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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 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 Two thirds of the 2,000 Tetanus cases notified in Europe between 1999 and 2008 occur in people aged over 65 years ECDC http://ecdc.europa.eu/en/publications/Publications/0910 20% of chronic cough in old adults are linked to an unrecognized Pertussis infection BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (1) 50% 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 WHO position paper. Wkly Epidemiol Rec 2005;80:31-9 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 Lower respiratory infections 4th cause of death in developed countries LIANG SY et al Clin Geriatr Med 2007; 23: 441-56 Streptococcus pneumoniae is the cause of 30% of communityacquired pneumonia BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (2) Most influenza-related and pneumococcal disease deaths occur in people aged 65 y.o. THOMPSON WW et al Jama 2003; 289: 179-86 WHO Wkly Epidemiol Rec 2007;82:93-104 http://www.who.int/vaccine_ research/diseases/ari/en/index3.html 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: 793-5 To summarize the problem In the US, approximately 1’000 to 3’000 children die each year of vaccine preventable diseases BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (3) Each year, approximately 50’000 to 70’000 US adults die of vaccine preventable diseases POLAND GA, Vaccine 2010, in Press Importance of herd immunity European Centre for Disease Prevention and Control, 2008 To summarize the problem In the US, approximately 1’000 to 3’000 children die each year of vaccine preventable diseases BURDEN of INFECTIOUS DISEASES in the OLD ADULTS (3) Each year, approximately 50’000 to 70’000 US adults die of vaccine preventable diseases This imbalance is striking and reflecting of a number of underlying structural, economic, cultural and political issues POLAND GA, Vaccine 2010, in Press Expected benefits of vaccination in the ageing population 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 penicillinresistant Streptococcus pneumoniae Cost effectiveness E.g. Herpes zoster vaccine quality-adjusted life years compared with no vaccination in older persons 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 Expected benefits of vaccination in the ageing population 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 Why vaccine coverage rate Decrease antibiotic use E.g. Antibiotic prescriptions were by 64% following influenza vaccination in a Canadian study of Decrease antibiotic-resistant infections old adults so low ? E.g. Pneumococcal conjugate vaccine nasopharyngeal carriage of penicillinE.g. Hospitalisations for influenza or pneumonia were by 27% in community dwelling older influenza vaccinees resistant Streptococcus pneumoniae Cost effectiveness E.g. Herpes zoster vaccine quality-adjusted life years compared with no vaccination in older persons 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 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 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 The innate and adaptive immune responses Capture of Ag IMMUNE RESPONSES Ag Presentation to T cells Dendritic cells Innate Neutrophils Nb = but functions Adaptive DCs = Nb functions Cellular immunity (T cells) Macrophages Nb = but functions Natural Killer cells or IL6, IL1, TNF-α Adapted from Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9 Ageing T-Cells Thymic involution ( of central production of T-cells) Memory Ratio of ----------------Naives Child Young adult Aged adult senescent T cells Memory CD45 RA- CD8 CD28 + Effector CD45 RA+ CD8 CD28 Adapted from GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: 243-84 Ageing T-Cells Thymic involution ( of central production of naive T-cells + shinkring of the peripheral T-cells pool) Memory Ratio of ------------------------Naives 1. Reduction of the repertoire of the naive T cells receptors (TCR) for Cytotoxic and Helper T cells 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 PFISTER G et al Ann N Y Acad Sci. 2006;1067:152-7 Based on TARGONSKI PV et al Vaccine 2007; 25: 3066-9 Ageing T-Cells Thymic involution ( of central production of T-cells) Memory Ratio of ------------------------Naives for Cytotoxic and Helper T cells 2. Loss of expression of CD28 cell surface marker EFFROS RB et al Exp Gerontol 1994; 29: 601-9 153 community dwelling persons (65-98 y.o.) 10% with CD28 AB production by 24% GORONZY JJ et al J Virol 2001; 75: 12182-7 1. Decrease of the telomerase activity at each replication resistance to apoptosis VALENZUELA HF et al Clin Immunol 2002; 105: 117-25 Changes in cytokines production throughout life Child Young adult Aged adult IL-2 TFN- IL15 IL-4 GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: 243-84 CHIU WK et al J Immunol 2006; 177: 7802-10 The innate and adaptive immune responses Capture of Ag IMMUNE