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

IMMUNOSENESCENCEand

VACCINE FAILURE

Jean-Pierre MICHEL et

Pierre Olivier LANGGeneva Medical University & Hospitals

DISCLOSUREI 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

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

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 cases

notified in Europe between

1999 and 2008concerned 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 2008occur in people aged over 65 years

ECDC http://ecdc.europa.eu/en/publications/Publications/0910

BURDEN ofINFECTIOUSDISEASES in

the OLD ADULTS (1)

In the EU, the number of excess deaths associated with influenza

is estimated between 40’000 and 220’000,

depending of the seasonal variationTILLETT HE et al Lancet 1980; 1: 793-5

Streptococcus

pneumoniae is

the cause of

30%

of community-

acquired

pneumonia

http://www.who.int/vaccine_

research/diseases/ari/en/index3.html

Most influenza-related

andpneumococcal

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

Lower respiratory infections4th cause of death

in developed countries LIANG SY et al Clin Geriatr Med 2007; 23: 441-56


the OLD ADULTS (2)

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 ofvaccine preventable

diseases

To summarize the problem


the OLD ADULTS (3)

POLAND GA, Vaccine 2010, in Press

European Centre for Disease Prevention and Control, 2008

Importance of herd immunity

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 ofvaccine preventable

diseases

To summarize the problem


the OLD ADULTS (3)

This imbalance is strikingand reflecting of a number of underlying

structural, economic, cultural and political issues

POLAND GA, Vaccine 2010, in Press

Avoid mortality linked to preventable infectious diseasesE.g. Influenza vaccine all-cause mortality by 48–50% in community-dwelling older persons

Reduce complications and hospitalisationE.g. Hospitalisations for influenza or pneumonia were by 27% in community dwelling older influenza vaccinees

Decrease antibiotic useE.g. Antibiotic prescriptions were by 64% following influenza vaccination in a Canadian study

Decrease antibiotic-resistant infectionsE.g. Pneumococcal conjugate vaccine nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae

Cost effectivenessE.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

Avoid mortality linked to preventable infectious diseasesE.g. Influenza vaccine all-cause mortality by 48–50% in community-dwelling older persons

Reduce complications and hospitalisationE.g. Hospitalisations for influenza or pneumonia were by 27% in community dwelling older influenza vaccinees

Decrease antibiotic useE.g. Antibiotic prescriptions were by 64% following influenza vaccination in a Canadian study

Decrease antibiotic-resistant infectionsE.g. Pneumococcal conjugate vaccine nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae

Cost effectivenessE.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

Why vaccine coverage rate

of old adults so low ?



2. Immunosenescence



immune responses



ImmunosenescenceDefinition

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

Innate Adaptive

NeutrophilsNb = but functions

Macrophages Nb = but functions

Natural Killer cells or

Dendritic cells

The innate and adaptive immune responses

IMMUNE RESPONSESCapture of Ag

Ag Presentation to T cells

DCs= Nb functions

IL6, IL1, TNF-α

Cellular immunity (T cells)


Ageing T-Cells Thymic involution ( of central production of T-cells)

Memory Ratio of -----------------

Naives

Adapted from GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: 243-84

Child Young adult Aged adult

senescent T cells Memory CD45 RA- CD8 CD28 + Effector CD45 RA+ CD8 CD28 -

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. Reductionof the repertoire of

the naive T cells receptors (TCR)

PFISTER G et al Ann N Y Acad Sci. 2006;1067:152-7

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

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 ------------------------- for Cytotoxic and Helper T cells

Naives

2. Loss of expressionof

CD28 cell surfacemarker

EFFROS RB et al Exp Gerontol 1994; 29: 601-9

1. Decrease of the telomerase activity

at each replication

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

Changes in cytokines production throughout life

GRUBECK-LOEBENSTEIN B Adv Immunol 2002; 80: 243-84

Child Young adult Aged adult

IL-2

IL-4

TFN- IL15

CHIU WK et al J Immunol 2006; 177: 7802-10

Innate Adaptive

NeutrophilsNb = but functions

Macrophages Nb = but functions

Natural Killer cells or

Dendritic cells

The innate and adaptive immune responses

IMMUNE RESPONSESCapture of Ag

Ag Presentation to T cells

DCsNb functions

IL6, IL1, TNF-α

Cellular immunity (T cells)

