of vaccine preventable diseases Each year, approximately 50’000 to 70’000 US adults die of vaccine preventable diseases To summarize the problem BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (3) This imbalance is striking and reflecting of a number of underlying structural, 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 vaccination in the ageing population NICHOL KL et al N Engl J Med 2007;357: ; 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 vaccination in the ageing population NICHOL KL et al N Engl J Med 2007;357: ; 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: Why vaccine coverage rate of old adults so low ?

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

13 Innate Adaptive Neutrophils Nb = but  functions Macrophages Nb = but  functions Natural Killer cells  or  Dendritic cells The innate and adaptive immune responses IMMUNE RESPONSES Capture of Ag Ag Presentation to T cells DCs =  Nb  functions  IL6,  IL1,  TNF-α Cellular immunity (T cells) 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  Adapted from GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: ChildYoung adultAged adult                                                                                                                                                                                         senescent T cells  Memory CD45 RA- CD8 CD28 +  Effector CD45 RA+ CD8 CD28 -

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  1. Reduction of the repertoire of the naive T cells receptors (TCR) PFISTER G et al Ann N Y Acad Sci. 2006;1067: 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 Based on TARGONSKI PV et al Vaccine 2007; 25:

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 expression of CD28 cell surface marker EFFROS RB et al Exp Gerontol 1994; 29: Decrease of the telomerase activity at each replication  resistance to apoptosis VALENZUELA HF et al Clin Immunol 2002; 105: community dwelling persons (65-98 y.o.) 10% with CD28-  AB production by 24% GORONZY JJ et al J Virol 2001; 75:

17 Changes in cytokines production throughout life GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: ChildYoung adultAged adult                                                                                                                                                                                        IL-2 IL-4 TFN-  IL15 CHIU WK et al J Immunol 2006; 177:

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

19 19 B-cell responses and ageing Adapted from SIEGRIST CA and ASPINALL R. Nat Rev Immunol 2009;9: Most bones contain haemotopoeitic bone marrow, rich in B-cell progenitors Large number of naive B-Cells (diverse specificity) Small number of memory B- cell clones  Production of naive B-cells Accumulation of memory B-cells (limited specificity) Decreased haematopoietic bone marrow with fat depsosits and decreased B-cell progenitors

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

21 Immunosenescence In summary 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 Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9

22 However large longitudinal studies showed that at the same age, old adults ARE NOT ALL immunosenescent STRANDHALL J Exp Gerontol 2007; 42: & WIKBY A et al Biogerontol 2008; 9:

23 1. 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 Protein energy malnutrition  Alteration of T cell responses   Delayed-type hypersensibility  IL2 production  T cell proliferation  Antibody response Micronutriment deficits  Vitamin E  Vitamin D  Vitamin B12  Selenium  Zinc  Immunodeficiency FATA FT et al Ann Int Med 1996; 124: 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 failure in the old population IgG anti-CMV carrier P TRZONKOWSKI et al Vaccine 2003; 21: Pre-vaccination chronic proinflammatory activity exacerbated by the vaccine 1) High cytokines profile:  IL10  IL6  TNFα 2) Low immunosupressive cortisol level ? Impaired immune response

27 1. 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 Age related changes INNATE Age related changes INNATE + ADAPTATIVE Age related changes ADAPTATIVE Altered cellular functions   Post vaccination antibody concentration Impaired elimination of pathogens   Persistance of antibody concentrations Chronic inflammatory process   Susceptibility to infections  Osteoporosis Atherosclerosis Sarcopenia  Mortality due to infectious diseases and cardio-vx diseases Adapted from B GRUBECK- LOEBENSTEIN Aging 2009; 21: 1-9

29 Post FLU vaccine response in young (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 1986 GOODWIN K et al Vaccine 2006; 24: ** * * %

30 FLU vaccine response in elders 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: ** % %

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

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. RUBINS JB et al Inf Immunity 1999: 67: % 48% 80%

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

34 Age-dependant persistence of antibody after TBE vaccine Time elapsed since last Tick-Borne Encephalitis (TBE) vaccination HAINZ U et al Vaccine 2005; 23:

