title: The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines.
abstract: Influenza remains the single most important cause of excess disability and mortality during the winter months. In spite of widespread influenza vaccination programs leading to demonstrated cost-savings in the over 65 population, hospitalization and death rates for acute respiratory illnesses continue to rise. As a person ages, increased serum levels of inflammatory cytokines are commonly recorded (TNF-α, IL-1, IL-6). Termed "inflammaging", this has been linked to persistent cytomegalovirus (CMV) infection and immune senescence, while increased anti-inflammatory cytokines (IL-10, TGF-β) are possibly associated with more healthy aging. Paradoxically, a shift with aging toward an anti-inflammatory (IL-10) response and decline in the IFN-γ:IL-10 ratio in influenza-challenged peripheral blood mononuclear cells is associated with a decline in the cytolytic capacity of CD8+ T cells responsible for clearing influenza virus from infected lung tissue. Thus, it is seemingly counter intuitive that the immune phenotype of healthy aging predicts a poor cell-mediated immune response and more serious outcomes of influenza. Herein we postulate a mechanistic link between the accumulation of late-stage, potentially terminally differentiated T cells, many or most of which result from CMV infection, and the immunopathogenesis of influenza infection, mediated by granzyme B in older adults. Further, adjuvanted influenza vaccines that stimulate inflammatory cytokines and suppress the IL-10 response to influenza challenge, would be expected to enhance protection in the 65+ population.
authors.affiliation: Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada. janet.mcelhaney@ubc.ca
authors.forename: Janet E
authors.initials: JE
authors.lastname: McElhaney
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: H Keipp
authors.initials: HK
authors.lastname: Talbot
authors.forename: Ernst
authors.initials: E
authors.lastname: Soethout
authors.forename: R Chris
authors.initials: RC
authors.lastname: Bleackley
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
mesh_terms: D000368:Aged; D000375:Aging / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D003586:Cytomegalovirus Infections / Q000453:epidemiology / Q000276:immunology; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007251:Influenza, Human / Q000401:mortality* / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; D007252:Influenza Vaccines