Humoral immunity (B cells)

Antibody production


19

B-cell responses and ageing

Adapted from SIEGRIST CA and ASPINALL R. Nat Rev Immunol 2009;9:185-94

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

B-cell responses and ageing

Adapted from SIEGRIST CA and ASPINALL R. Nat Rev Immunol 2009;9:185-94

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 depositsand decreased

B-cell progenitors

ImmunosenescenceIn 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 functionsDefects 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



2. Immunosenescence



immune responses



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: 299-304LESSOURD 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 failurein the old population

IgG anti-CMV carrier

P TRZONKOWSKI et al Vaccine 2003; 21: 3826-36

Pre-vaccination chronic proinflammatory activity

exacerbated by the vaccine

1) High cytokines profile: IL10 IL6 TNFα

2) Low immunosupressive cortisol level

?

Impaired immune response



2. Immunosenescence



immune responses



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 inflammatoryprocess

Susceptibility to infections

Osteoporosis

AtherosclerosisSarcopenia

Mortality due to infectious diseases

and cardio-vx diseases Adapted from

B GRUBECK- LOEBENSTEINAging 2009; 21: 1-9

Post FLU vaccine response inyoung (N = 913) and old adults (N = 4492)

0

20

40

60

80

H1N1 H3N2 B

0

20

40

60

80

H1N1 H3N2 B

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

****

**

* *

% %

s122050

On est en plein dans la controverse voir Skowronski et al JID 2008:197 concernant la diminution des la reponse humoral avec l'avancee en age et l'implication de l'immunite cellulaire dans la reponse au vaccine contre la grippe voirNichol KL, vaccine 2009:27Simonsen L et al Vaccine 2009:27Fireman B et al Am J epidemiol 2009:170

FLU vaccine response in elders < 75 y. (N = 1945) and > 75 y. (N= 2492)

0

20

40

60

80

H1N1 H3N2 B

0

20

40

60

80

H1N1 H3N2 B

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

**

**

**

** ****

% %

RUBINS JB et al Inf Immunity 1999: 67: 5979-84

Antibody responses of old adults to all 23 capsular polysaccharides after

Pneumococcal vaccine

N = 53, m.a = 71 y.

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: 5979-84

3.7%

48%

80%

Age-related antibody responses after Pneumococcal vaccination

0

5

10

15

20

25

6B 14 19F 23F

22-46 y.o. 63-79 y.o. 80-89 y.o. > 90 y.o

Eli

sa I

gG

GM

C (g

/ml)

ROMERO-STEINER S Clin Inf Dis 1999; 29: 281-8

Immune Response to 23-v PnPS

HAINZ U et al Vaccine 2005; 23 : 2232-5

Age-dependant persistence of antibody after tetanus vaccine



2. Immunosenescence



immune responses

5. Strategy to address immunosenescence and

vaccine failure


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

s122050

Une strategie a ne pas oublier est REVERSER l'immunosenscence - voir paragraphe joint au courrielReverser l'immunosensncence.doc

s122050

Un autre point qui me semble important est comment identifier les sujets immunosenescents.....car notammnet pour le point 5 et pour le commentaire s11, ces strategies doivent-elles etre appliquees a tous les sujets ages ou seulement aux sujets immunosenscents.ce commentaire ne s'applique bien entendu pas aux politiques vaccinales (points 1 a 3)

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?

Scientificknowledge

Pregnancy

ChildrenHow to improve their growth ?

Are they healthy ?

Scientificknowledge

Very effective

Precise guidelines

Well accepted

Herd immunity

Infant immunity may indirectly protect the elderly

Rate of VT- IPD before and after introduction of PCV7 USA 1998-2003

MMWR, Sept 16, 2005 / 54(36);893-897

Reduced incidence of Invasive Pneumococcal Disease (IPD-VT) in the elderly after introduction

of PCV7 in infants

REICHERT TA et al N Engl J Med 2001; 344: 889-96

Exc

ess

De

ath

s F

rom

Pn

eu

mo

nia

an

d I

nflu

en

za

(pe

r 1

00

,00

0 P

op

ula

tion

)

0

2

4

6

8

10

12

14

1950

1954

1958

1962

1966

1970

1974

1978

1982

1986

1990

1994

1998

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

CommunityP&I = Pneumonia & Influenza mortality rate


1. Promoting life long vaccine programs







TIME

Vaccine programs

for a better life

Clinicalrecommendationsfor the ageing and

aged adults

Part ofPREVENTIVEMEDICINE !


