Immunization in the elderly:

Immunology of aging #2

Graham Pawelec, University of Tübingen

• Response to most vaccines requires antigen presentation by dendritic cells

• Antigen must be recognised by T cells present in the repertoire

• T cells must differentiate to helper and cytotoxic cells

• B cells must be present in the repertoire and able to produce antibody

Immunity: pre-requisites

Reduced numbers of DC and LC

Impaired function of DC and LC

Altered cytokine production

Failure to stimulate CD4+ T cells

Changes in TLR signaling

Ageing Ab

BC

Treg

Th2

Naïve T cell

Th1

CD8

IL-4 IL-5 IL-13

IL-10 TGF-β

IFN-γ

IFN-γ

NKT cell

Langerhans cell

Dendritic cell

Pathogen TLR PAMP

Ageing and Immunity

3 From Müller & Pawelec, Handbook of the Biology of Aging, 8th Ed, 2017

Age-related defects in T-cell activation

Altered signal transduction pathways

Compromised assembly into signalosome

Alterations to TCR-structure

Alterations to co-stimulatory receptor

Th1

GATA3

Th2

Th17

Treg

FoxP3

RORg

Tbet

TGF-ß

IL-17

IL-4

IL-7

Pro-inflammatory cytokines

Naïve T cell

Dendritic cell

Deficits in T cell activation

From Müller & Pawelec, Handbook of the Biology of Aging, 8th Ed., 2017

Bottom line for WEIRD subjects Age-associated changes in the bone marrow skew the output of myeloid-vs-lymphoid cells (more neutrophils and fewer B cells associated with poorer survival in OCTO/NONA) Thymic involution drastically reduces the output of naive T cells after puberty Most age-associated immune marker changes are likely to be due to individual exposures, especially to persistent pathogens (CMV!), and are probably compensatory Hence, measurements of immune ageing are context (population and individual)-dependent Additionally, the genetic background, gender and socioeconomic status influence how the individual immune system deals with CMV and presumably other pathogens

Two major problems with “immunosenescence”

Too many exhausted memory T-cells

might compromise immune memory exhausted memory cells might contribute to inflammageing

Too few naïve T-cells

holes in the repertoire would prevent

response to novel challenge

Duration of immune protection

Pertussis 4-6 years Diphtheria Around 10 years Tetanus 96% protected 13-14 years, 72% >25 yr Polio >99% protected for at least 18 years Hepatitis B >20 years to date Measles Life-long in >96% vaccines Mumps >10 years in 90%, waning slowly Rubella Most vaccinees (>90%) protected >15 yr Pneumococcal >4-5 years so far for conjugate vaccines Human Papillomavirus >5 years to date

Do we know that few naïve cells are really bad?

They can be, for responses to new challenges: One of the few studies available explored human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8+ T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4+ T cell immunity. Low numbers of naive CD4+ T cells and low numbers of dendritic cells correlated well with reduced acute responsiveness and altered long- term persistence of human cellular immunity to YF vaccination. A.R. Shulz et al. J Immunol, 2015, 195: 4699–4711.

Do we know that few naïve cells are really bad?

- They don´t have to be, it depends on the context:

Individual ageing trajectories are highly context-dependent – and we need to know why for each

specific population

● Risk factors for disease and mortality may be different at different ages (“younger” and “older” elderly different) as in our Swedish studies and in the Leiden 85-Plus study. ● Risks are influenced by genetics (LLS, and our Danish twin studies) ● Risk factors may be different in different populations - most studies have been performed on WEIRD people (subtle differences seen in our studies of Pakistanis and Singaporeans) ● Wide-ranging data for each individual must be collected to integrate the impacts of diverse parameters on outcomes (nutrition, psychosocial, socioeconomic, infection history, cognitive, medical, etc., as in our Berlin studies)

Evidence for similarities and differences in immune parameters in

WEIRD-vs-LMICs populations?