RESPONSES Ag Presentation to T cells Dendritic cells Innate Neutrophils Nb = but functions Adaptive DCs Nb functions Cellular immunity (T cells) Macrophages Nb = but functions Natural Killer cells or IL6, IL1, TNF-α Humoral immunity (B cells) Antibody production Adapted from Beatrix GRUBECK-LOEBENSTEIN et al Aging Clin Exp Res 2009; 21: 1-9 B-cell responses and ageing Most bones contain haemotopoeitic bone marrow, rich in B-cell progenitors Decreased haematopoietic bone marrow with fat depsosits and decreased B-cell progenitors Large number of naive B-Cells (diverse specificity) Small number of memory Bcell clones Production of naive B-cells Accumulation of memory B-cells (limited specificity) 19 R. Adapted from SIEGRIST CA and ASPINALL Nat Rev Immunol 2009;9:185-94 B-cell responses and ageing Most bones contain haemotopoeitic bone marrow, rich in B-cell progenitors Decreased haematopoietic bone marrow with fat deposits and decreased B-cell progenitors Large number of naive B-Cells (diverse specificity) Small number of memory Bcell clones Production of naive B-cells Accumulation of memory B-cells (limited specificity) 20 R. Adapted from SIEGRIST CA and ASPINALL Nat Rev Immunol 2009;9:185-94 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 However large longitudinal studies showed that at 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 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 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: 299-304 LESSOURD B Am J Clin Nutr 1997; 66: 478S-84S FULOP T et al Clin Infect Dis 2009;48:443-8 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 Other causes of vaccine failure in 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 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 Consequences of age related immune system changes Age related changes INNATE Age related changes INNATE + ADAPTATIVE Age related changes ADAPTATIVE Post vaccination antibody concentration Impaired elimination of pathogens Persistance of antibody concentrations Altered cellular functions 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 Post FLU vaccine response in young and old adults (N = 913) % % 80 80 60 (N = 4492) * * 60 ** ** ** 40 40 20 20 0 0 H1N1 H3N2 B H1N1 H3N2 B Seroconversion Seroprotection (% of subjects with 4-fold AB increase) (% of subjects with AB titres > 40) Meta-analysis of 50 surveys performed since 1986 GOODWIN K et al Vaccine 2006; 24: 1159-69 FLU vaccine response in elders < 75 y. (N = 1945) and > 75 y. (N= 2492) % % 80 80 ** 60 ** ** 60 ** 40 40 ** ** 20 20 0 0 H1N1 H3N2 B H1N1 H3N2 B Seroconversion Seroprotection (% of subjects with 4-fold AB increase) (% of subjects with AB titres > 40) Meta-analysis of 50 surveys performed since 1986 GOODWIN K et al Vaccine 2006; 24: 1159-69 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 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 Age-related antibody responses after Pneumococcal vaccination Immune Response to 23-v PnPS 25 20 15 10 5 0 14 6B 22-46 y.o. 63-79 y.o. 23F 19F 80-89 y.o. > 90 y.o ROMERO-STEINER S Clin Inf Dis 1999; 29: 281-8 Age-dependant persistence of antibody after tetanus vaccine HAINZ U et al Vaccine 2005; 23 : 2232-5 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 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 Vaccine programs for a better life Scientific knowledge Very effective Pregnancy Precise guidelines How to improve their Well accepted growth ? Children Are they healthy ? Herd immunity Scientific knowledge Acceptance: +/Previous exposures to pathogens Immunosenescence Individual variations !! The target: old adults How to improve it ? How good is their health? Infant immunity may indirectly protect the elderly Rate of VT- IPD before and after introduction of PCV7 USA 1998-2003 Reduced incidence of Invasive Pneumococcal Disease (IPD-VT) in the elderly after introduction of PCV7 in infants MMWR, Sept 16, 2005 / 54(36);893-897 Excess Deaths From Pneumonia and Influenza (per 100,000 Population) Japanese school vaccination program with TIV reduced mortality in the Community 14 P&I*&Mortality Rate mortality rate P&I = Pneumonia Influenza 12 10 8 6 1987: Parents allowed to refuse vaccination 4 2 1994: Program discontinued 1962: Program to vaccinate school children with inactivated influenza vaccine begins 0 REICHERT TA et al N Engl J Med 2001; 344: 889-96 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 Vaccine programs for a better life Scientific knowledge Very effective Pregnancy Precise guidelines How to improve their Well accepted growth ? Scientific knowledge Continuity of the vaccine program !! HEALTHY AGEING Children Are they healthy ? Midlife adults How to improve it ? How good is their health ? Scientific knowledge 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? ? 