How to improve it ?


Scientificknowledge

Continuity ofthe vaccine program !!

HEALTHY AGEING How to improve it ?Midlife adults

How good is their health ?

Scientificknowledge

Pregnancy


Are they healthy ?

Scientificknowledge

Very effective

Precise guidelines

Well accepted

?

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

SISCOVICK DS et al Am J Epidemiol 2000; 152: 674-7

Influenza vaccination seemed to be associated with

a reduced risk ofprimary cardiac arrestOR = 0.51 [0.33- 0.79]

Coronary Artery Disease (CAD) and

Influenza vaccineRandomized, 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 assecondary prevention of

Cardio Vascular Diseases (CVD)

The American Heart Association and American College of Cardiology

recommendInfluenza 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

INFLUENZA(Seasonal Flu)

http://upload.wikimedia.org/wikipedia/commons/7/7f/Influenza_A_-_late_passage.jpg

Flu Vaccine coverage rate in the 65+ population

71% 70%68%

66%63%

53% 53%51%

37%

30%

25%

0% 0%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

A B C D E F G H I J K

2006

/7 V

acci

natio

n C

over

age

Rat

e (%

)

≥65 years < 65 years at risk Healthcare Workers* Source: TNS survey 2006/7Data in file

2014 WHO goal = 75%

2006 WHO goal = 50%

2006/2007

Flu Vaccine coverage rate in the population < 65 at risk

71% 70%68%

66%63%

53% 53%51%

37%

30%

25%28%

17%

24%

14%

0%

37%37%

56%

35%39%

34%

17%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


2006

/7 V

acci

natio

n C

over

age

Rat

e (%

)


2014 WHO goal = 75%

2006 WHO goal = 50%

Flu Vaccine coverage rate in the health care workers (HCWs)

71% 70%68%

66%63%

53% 53%51%

37%

30%

25%28%

17%

24%

14%

22%

17%

34%

39%35%

56%

37% 37%

24% 24%

17%13%

22%25%

22%

16%

25%

20%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


2006

/7 V

acci

natio

n Co

vera

ge R

ate

(%)


HERD IMMUNITY !

Correlation between pre- and post- vaccination antibody concentrations

KAML M et al Vaccine 2006; 24: 6808-11

0

20

40

60

80

100

Day 0 Day 30 Day 90

With nutritional supplements

Without nutritional supplements

Responses to TT vaccine with and without ready to use canned food

LESSOURD B Nature Rev 1995; 53: S86-94







6. Understanding the links between frailty and immunosenescence


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; 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

Reversing immunosenescencePossible 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

Vaccine programs

for a better life

Part ofpreventivemedicine !

Developing aconsensual

vaccineprogramme


How to improve it ?


Scientificknowledge

Pregnancy


Are they healthy ?

Scientificknowledge

Very effective

Precise guidelines

Well accepted

TIME

!

How to improve it ?Midlife adults

How good is their health ?

Scientificknowledge

Continuity of the vaccine programHEALTHY AGEING

BURDEN of PREVENTABLE INFECTIOUS DISEASES

in the ELDERLY

European Union + European Economic Area + European Free Trade Associaion

European Union Geriatric Medicine Society

Proposed EUGMS and IAGG-ERvaccine 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

- 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: 127-35



2. Immunosenescence



immune responses



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

« A transitional state »

ROBUSTNESS

FRAILTY

ADLDEPENDENCE

FRAILTY life long processtime

DEATHPhysiological reserves

Total

Used

AVAILABLE

Age, Gender, Lifestyle, Socio-economic status,

Co-morbidities, Affective, Cognitive and Sensory

Impairments (…)

Adapted from FRIED LP et al Sci Aging Knowl Environ 2005; 31: pp 24 (sageke.sciencemag.org)

Sarcopenia Total energyexpenditure

CYCLEof

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 ?

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

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