Immunizations in the Older AdultWAO 2011

Monroe James King, DO, FAAAAIDivision of Allergy and Immunology

University of South Florida, USA

• Our current understanding is that there are genetic, epigenetic and environmental factors that result in aging.

• Proinflammatory cytokines, particularly IL-6 consistently found to be elevated in frail elderly.

• These create picture of chronic inflammatory disease (cachexia, sarcopenia, osteoporosis, etc.).

• Dysregulation of NFkB may be the upstream lesion and the target for future intervention.

EndocrineSenescence

Cytokine Imbalance

Autoantibody

Paraproteinemia

CHRONIC, LOW-LEVEL INFLAMMATION

Cytokine Imbalance

Autoantibody

Immune or InflammatoryDysregulation

Genetic Factors

Chronic AgExposure

Genetic Factors

? ReplicativeSenescence

Thymic Involution

QualitativeT Cell Defects

Accumulation of Memory Cells,Fewer Naïve Cells

MILD TO MODERATEIMMUNEDEFICIENCY

EnvironmentalFactors, ROS

Aging Heterogeneity Frailty • Occurs:

• 7% at age 65• 40% at age 80

• Risk increased with comorbidities

• Impacts physical & cognitive function

• Reduced functional reserve• Susceptibility to stress and

diseases• Predicts negative health

outcomes, including nursing home placement

Clinical Impact of Immune Senescence Upon Elderly

Diminished protective response to vaccination (influenza, pneumococcus)

Increased susceptibility to viral and bacterial infectionAltered response to CMV

Reflects modified CD4+ and CD8+ T-cell repertoireChronic heightened pro-inflammatory state

Increase risk auto-immune disease, malignancy, atherosclerosis

Healthiest elderly forestall immune senescencePawelec G. Immunity and ageing in man. Experimental Gerontology 2006; 41: 1239–42

Adaptive Immunity And Aging

T-cellsProgressive involution of thymus does not alter T-

cell number, but decreases the T cells ability to proliferate in response to antigen*

CD4+/CD8+ ratio (BAL) increases with ageReflects primed T-cells from repeated antigenic

stimulation**

Reduced naïve, increased memory T-cells****Sharma G, Goodwin J. Clinical Interventions in Aging 2006; 1(3): 253-60**Meyer KC et al. Am J Respir Crit Care Med 1996; 153:1072-9.***Katial R. Clin Chest Med 2007; 28:663-72.

Adaptive Immunity and Aging - 2B-cells

Decline in total lymphocyte number and response to phytohemaglutinin*

Antibody production less efficientReduced affinity for specific antigens

Decline in somatic hypermutation*

Immunoglobulins in the lung BAL fluid**Total IgA, IgM, & IgG increase with age.

Increased IL-6 also identified

*Liu J et al. Mech Ageing Dev 2007; 94:177-82.**Katial R. Clin Chest Med 2007; 28:663-72.

Summary of Age-related Changes in Adaptive Immunity

• Dendritic cells _ Phagocytosis, pinocytosis, TLR expression and function, IL6 and TNFα

• T cells - response and proliferation, CD28 expression, TCR diversity, accumulation of CD8+CD28+ T cells

• B cells – produce low affinity antibodies, oligoclonal expansion, MHCclass II molecule expression

Busse&Mathur, JACI 2010

Hypothesized Mechanisms Underlying Immune Senescence*

• Oligoclonal expansion of inhibitory CD8+ cells• Age-associated accumulation of inhibitory

proteins on the cell surfaces• Reduction in telomere length in human

lymphocytes

High _ Workshop on Immunizations in Older Adults

Vaccines for Older Adults

InfluenzaPneumococcal

Zoster

Influenza

• 5th leading cause of death in people over 50• Vaccine efficacy in those age 65 or older -23%

Compared to Children 2 or older – 38% *• Cochrane database review of 31 studies in

adults showed 50-80% efficacy in preventing influenza illness in healthy adults –no data for elderly or those with comorbidity.**

* Jefferson T et al,** Jefferson T CDB

Influenza VaccineExperimental Efficacy ex vivo

In response to vaccine adults ≥64 adults compared to age 20-50

• PBMC produce less IFNγ• Decreased CD8+ cell response • Frail had even poorer response

Deng et al

Influenza Vaccine Problems

• New strains• Viral drift• Age specific responses• Difficult to measure effectiveness in

populations, age groups and frailty

Possible fixes for Influenza vaccines

• Adjuvants-DNA that encodes a key viral-surface protein called hemagglutinin (HA) as booster

• Age specific flu vaccine for older patientsHigh dose Fluzone® has 4 times the dose of

regular Fluzone®– Produces higher antibody levels– CDC has not made dosage recommendation– Also available for intradermal admin.

Pneumococcal Vaccine

• 23 valent polysacharide vaccine• Recommend once after age 65 (if more than 5 years

since original vaccine)• CDC does not recommend repeat boosters as may

even increase susceptibility in older adults • Does antibody response predict protection?

– No difference in patients hospitalized for CAP * (Spain)

– Some evidence for protection but not age specific

*Manzur et al

Herpes Zoster • Reactivation of chicken pox virus (Varicella)• A DNA virus, persists in sensory nerve ganglia• 1 of 3 persons will develop shingles during lifetime (CDC)• Cell mediated immunity is major determinant of incidence

and severity• Immunocompromised persons may get disseminated

disease with skin, CNS, pulmonary and hepatic involvement• Usually unilateral on trunk or 5th cranial nerve• Post herpetic neuralgia may be severe

.

Zoster outbreak

Herpes Zoster Opthalmica

Herpes Zoster

• Associated with:– Aging– Immunosuppression– Intrauterine exposure– Varicella at younger than 18 months of age

Herpes Zoster Vaccine

• Zoster vaccine changes host-virus relationship rather than preventing primary infection

• Live virus vaccine boosts cell mediated immunity

• Reduces frequency and severity of shingles and burden of illness (pain) in older adults

• Expensive ($161 in US) not covered by Medicare

• http://www.cdc.gov/shingles/vaccination.html

Herpes Zoster Vaccine Administration

• Age 50 or older• Less effective within 4 weeks of Pneumovax

Zoster Vaccine Contraindications and Precautions

• Contraindications:– Severe allergic reaction to vaccine components

• Gelatin, neomycin,– Pregnancy– Immunosuppression and immunodeficiency – Tuberculosis –active untreated

• Precautions:– Moderate or severe acute illness– Current treatment with antiviral drug– Immune modulators and recombinant human

mediators

Bibliography

• Deng Y et al. Age-related type1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTI, culture in vitro and blunted response to influenza vaccine in the elderly. J Immunol 2004:172:3437-3446Gruver AL, Hudson LL, Sempowski GD: Immunosenescence of Aging, J of Pathology 2007:211:144-156

• Hanania NA, King MJ et al: Report of a Workshop on Asthma in the Elderly, JACI 2011: Supp 3. Sep S4=S22

Bibliography (2)• Jefferson T et al: Assessment of the efficacy and

effectiveness of influenza vaccines in elderly people a systematic review. Lancet 2005:336:1165-1174.

• Jefferson T et al. Vaccines for preventing influenza in health adults. Cochrane database Syst Review. 2007 Apr 18;CD001269

• Manzur A et al: Influence of prior pneumococcal vaccine on outcomes of older adults with community acquired pneumonia. J American Geriatric Society 2011: 59:171-1716