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 Influenza vaccination seemed to be associated with a reduced risk of primary cardiac arrest OR = 0.51 [0.33- 0.79] SISCOVICK DS et al Am J Epidemiol 2000; 152: 674-7 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 [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 Inst 2004; 31: 28-32 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 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: 1498-502 INFLUENZA (Seasonal Flu) Flu Vaccine coverage rate in the 65+ population 100% 2006/2007 2006/7 Vaccination Coverage Rate (%) 90% 2014 WHO goal = 75% 80% 71% 70% 68% 70% 66% 63% 2006 WHO goal = 50% 60% 53% 53% 51% 50% 37% 40% 30% 30% 25% 20% 10% 0% 0% 0% A * Source: TNS survey 2006/7 Data in file B C D ≥65 years E F < 65 years at risk G H Healthcare Workers I J K Flu Vaccine coverage rate in the population < 65 at risk 100% 2014 WHO goal = 75% 2006/7 Vaccination Coverage Rate (%) 90% 80% 71% 70% 68% 70% 66% 63% 60% 56% 53% 53% 2006 WHO goal = 50% 51% 50% 40% 37% 35% 37% 39% 37% 34% 30% 28% 30% 25% 24% 17% 20% 17% 14% 10% 0% 0% A * Source: TNS survey 2006/7 Data in file B C D ≥65 years E F < 65 years at risk G H Healthcare Workers I J K Flu Vaccine coverage rate in the health care workers (HCWs) 100% HERD IMMUNITY ! 2006/7 Vaccination Coverage Rate (%) 90% 80% 71% 70% 68% 70% 66% 63% 60% 56% 53% 53% 51% 50% 40% 37% 39% 37% 35% 37% 34% 30% 28% 30% 25% 24% 25% 22% 20% 20% 17% 17% 16% 24% 25% 24% 22% 22% 17% 14% 13% 10% 0% A B * Source: TNS survey 2006/7 Data in file C D ≥65 years E F < 65 years at risk G H Healthcare Workers I J K 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 Correlation between pre- and post- vaccination antibody concentrations KAML M et al Vaccine 2006; 24: 6808-11 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 Responses to TT vaccine with and without ready to use canned food 100 80 60 40 20 0 Day 0 Day 30 Day 90 With nutritional supplements Without nutritional supplements LESSOURD B Nature Rev 1995; 53: S86-94 Strategy to address immunosenescence 1. 2. 3. 4. 5. 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 6. Understanding the links between frailty and immunosenescence 7. Establishing vaccine recommendations for the ageing population Improving immune response in old adults • Increasing of the dosage of antigens in the vaccine • Developing novel vaccines based on viruslike 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; 3871-8; GUEBRE-XABIER M et al J Virol 2004; 78:7610-8 FRECH SA et al Vaccine 2005; 4:946-50; GLENN GM et al Immunol 2006;304:247-68 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 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 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 Vaccine programs for a better life Scientific knowledge Very effective Pregnancy Precise guidelines How to improve their Well accepted growth ? Scientific knowledge Continuity of the vaccine program HEALTHY AGEING Children Are they healthy ? Midlife adults How to improve it ? How good is their health ? Part of preventive medicine ! Developing a consensual vaccine programme Scientific knowledge The target: old adults How to improve it ? How good is their health? ! European Union + European Economic Area + European Free Trade Associaion BURDEN of PREVENTABLE INFECTIOUS DISEASES in the ELDERLY European Union Geriatric Medicine Society Proposed EUGMS and IAGG-ER vaccine programme for the old adults By the 7th decade /Retirement age (after a clinical assessment of the vaccine status) - TdaP or Td vaccine - Influenza vaccine - Pneumococcal vaccine - Herpes Zoster vaccine Each year after the retirement age (after assessment of the vaccine status) - Influenza vaccine New medical/injury event Multiple hospital stays (after assessment of the vaccine status) (after assessment of the vaccine status) - Td or TT vaccine - Pneumococcal vaccine By the 9 th decade of age / Nursing Home admission - TdaP or Td or TT vaccine - Influenza vaccine - Pneumococcal vaccine - Herpes Zoster vaccine* MICHEL JP et al Rejuvenation Research 2009; 19: 127-35 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 Preventable infectious diseases are forgotten, but not gone! LIFE COURSE VACCINE PROGRAMME GUSMANO M & MICHEL JP AGING 2009; 21: 258-63 Mrs Quality of Life and I thank you for your attention FRAILTY life long process time « A transitional state » Age, Gender, Lifestyle, Socio-economic status, Co-morbidities, Affective, Cognitive and Sensory Impairments (…) ROBUSTNESS Total FRAILTY AVAILABLE Used ADL DEPENDENCE Physiological reserves DEATH . Age . Malnutrition . Disease(s) . Environment Dysregulations . Hormones . Immunologic . Inflammation . Coagulation Chronic undernutrition CYCLE Total energy expenditure of FRAILTY Sarcopenia Resting metabolic rate Immobilisation Impaired balance Infections Hospital admissions Disabilty Institutionalisation Falls / trauma Drugs use Dependence Death Relationship between frailty and vaccines ? Adapted from FRIED LP et al Sci Aging Knowl Environ 2005; 31: pp 24 (sageke.sciencemag.org)