Declining immune function of older adults Is a hallmark of aging and affects the ability of this vulnerable population to resist influenza and respond to vaccination. Rising hospitalization and death rates due to influenza over the last two decades in spite of widespread influenza vaccination programs, call for more effective influenza vaccines in the older population. There have been major advances in vaccine technology but the phases of clinical development are entirely dependent on antibody responses as correlates of protection and measures of vaccine efficacy. This approach to vaccine development lacks a mechanistic understanding of the age-related changes In the development and maintenance of T cell memory in the response to influenza and Influenza vaccination. This project provides a translational approach to understanding how mechanisms of decline with aging of influenza-specific T cell memory responses found in mouse models, apply to studies of peripheral blood mononuclear cells (PBMC) from older people. How T cell memory may be generated or restimulated in response to adjuvanted influenza vaccine formulations is of particular interest. Our long-term goal is to understand how aging affects the Immune response to Influenza and how vaccines could be designed to provide better protection in older people. We will conduct studies to translate recent promising findings In mouse models to establish whether the insights gained will be applicable to comparable human naive and memory CD4 and CD8 T cells. This 5-year proposal will address the following aims: 1) Elucidate defects in the generation of effector and memory functions in aged naive CD4+ T cells and determine their potential reversibility. 2) Identify age-related changes in the phenotype and function of memory T-cell subsets responding to live influenza virus challenge. 3) Determine how CD4 and CD8 T cell responses to influenza vaccination may be enhanced by adjuvants/vaccines in older adults.

Public Health Relevance

Relevance: While it is well recognized that current split-virus vaccines provide limited protection in older people, strategies that completely rely on antibody titers have failed to develop more effective vaccines. A mechanistic approach to vaccine development and a greater understanding of how to improve aged memory T cell responses to influenza is needed;an adjuvanted vaccine formulation holds the greatest promise for better protection in this population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG021600-10
Application #
8733495
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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McElhaney, Janet E; Kuchel, George A; Zhou, Xin et al. (2016) T-Cell Immunity to Influenza in Older Adults: A Pathophysiological Framework for Development of More Effective Vaccines. Front Immunol 7:41
Lefebvre, Julie S; Masters, April R; Hopkins, Jacob W et al. (2016) Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Sci Rep 6:25051
Bartley, Jenna M; Pan, Sarah J; Keilich, Spencer R et al. (2016) Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy. Aging (Albany NY) 8:620-35
Lefebvre, Julie S; Lorenzo, Erica C; Masters, April R et al. (2016) Vaccine efficacy and T helper cell differentiation change with aging. Oncotarget 7:33581-94

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