More dysfunctional DCs in LMICs? - don´t know More rapid loss of naïve cells in LMICs? - very likely yes More marked accumulation of late-stage memory cells, potentially exhausted, in LMICs? - very likely yes But what this means clinically will depend on the context

Foxp3+CD127loCD25+/CD4+

0 2 4 6 80

20

40

60

80

100LowHigh

Time from baseline (years)

Perc

ent s

urvi

val

More Tregs in the elderly – but no effect on survival in Leiden 85-plus

Derhovanessian et al., J. Gerontol, 2014

Significant survival advantage for people with higher CD8+ effector memory cells in

the Leiden 85+ study

p=0.0002

Derhovanessian et al. Age (Dordr). 2013 Aug;35(4):1387-99

What is BASE-II?

• Cross-sectional survey of 600 20-32 and 1600 60-72 year-old Berliners

• Longitudinal follow-up planned on all subjects • Collaborative project establishing databases and sample

banks from these 2200 subjects • Medical, Genetic, Psychological and Social sciences

values will be integrated • And GWAS to seek those genes..... • Younger cohort: 25% CMV-seropositive; older cohort:

65% CMV-seropositive

Distribution of CD8+ T-cell phenotypes in Berlin: affect of age and CMV serostatus

Y- Y+ O- O+0

25

50

75

100**

******

******

***

% o

f tot

al C

D8+

Y- Y+ O- O+0

20

40

60

******

***

***

% o

f tot

al C

D8+

Y- Y+ O- O+0

20

40

60

80***

***

***

***

***

***%

of t

otal

CD

8+

N

CM

EM TEMRA

Y- Y+ O- O+0

25

50

75

*** ******

***

***

% o

f tot

al C

D8+

Higher frequencies of CD8 memory T cells in CMV+ elderly people than young

0

5

10

15

20

25

30

35

40

40 50 60 70 80Age

% C

D45

RA

mid

CC

R7-

CD4+CD8+

Derhovanessian et al, J Immunol 2010

No significant differences between young and old CMV-negative people

05

1015

202530

3540

4550

40 50 60 70 80Age

% C

D45

RA

+CC

R7+

CD

27+C

D28

+CD

57-

KLR

G1- CD4+

CD8+

Derhovanessian et al., J Immunol 2010

CMV seropositivity in NHANES

10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 850

20

40

60

80

100bottom quartiletop quartile

income

Data from Dowd et al., Epid Infect 2008

Age

perc

ent s

erop

ositv

eCMV seroprevalence in the US

CMV maybe not so “harmless”after all? All-cause mortality, NHANES III, n=14011 >25 years old

Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE. PLoS One. 2011 Feb 17;6(2):e16103.

Singaporean Longitudinal Aging Study II Identification of variables associated with successful aging in: • > 1200 elderly (>55 years) from Singapore community

centers, serving as representative of the population. At baseline: • 5 – 6 detailed interview sessions at their homes, on-site

clinical assessments, performance based testing Assessment of an extensive range of demographic, medical, biological, psychological, behavioral and neurocognitive variables 100% CMV-seropositive Study leader: Yap-Seng Chong

Peshawar Nutrition and Immunosenescence Study

• Study Site and Sample Location – Peshawar, KPK Pakistan • Sample Selection – City Registration Data (NADRA) • Sample Size – Convenience Sampling of 525 Elderly and 252

Young (For Field Data Collection) and 100 (50 Y, 50 Old) for blood collection

• 100% CMV+ • Study leader Iftikhar Alam

21

Obesity

Since 2000, BMI has been increasing in LMICs, whereas underweight has become less widespread Linked to higher levels of inflammation Linked to immune dysregulation Associated with increasing cancer in LMICs?

