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Ageing and Immunity: implications for vaccine responsiveness Dr Mansel Haeney Consultant Immunologist Salford Royal NHS FT Invasive Pneumococcal Infection England & Wales Incidence per 100,000 by age group, 2000 80 60 40 20 0 <1 m 1 - 11 m 1-4y 5-9 y 10 - 14 y 15 - 44 y 45 - 64 y 65 - 74 y > 75 y from Dr Robert George, RSIL, HPA West Nile virus epidemic – USA 2002 > 4 000 cases 284 deaths Median age deceased = 78yr O`Leary et al 2004 Thymic involution Cellular Immunity in the Elderly Altered T cell phenotype naïve T cells; memory T cells Reduced T cell responses response to TCR stimulation T cell proliferation expression of IL2-R IL2 production Ginaldi et al 1999 Immune Risk Phenotype Longitudinal immunological study to establish predictive factors of longevity OCTA / NONA study ( Wikby et al) Immune risk phenotype CD4:CD8 ratio < 1.00 CD8+ CD28- cells CD8+ CD28- CD27- in very old B cells Poor in vitro T cell proliferation CMV seropositivity Innate immunity Natural ; non-specific Responses of the elderly to immunisation Fig. 2. Serum concentrations of anti-KLH IgM (A) and IgG (B) were assessed in young and older physically active and sedentary men after KLH immunization Smith, T. P. et al. J Appl Physiol 97: 491-498 2004; doi:10.1152/japplphysiol.01404.2003 Copyright ©2004 American Physiological Society Pneumococcal antibody production 1. Low pre – and post – immunization titres 2. Reduced frequency of 2 x increase in titre 3. 4. Reduced frequency of ‘protective’ ab. titres at 1 month Rapid decline in ab. titres by 1 year JCVI/mins-pneumococcal-220108 What can be done to better protect the elderly? Reversal of Thymic Atrophy Surgical or chemical castration ( in mice) alters TREC levels Chemical castration improves TREC levels in humans IL-7 reverses thymic atrophy in older animals – role of fusion protein CCR9-IL7? Effect of CMV infection on immune function in the elderly? Viral infection normally cleared by CD8+ virus-specific T cells Up to 50% CD8+ T cells in elderly reported to be CMVspecific : may lead to impaired responsiveness to other viral infections in elderly people KLRG-1 is a marker of senescence: KLRG-1 + T cells do not proliferate in vitro 96% CMV+ CD8+ T cells expressed KLRG-1 In elderly, fewer CMV+ CD8+ T cells secreted IFNγ compared with cells from younger people Does immunological senescence negate the benefits of immunisation? Prospective cohort study 25,000 independently living people : 50% reduction in mortality Repeated immunisation seems advantageous 1st immunisation : 9% reduction in mortality 2nd/repeat immunisation: 75% reduction Does immunological senescence negate the benefits of immunisation? 200 hospitalised elderly patients with proven influenza: 61% had received influenza vaccine Influenza epidemics: hospitalisation of elderly lags 2 weeks behind peak in community. Are children `the engine that drives the epidemic?` Epidemic influenza Elderly have greatest risk of mortality Children responsible for most transmission Immunisation of children reduces infection rate in children, adults and elderly Predictions suggest vaccination of 30% schoolchildren should reduce spread from 90% to 65% Vaccination of 70% children should reduce spread to 4% Herd immunity may provide cost-effective protection of elderly (Reichert, NEJM,2001; Cohen, Science, 2004) Impact of PCV vaccination USA data: 94% fall in invasive pneumococcal disease caused by 7 serotypes in children < 5yrs 62% fall in IPD in individuals > 5yrs who had NOT been immunised Implies elderly may benefit more from `herd immunity` effect of childhood PCV programme than from PPV immunisation Confounding variables Pace of ageing Spectrum of `youngold (>65y) to extremely old (>95y) Survivor bias Institutionalisation Physical fitness Conclusions Immunosenescent changes particularly affect T cell populations and function Immunosenescence affects the response to vaccines Vaccine-induced antibody responses wane rapidly in the elderly Better vaccine efficacy in the elderly may require (i) improved immune responsiveness and (ii) changes to vaccine formulation Herd immunity applies to the elderly as well as to the young You can live to be a hundred You can live to be a hundred if you give up all the things that make you want to live to be a hundred Woody Allen