35 HAINZ U et al Vaccine 2005; 23 : Age-dependant persistence of antibody after tetanus vaccine

36 Varicella-zoster virus-specific immune responses according to age groups - Baseline LEVIN MJ et al J Inf Dis 2008:197: RCF: Responder cell frequency (RCF) value Number of responding cells per 10 5 peripheral blood mononuclear cells ELISPOT count: Number of spot-forming cells per 10 5 peripheral blood mononuclear cells gpELISA: Glycoprotein ELISA titers gpELISA units/ml

37 Varicella-zoster virus-specific immune responses according to time of randomization LEVIN MJ et al J Inf Dis 2008:197: RCF: Responder cell frequency (RCF) value Number of responding cells per 10 5 peripheral blood mononuclear cells ELISPOT count: Number of spot-forming cells per 10 5 peripheral blood mononuclear cells gpELISA: Glycoprotein ELISA titers gpELISA units/ml

38 1. 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 and vaccine failure 6. Take home messages

39 Strategy to address immunosenescence 1.Promoting life long vaccine programmes 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Reversing immunosenescence 7.Establishing vaccine recommendations for the ageing population

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

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

42 REICHERT TA et al N Engl J Med 2001; 344: Excess Deaths From Pneumonia and Influenza (per 100,000 Population) P&I* Mortality Rate 1962: Program to vaccinate school children with inactivated influenza vaccine begins 1987: Parents allowed to refuse vaccination 1994: Program discontinued Japanese school vaccination program with TIV reduced mortality in the Community P&I = Pneumonia & Influenza mortality rate

43 Strategy to address immunosenescence 1.Promoting life long vaccine programs 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Reversing immunosenescence 7.Establishing vaccine recommendations for the ageing population

44 TIME Vaccine programs for a better life Clinical recommendations for the ageing and aged adults Part of PREVENTIVE MEDICINE ! The target: old adults How to improve it ? How good is their health? Scientific knowledge Continuity of the vaccine program !! HEALTHY AGEING How to improve it ? Midlife adults How good is their health ? Scientific knowledge Pregnancy Children How to improve their growth ? Are they healthy ? Scientific knowledge Very effective Precise guidelines Well accepted ?

45 Influenza vaccination and risk 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 SISCOVICK DS et al Am J Epidemiol 2000; 152: Influenza vaccination seemed to be associated with a reduced risk of primary cardiac arrest OR = 0.51 [ ]

46 Coronary Artery Disease (CAD) and Influenza vaccine Randomized, controlled trial 301 patients hospitalized for CAD (myocardial infarction or planned angiography/stenting)  After one year RR of cardiovascular mortality = 0.25 [ ] 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: and GURFINKEL EP et al Tex Heart Inst 2004; 31: 28-32

47 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 [ ] (P =0.13) -Coronary ischemic event: HR: 0.54 [ ] (P =0.047) Does Influenza vaccine significantly improve the clinical course of CAD patients? CISZEWSKI A et al Eur Heart J 2008; 29:

48 Influenza vaccination as secondary prevention of Cardio Vascular Diseases (CVD) The American Heart Association and American College of Cardiology recommend Influenza vaccine (TIV intra muscular) as part of « secondary » prevention in persons with coronary and other atherosclerotic diseases DAVIS MM et al JACC 2006; 48:

49 INFLUENZA (Seasonal Flu)

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

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

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

53 Strategy to address immunosenescence 1.Promoting life long vaccine programmes 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Reversing immunosenescence 7.Establishing vaccine recommendations for the ageing population

54 Correlation between pre- and post- vaccination antibody concentrations KAML M et al Vaccine 2006; 24:

55 Strategy to address immunosenescence 1.Promoting life long vaccine programmes 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Reversing immunosenescence 7.Establishing vaccine recommendations for the ageing population

56 Responses to TT vaccine with and without ready to use canned food LESSOURD B Nature Rev 1995; 53: S86-94

57 Strategy to address immunosenescence 1.Promoting life long vaccine programmes 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Understanding the links between frailty and immunosenescence 7.Establishing vaccine recommendations for the ageing population

