Graham Pawelec, University of Tübingen. Immunization in the elderly: Immunology of aging #2

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1 Graham Pawelec, University of Tübingen Immunization in the elderly: Immunology of aging #2

2 Immunity: pre-requisites 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

3 Ageing and Immunity Dendritic cell NKT cell CD8 IFN-γ Reduced numbers of DC and LC Th1 IFN-γ Impaired function of DC and LC Treg IL-10 TGF-β Altered cytokine production Naïve T cell Failure to stimulate CD4+ T cells Pathogen PAMP TLR Langerhans cell Th2 IL-4 IL-5 IL-13 Changes in TLR signaling BC Ab Ageing From Müller & Pawelec, Handbook of the Biology of Aging, 8th Ed,

4 Deficits in T cell activation Dendritic cell Tbet Pro-inflammatory cytokines Alterations to TCRstructure Th1 IL-7 GATA3 IL-4 Compromised assembly into signalosome Th2 Altered signal transduction pathways Naïve T cell Th17 RORg IL-17 Alterations to costimulatory receptor Treg FoxP3 TGF-ß Age-related defects in T-cell activation From Müller & Pawelec, Handbook of the Biology of Aging, 8th Ed., 2017

5 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

6 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

7 Duration of immune protection Pertussis 4-6 years Diphtheria Around 10 years Tetanus 96% protected 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

8 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 longterm persistence of human cellular immunity to YF vaccination. A.R. Shulz et al. J Immunol, 2015, 195:

9 Do we know that few naïve cells are really bad? - They don t have to be, it depends on the context:

10 Individual ageing trajectories are highly contextdependent 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)

11 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

12 More Tregs in the elderly but no effect on survival in Leiden 85-plus Foxp3+CD127loCD25+/CD4+ Percent survival Low High Time from baseline (years) Derhovanessian et al., J. Gerontol, 2014

13 Significant survival advantage for people with higher CD8+ effector memory cells in the Leiden 85+ study p= Derhovanessian et al. Age (Dordr) Aug;35(4):

14 What is BASE-II? Cross-sectional survey of and 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

15 Distribution of CD8+ T-cell phenotypes in Berlin: affect of age and CMV serostatus % of total CD8+ N ** *** *** *** *** *** % of total CD *** *** *** *** *** CM 0 Y- Y+ O- O+ 0 Y- Y+ O- O+ % of total CD EM *** *** *** *** % of total CD *** *** *** *** *** *** TEMRA 0 Y- Y+ O- O+ 0 Y- Y+ O- O+

16 Higher frequencies of CD8 memory T cells in CMV+ elderly people than young % CD45RAmidCCR Age CD4+ CD8+ Derhovanessian et al, J Immunol 2010

17 No significant differences between young and old CMV-negative people % CD45RA+CCR7+CD27+CD28+CD57- KLRG Age CD4+ CD8+ Derhovanessian et al., J Immunol 2010

18 CMV seroprevalence in the US percent seropositve CMV seropositivity in NHANES income bottom quartile top quartile Age Data from Dowd et al., Epid Infect 2008

19 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 Feb 17;6(2):e16103.

20 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

21 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

22 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 23

24 CD8+ T cells in young (<25) and old (>50) Pakistani men 24

25 CD4+ T cells in young (<25) and old (>50) Pakistani men 25

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 26

27 B cells and NK cells in young and old Pakistani men 27

28 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.

29 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

30 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

31 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

32 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

33 Does patient age affect anti-cancer immunity? Under conventional treatment? Responses to cancer vaccines? Responses to checkpoint blockade?

34 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

35 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 Center for Medical Research Waldhörnlestr. 22 Tübingen-Derendingen Germany Funding: EU, DFG, BMBF, Croeni Foundation 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

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

37 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?