Immunosenescence: which are the consequences? J Gaillat Annecy France ESCMID eLibrary by author Links of interests

No financial interests with pharmaceutical industry: Honorarium as an Expert for scientific and advisory boards or symposia: o Sanofi, Sanofi Pasteur, MSD, Pfizer Invitations for congress : o Pfizer, Gilead, Sanofi Pasteur MSD.

ESCMID eLibrary 2 by author • Aging an inescapable and increasingly situation • With • Immunological • Epidemiological • Vaccine prevention …. consequences ESCMID eLibrary by author A demographic (r)evolution

EU population is rapidly aging, population pyramid is « inverting »: media media n age - Longer life expectancy n age - Declining fertility rates In 2050, 37% of the population will be 60+ A success but a medical, societal and economical challenge Source: The 2015 Report. European Commission. 2015 p20 ESCMID1. Health at a Glance 2015: OECD Indicators. 2015: pp 192 eLibrary by author Age specific notifiable bacterial infections in Norway

Chart Title 250

200

150 100,000

100

50

0 <5 y 5-19y 20-64y ≧65 Invasive Pneumococcal Disease Invasive Streptococcus B Pertussis Campylobacteriosis Lyme disease ESCMIDSteens eLibraryet al. BMC Infectious Diseases 2014, 14:57 by author Invasive pneumococcal disease

• Incidence < 5y : 21,1/100.000, ≥ 65+: 38,7/100.000

1400 7

1300 cases N° 1200 6 rate 1100

1000 5

900

800 4

700 per 100 000

600 3

500 400 2

Number Number ofCases 300

200 1 Rates of Rates

100

0 0 <1y 1y 2-4y 5-17y 18-34y 35-49y 50-64y ≥65y 4.8 % meningitis, 19.4% bacteraemia, 70.2% pneumonia 43 500 cases, 5 000 deaths

CDC, Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Streptococcus pneumoniae, 2009 ESCMIDhttp://www.cdc.gov/abcs/reports-findings/survreports/spneu09.pdf eLibrary accessed on 5-04-2011 by author Infective endocarditis: increased incidence with age

ESCMID eLibrarySelton-Suty Clin Infect Dis 2102, 54 : 1230-9 by author Impact of age on influenza : general population Rate of laboratory-confirmed influenza infections by age and season (per 100,000) in Alberta Canada, Flu Season 2014-15 People > 65 years : 92% of all reported deaths 75% of all admission in ICU 82% of adults hospitalizations due to Influenza Flu severity in elderly

WHO WER 2015;90:281-96 ESCMIDSource CRDS Alberta Health eLibrary by author A clear relationship between age, Herpes Zoster incidence and PHN

Incidence 50% of cases PHN

1. Stein AN et al. Vaccine. 2009;27:520–529. 2. Helgason S et al. BMJ. 2000;321:794–796. 3. Weitzman D et al. J Infect. 2013;67:463–469. 4. Gialloreti LE et al. BMC Infect Dis. 2010;10:230. 5. Ultsch B et al. Eur J Health Kawai K et al. BMJ Open 2014 Econ. 2013;14:1015–1026. 6. Opstelten W et al. Fam Pract. 2002;19:471–475. 7. Jih JS et al. Acta Derm Venereol. 2009;89:612–616. 8. Gauthier A et al. Epidemiol ESCMID eLibraryInfect. 2009;137:38–47. 9. Yawn BP et al. Neurology. 2013;81:928–930. by author Not only more frequent but more severe infection with sepsis

Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old) Mortality : from 10% in children to 38.4% in those >85 yrs old

ESCMID eLibraryAngus Crit Care Med Crit 2001 Jul;29(7):1303-10 by author Aging population is increasing Infectious diseases are linked to aging

ESCMID eLibrary by author Infection in elderly driven by Immunosenescence • Biological aging process associated with progressive decline in systemic immunity and increased prevalence of , autoimmune and chronic diseases, increased vulnerability to infectious diseases and poor response to vaccines • Not synonymous of but in one hand a decline of the Immunological functions and in an other hand some elements are preserved some prefer Immune Remodelling • Inflammaging is associated, driven by reactivation of old infections such as CMV, with consequences as chronic , modifications of secretion, tissue damages ESCMID eLibraryDewan et al Clin Med J 2012; 125:3325-31 by author objectives

• 1) impact of age on the • 2) efficacy/effectiveness of the current vaccines • 3) how to improve vaccine efficacy in the elders : new strategies of vaccination

