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
Kuchel, George A (2018) Frailty and Resilience as Outcome Measures in Clinical Trials and Geriatric Care: Are We Getting Any Closer? J Am Geriatr Soc 66:1451-1454
Lorenzo, Erica C; Bartley, Jenna M; Haynes, Laura (2018) The impact of aging on CD4+ T cell responses to influenza infection. Biogerontology 19:437-446
Parham, Kourosh; Kuchel, George A; McElhaney, Janet E et al. (2018) A Relationship Between Blood Levels of Otolin-1 and Vitamin D. Otol Neurotol 39:e269-e273
Lanzer, Kathleen G; Cookenham, Tres; Reiley, William W et al. (2018) Virtual memory cells make a major contribution to the response of aged influenza-naïve mice to influenza virus infection. Immun Ageing 15:17
Swain, Susan L; Kugler-Umana, Olivia; Kuang, Yi et al. (2017) The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age. Cell Immunol 321:52-60
Tabtabai, Ryan; Haynes, Laura; Kuchel, George A et al. (2017) Age-Related Increase in Blood Levels of Otolin-1 in Humans. Otol Neurotol 38:865-869
Masters, A R; Haynes, L; Su, D-M et al. (2017) Immune senescence: significance of the stromal microenvironment. Clin Exp Immunol 187:6-15
Brahmakshatriya, Vinayak; Kuang, Yi; Devarajan, Priyadharshini et al. (2017) IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo. J Immunol 198:2819-2833
Merani, Shahzma; Pawelec, Graham; Kuchel, George A et al. (2017) Impact of Aging and Cytomegalovirus on Immunological Response to Influenza Vaccination and Infection. Front Immunol 8:784
Bartley, Jenna M; Zhou, Xin; Kuchel, George A et al. (2017) Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses. Front Immunol 8:1164

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