58 Improving immune response in old adults Increasing of the dosage of antigens in the vaccine Developing novel vaccines based on virus- like particles Including more powerful adjuvants in the vaccine composition Combining vaccination with simultaneous immuno-stimulant patches (although chronic or repeated immuno-stimulation is deleterious in ageing) Exploring new routes of administration BRIGHT RA et al Vaccine 2007; 10; ; GUEBRE-XABIER M et al J Virol 2004; 78: FRECH SA et al Vaccine 2005; 4:946-50; GLENN GM et al Immunol 2006;304:247-68

59 Strategy to address immunosenescence 1.Promoting life long vaccine programmes 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Reversing immunosenescence 7.Establishing vaccine recommendations for the ageing population

60 Reversing immunosenescence Possible therapeutical targets Major detrimental role of thymic atrophy –Treatment with recombinant IL-7 reverses thymic atrophy and increases thymic output Negative effect of senescent CD8+CD28- –Physical removal from the circulation –Inducing apoptosis of these cells Adverse impact of chronic CMV infection –CMV vaccine to be administrated during childhood But !!!!!!!! Pierre Olivier LANG Personal communication 2010

61 Strategy to address immunosenescence 1.Promoting life long vaccine programmes 2.Filling the adult vaccine gap 3.Reminding vaccine boosters 4.Improving macro- and micro- nutritional status 5.Developing new vaccines designed for old population 6.Reversing immunosenescence 7.Establishing vaccine recommendations for the ageing population

62 Vaccine programs for a better life Part of preventive medicine ! Developing a consensual vaccine programme The target: old adults How to improve it ? How good is their health? Scientific knowledge Pregnancy Children How to improve their growth ? Are they healthy ? Scientific knowledge Very effective Precise guidelines Well accepted TIME ! How to improve it ? Midlife adults How good is their health ? Scientific knowledge Continuity of the vaccine program HEALTHY AGEING

63 BURDEN of PREVENTABLE INFECTIOUS DISEASES in the ELDERLY European Union + European Economic Area + European Free Trade Associaion European Union Geriatric Medicine Society

64 Proposed EUGMS and IAGG-ER vaccine programme for the old adults By the 7 th decade /Retirement age (after a clinical assessment of the vaccine status) - TdaP or Td vaccine - Influenza vaccine - Pneumococcal vaccine - Herpes Zoster vaccine - Influenza vaccine New medical/injury event (after assessment of the vaccine status) Multiple hospital stays (after assessment of the vaccine status) - Td or TT vaccine- Pneumococcal vaccine - TdaP or Td or TT vaccine - Influenza vaccine - Pneumococcal vaccine - Herpes Zoster vaccine* Each year after the retirement age (after assessment of the vaccine status) By the 9 th decade of age / Nursing Home admission MICHEL JP et al Rejuvenation Research 2009; 19:

65 1. 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

66 Preventable infectious diseases are forgotten, but not gone! LIFE COURSE VACCINE PROGRAMME GUSMANO M & MICHEL JP AGING 2009; 21:

67 Mrs Quality of Life and I thank you for your attention

68

69 « A transitional state » ROBUSTNESS FRAILTY ADL DEPENDENCE FRAILTY  life long process time DEATH Physiological reserves Total Used AVAILABLE Age, Gender, Lifestyle, Socio-economic status, Co-morbidities, Affective, Cognitive and Sensory Impairments (…)

70 Adapted from FRIED LP et al Sci Aging Knowl Environ 2005; 31: pp 24 (sageke.sciencemag.org) Sarcopenia  Total energy expenditure CYCLE of FRAILTY Chronic undernutrition. Age. Malnutrition. Disease(s). Environment Dysregulations. Hormones. Immunologic. Inflammation. Coagulation  Resting metabolic rate Immobilisation Impaired balance Falls / trauma Infections  Drugs use  Hospital admissions Disabilty Dependence Institutionalisation Death Relationship between frailty and vaccines ?


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