ESCMID eLibrary by author ESCMIDCourtesy eLibrary B Combadières ADAPTATIVE RESPONSE INNATE RESPONSE • • Secondary by authorLower affinity Ag/Ab maturity reduction Decrease in B cells production & • shorter shorter duration of immune response Decrease of Bone Blood Lymphatic Bone Delves et al. marrow lymphoids marrow cells Memory B : , Phagocytes: vessels plasmocyes Roitt's Vaccination (+/ Vaccination organs neutrophiles eosinophiles Mastocytes, Immune essential essential immunology. 11th ed. 2006. • Weinberger B et al. Immunosenescence live time - adjuvant) Plasmocytes Inflammation  Long Live Plasmocytes Plasmocytes LiveLong mecanisms naive cells B Co Folliculary cells Pathogen - stimulation helper T Dendritic ( eg Memory Memory , Naïve T cells cells Effectrice Effectrice CD4 , CD4 memory memory ) Clin Naïve T Infect Dis. 2008;46:1078 Cells cells of CD4 CD8 & Memory Memory • • • • • dysregulation Proinflammatory Neutrophil function alteration TLR expression decreased presenting Antigen cells Functional alteration of Effectrice Effectrice CD8 basal basal Inflammation memory memory • • limited specificity for Ag Increase of T with cells a response cells Reduction in naive T Cells - CD8 84. - & > loose of primary cytokines cytokines Immunity and ageing

When, Who, Why?

 Quantitative and qualitative decrease  of the adaptative immunity InnateInnate immunity immunity decreased decreased,

 “inflammaging” Immunité Age • Aspinall R et al. J Comp Pathol. 2010;142 Suppl 1:S111-5. • Frasca D et al. Ageing Res Rev. 2011;10(3):330-5. • Panda A et al. J Immunol. 2010;184(5):2518-27. • Weiskopf D et al. Transpl Int. 2009;22(11):1041-50. ESCMID• Siegrist CA, AspinalleLibraryR. Nat Rev Immunol. 2009;9(3):185-94. by author // with aging immune system & Alzheimer Disease

• to simplify : immunosenescence is as Alzheimer disease: • loss of memory to remind only very old things • Incapability to acquire new knowledge : restriction of T cells functionnality and quantitatively Not able to adapt in front of a new situation • Restriction of the over all immune repertoire, reduction of diversity • As for Alzheimer disease there is a large heterogeneity in clinical presentations, age is not the only explanation, you can have an Alzheimer disease earlier in some people, and never for some very old. • Genetic factors ESCMID eLibrary by author Immunosenescence : a multifactorial situation

CourtesyESCMIDB Combadières eLibrary 17 by author efficacy/effectiveness of the current vaccines

• DTP • Flu • Pneumococcal • HSV

ESCMID eLibrary by author D T P

ESCMID eLibrary by author Influenza Vaccine Efficacy decreases with age

• Seasonal epidemic US • 2012-2013 : VE (H3N2) = 39%, 52% for 55-64y, 11% for 65+ y • 2013-14 VE in general population : 32%, 9% for the 65+ • 2014-early 2015, VE in general population 23% , 14% for the 50+ • Globally : VE : 59% in 18-64 y and 39-49% in 65+ for Flu lab diagnosed • Persistance of Flu epidemics despite a high vaccine uptake in LTCF

Mac Lean JID 2015;211:1529–40 CDC, MMWR Morb Mortal Wkly Rep, 2013; 62: 997-1000. CDC MMWR / January 16, 2015 / Vol. 64 / No. 1 Beyer Vaccine 2013, 31:6030-6033 ESCMIDMonto Clin Infect Dis 2004;39: 459-64 eLibrary by author Virus neutralizing antibodies (VNA) and age (year 2012/2013)

N=35, mean Age: 76y N=28 mean Age: 35y

Naive B Cells (CD19+IgD+) 3 times higher in Younger High B & T attenuator expression on mature B cells linked to higher IgG response to H1N1 v, more frequent in younger ESCMID eLibraryKannan et al oncotarget2015;6 :19445-55 by author Effectiveness of PPV 23 is age dependant and limited in time

Age N < 3 y 3-5 y > 5 y % effectiveness IC 95 < 55 125 93 [82-97] 89 [74-96] 85 [62-94] 55-64 149 88 [70-95] 82 [57-93] 75 [38-90] 65-74 213 80 [51-92] 71 [30-88] 58 [-2-83] 75-84 188 67 [20-87] 53 [-15-81] 32 [-67-72]  85 133 46 [-31-78] 22 [-90-68] -13 [-174-54]

ESCMID ShapiroeLibrary et al NEJM.1991;325:1453-60 by author Opsonization after PPV23