23

24

CD8+ T cells in young (50) Pakistani men

25

CD4+ T cells in young (50) Pakistani men

26

Distribution of CD27+CD28+KLRG1−CD57−, CD27−CD28−KLRG1+CD57+

cells within CD8+ (a), CD4+ (b), and Tregs in young and elderly Pakistani men

27

B cells and NK cells in young and old Pakistani men

Inflammaging Chronic inflammation keeps resources unecessarily diverted to pathogen resistance and away from somatic maintenance Intervention: anti-inflammatories? These inflammatory factors can easily be measured in serum, and routine assessments of levels of interleukin 6 (IL 6) and tumour necrosis factor (TNF), as well as C-reactive protein CRP) are cheap.

Inflammaging and Anti-inflammaging

Higher levels of inflammatory mediators in elderly humans can be paralleled by higher levels of anti-inflammatory mediators These factors can also easily be measured in serum, e.g. Interleukin 10 (IL 10) This implies that a balance should be determined, most likely clusters of biomarkers, not single biomarkers, will be useful

Effects of socioeconomic status

Pro-inflammatory gene expression is higher in people experiencing low SES in early life regardless of later SES Consistent with the idea of a „biological residue of early life social class“ as a result of epigenetic programming

Effects of socioeconomic status

Some effects of SES may be via higher frequencies of CMV infection in lower SES and poorer control of the virus Intervention: improve SES early in life and use anti-viral agents later in life

Individual ageing trajectories are highly context-dependent –

and we need to know why for each specific population

● Gender differences! ● Risk factors for disease and mortality may be different at different ages ● Risk factors may be different in different populations - most studies have been performed on WEIRD people ● Wide-ranging data for each individual must be collected to integrate the impacts of diverse parameters on outcomes

Does patient age affect anti-cancer immunity?

Under conventional treatment? Responses to cancer vaccines? Responses to checkpoint blockade?

State of Play

In the patients we have studied so far:

• No obvious detrimental effects of „immunosenescence“ on responses to cancer immunotherapy – neither active vaccination, nor ipi-treatment, nor conventional

• Immunosenescence may only be relevant for susceptibility to infectious disease to which the person was not previously exposed (i.e. neoantigen repsonses)

• If neoantigens are most important in cancer immunosurveillance, age should impact on response and survival, but we have no evidence for this yet

Acknowledgements Current lab members David Goldeck Chris Shipp Alex Martens Kilian Wistuba-Hamprecht Nicole Janssen Lisa Speigl Lilly Oettinger Svetlana di Bendetto Alexandra Grieb Previous members Evelyna Derhovanessian Karin Haehnel Jithendra Kini Anis Larbi Jürgen Kempf Collaborators Rudi Westendorp, Leiden Cathy Mathei, Leuven Anders Wikby, Jönköping Allison Aiello, Chapel Hill Tamas Fülöp, Sherbrooke Iftikhar Alam, Peshawar Per thor Straten, Copenhagen Klaus Hamprecht, Tübingen Yap-Seng Chong, Sincapore

Funding: EU, DFG, BMBF, Croeni Foundation

Center for Medical Research Waldhörnlestr. 22 Tübingen-Derendingen Germany

http://www.medizin.uni-tuebingen.de/tati/zmf%20spring%202003.jpg

Tübingen Ageing and Tumour Immunology Group at the Center for Medical Research, University of Tübingen

Questions posed by the WHO for this presentation

• What is the immunological basis for different risks of vaccine preventable diseases among elderly persons globally • As opposed to chronological age, can we determine an immunological age with relevance to vaccination strategies?

• Which strategies may overcome immune senescence in the elderly and restore vaccine responsiveness?

Slide Number 1Slide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13What is BASE-II?Distribution of CD8+ T-cell phenotypes in Berlin:�affect of age and CMV serostatusHigher frequencies of CD8 memory T cells in CMV+ elderly people than youngNo significant differences between �young and old CMV-negative people Slide Number 19Singaporean Longitudinal Aging Study IIPeshawar Nutrition and Immunosenescence StudyObesitySlide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33State of Play�Slide Number 35Slide Number 36Slide Number 37