* *

GMT * *

* significant

Opsonophagocytosis is lower for the 65 +, for more than 50% of the serotypes To obtain an opsonization at 1:8, more antibodies needed in elderly, Lower avidity ESCMIDLee eteLibrary al. BMC Infectious Diseases 2010, 10:60 by author HZ Live vaccine efficacy/effectiveness

Efficacy Effectiveness

Author SPS1 Oxman Tseng 2 Langan 3 Marin 4 age ≥ 60y ≥ 60y ≥ 65y ≥ 60y population 38 546 75 761 766 330 569 year 2005 2011 2013 2015 VE [CI 95%] VE VE [CI 95%] VE [CI 95%] HZ incidence 51% [44-58] 55% 48% [39-56] 54[32-69] reduction PHN incidence 66.5% [47.5-79.2] 59% [21-79] 61% [22-80] reduction

1 Oxman NEJM.2005;352:2271-84 2 Tseng JAMA JAMA. 2011;305(2):160-166 3 Langan Plos Medicine 2013 ESCMID4 Marin http://dx.doi.org/10.1080/21645515.2015.1016681 eLibrary by author HZ Vaccine efficacy on zoster (SPS) decreases with age

ESCMID eLibraryOxman NEJM.2005;352:2271-84 by author HZ Vaccine efficacy on PHN (90 days) is not influenced by age

70% of PHN occured in the 70+ ESCMID eLibraryOxman NEJM.2005;352:2271-84 by author Can we and How To Improve Vaccines in elderly

• DTP : • FLU • S pneumoniae • VZV

ESCMID eLibrary by author Enhanced Immune Antigen quantity administration response Vaccination schedule Various route of delivery Adjuvanted vaccines Vaccine improvement : Use of DNA-based or Better immune & cells viral vector-based response Identify and utilize new vaccines, virus-like epitopes to optimize immune particles, virosomal response vaccines Measure of improvement Correlates of protection and their measure Randomized controled trials To Vaccine the surrounding people Antigen presentation Conjugated vaccines ESCMIDAdapted from HaqeLibrary Current Opinion in Immunology 2014, 29:38–42 by author Tetanus DTPolio pertussis just follow the schedule : booster dose

Unprotected Protected before/protected before & after after

Unprotected Protected before/unprotected before & after ESCMIDafter eLibrary by author Influenza

• To increase Ag concentration • Booster doses • Route of administration • Adjuvant, virosomes

ESCMID eLibrary by author High Dose (60 µG) antigen

• Immunogenicity • HD versus SD TIV : improved immunogenicity with HD • HD in olders = SD in younger adults • HD versus intradermal SD : HD vaccine is more immunogenic than the ID vaccines in older adults • Efficacy • RCT double blind 31,989 participants, 2 seasons, HD versus SD, ILI laboratory proven, mean age 73y • HAI titers and seroprotection rates significantly higher in HD group • Relative efficacy : 24.2% (CI 95%=9.7-36.5) • absolute efficacy of IIV3-HD would be estimated at 62% • Well tolerated

Cate et al Vaccine 2010, 28:2076-2079. Diaz Granados Ca et al . Vaccine 2013, 31:861-866 Falsey et al Journ InfectDis 2009; 200:172–80. Tsang et al Vaccine 32 (2014) 2507–2517 ESCMIDDiazGranados NEJM 2014;317:635-645 eLibrary by author Intradermal administration Immunogenicity in adults ≧ 60y Primary endpoint: Superiority of the ID 15 µg vaccine was demonstrated with respect to seroprotection rates* for all strains.

EMA criteria: EMA criteria were fulfilled for all three strains Seroconversion or Seroprotection rate (%) GMTR 4-fold increase (%) 100 ** 100 10 80 ** 80 8

60 ** 60 6

40 40 4

20 20 2

0 0 0 H1N1 H3N2 B H1N1 H3N2 B H1N1 B Dendritic cells H3N2 ID IM * SPR ID-IM, 95% CI>0 for each strain ESCMID** Significantly highereLibrary vs IM vaccine, p<0.005 Arnou et al. Vaccine 2009; 7304-12 by author Adjuvanted Vaccine

• Adjuvant higher antibody response, development of B cells that recognize a larger variety of HA epitopes, and broadened and more vigorous CD4 responses[

• MF59 (ATIV)1: oil in water adjuvant • Better immunogenicity versus TIV, 25% more effective to prevent hospitalization • Case/controls Laboratory confirmed cases, mean age 83 y. VE ATIV : 58%, overall and 72% in non LTCF. VE TIV : non significant • ASO32 : oil inwater adjuvant • 43 802 participants, 65+, 21 893 with ASO3 versus 21 802 TIV, • Virus A&B Relative efficacy : 12% (95% CI : –3.40 to 25.29; superiority not established) • AH3N2 : relative efficacy 22.0%,(95% CI 5.68–35.49) Higher efficacy to prevent H3N2,

1 Tsai Infect Chemother 2013, 45:159-174. Van Buynder Vaccine 2013, 31:6122-6128. ESCMID2 Mannino Am J Epidemiol 2012, 176:527-533. McElhaney Lancet InfecteLibrary Dis 2013, 13:485-496. by author Flagellin : TLR5 agonist seroconversion and seroprotection rates similar to young adults. ESCMID eLibrary by author Pneumococcal vaccine

To increase antigen concentration has no significant impact on immune ESCMID eLibraryresponse by author PCV13 Pivotal : non-inferiority study in PPV pre- immunised* adults ≥ 70 years of age

Study design

Mean age: 77 years * Pre-immunised with PPV ≥ 5 years

ESCMIDJackson L et al. Vaccine 31 (2013) 3585– 3593 eLibrary by author PCV 13 functional antibody response in adults 70 years of age previously vaccinated with PPV

1 month after dose 1 •Antibody responses elicited by Prevenar 13 were non-inferior to PPV among shared serotypes* •Prevenar 13 induced superior antibody responses for 10 common serotypes** and for serotype 6A* Global population ≥80 years of age

* Primary endpoint ** Secondary endpoint 1 month after dose 1 For serotype 6A, which is unique to Prevenar 13, a statistically significantly greater response was defined as the lower bound of the 2-sided 95% CI for the GMR being greater than 2. OPA GMTs following PCV13 administered after PPSV23 were statistically significantly lower for all 13 serotypes ESCMIDJackson L et al. Vaccine 31 (2013) 3585– 3593 eLibrary by author Immunogenicity at 1 month and antibody persistence 1 year after single PCV7 or PPV23 immunization

595 adults 50–80 years of age. PCV7 naïve and no PPV23 in the past 5 years Received either one dose of PCV7 or PPV23 4-6 weeks 12 months post-dose post-dose PCV7 * P <0,05 PCV7 20 PPV23 PPV23

15

10 * * * *

GMC μg/ml GMC 5 *

0 4 6B 9V 14 18C 19F 23F 4 6B 9V 14 18C 19F 23F Serotypes  Responses to both vaccines decreased 10% with each decade of life  One year after immunization, the PCV7 and PPV23 groups were similar for 6/7 serotypes tested. Only serotype 23 differed 38 ESCMIDGoldblatt C I D 2009;49:1318–25 eLibrary by author Post hoc Analysis of Capita study VE decreased Not explained by differences in IgG titres or OPA Other age-related changes in the immune system: reduced phagocytic function of macrophages?

ESCMIDvan Werkhoven,CID 2015;61(12):1835 eLibrary–8 by author Herpes Zoster Vacine

Sub Unit gE adjuvanted with ASO1, 2 injections IM, 2 months apart Randomized, placebo control, 18 countries To assess efficacy vaccine in reducing HZ incidence, people > 50 y 7713 placebo vs 7698 HZ/su vaccine Mean age at 1st dose : 62.3 ± 9 yrs Mean follow-up : 3.2 yrs

ESCMID eLibraryLal et all DOI/ 10.1056/NEJMoa1501184 by author HZ/SU efficacy on HZ incidence

TOTAL COHORT 97.2 [CI 95% 89.6-99.3]

50-59 Yrs 96.6 [CI 95% 89.6-99.3]

60-69 Yrs 97.4 [CI 95% 90.1-99.7]

70+ yrs 97.9 [CI 95% 87.9-100

60+ yrs 97.6 [CI 95% 92.4-99.2

0 60 80 1OO ESCMID LaleLibraryet all DOI/ 10.1056/NEJMoa1501184 by author To avoid exposition : indirect protection

• Influenza vaccination of health care workers; household people etc

ESCMID eLibrary by author conclusion

• The elderly population is increasing • Infection increase with age driven by immunosenescence • immunosenescence characterized by weakened T cell help, and decreased and responses, all culminate in unproductive priming and recall responses to vaccination in older adults. • 7 Vaccine preventable diseases are clearly defined • the currently available vaccines are not optimal ESCMID eLibrary by author Action

• Use what you have to day : elderly are not well vaccinated • Improvement are expected • more research is needed to develop novel vaccines for the elderly • Universal vaccine for Influenza virus & S pneumoniae? • Safety of new vaccines will be crucial. ESCMID eLibrary by author Thank you for your attention

ESCMID eLibrary 45 by author