Clinicians currently do not have methods to predict influenza vaccine responses in older adults that are accessible and relatively inexpensive. The long-term goal of this research is to identify the T-cell responses that are surrogates (biomarkers) of serious complications of influenza and can be used to predict vaccine effectiveness. Such loosely termed biomarkers would provide clinicians with the ability to decide who might benefit from newer or more reactogenic vaccines, such as a higher antigen dose vaccine, or who might require chemoprophylaxis during influenza season due to inadequate response to vaccination. This 5-year proposal is a randomized study of split-virus influenza vaccine (SVV) in a high-dose (HD) vs. standard dose (SD) formulation in each of five influenza seasons to define the key determinants of vaccine-mediated protection against influenza and how these immunologic mediators may be enhanced by vaccination with a newly approved high-dose influenza vaccine in frail older subjects. This study will allow us to address the following aims:
AIM I : Determine whether a newly marketed high dose vaccine performs better than standard doses in achieving protective increases in IFN?:IL-10 ratios and GrzB levels. Our hypothesis is that the proportion of subjects above the threshold level for the IFN?:IL-10 ratio (>10) and/or GrzB (>990 U/mg protein) following vaccination will be significantly higher in those receiving the high-dose SVV vs. standard-dose SVV.
AIM II : Evaluate the association of degree of frailty to CMV status and GrzB levels in resting T cells (bGrzB). Frailty represents a validated and measurable state of enhanced vulnerability in older individuals. Our hypothesis is that increasing frailty will be positively associated with higher bGrzB levels.
AIM III : Establish predictors of vaccine-mediated protection that can be developed for point-of-care testing. Our hypothesis is that increased levels of frailty, CMV seropositive status, and bGrzB activity are associated with lower cytolytic activity, diminished Th1:Th2 responses to influenza challenge, and an enhanced risk of an influenza illness.

Public Health Relevance

The progressive loss of vaccine efficacy with aging and the rising hospitalization and death rates due to influenza in spite of widespread influenza vaccination programs call for significant improvements in the available influenza vaccines and for a better way to identify those at highest risk for vaccine failure. Using immunologic biomarkers of the response to influenza vaccination, we will determine if the aged immune system can be effectively stimulated by a new vaccine, and will look to develop a clinical tool and test a possible biomarker to determine which patients will not respond to traditional vaccine. This project will tell us how to develop and test new influenza vaccines to provide better protection against the disabling complications of influenza in older people.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Fuldner, Rebecca A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Connecticut
Other Health Professions
Schools of Medicine
United States
Zip Code
Justice, Jamie N; Ferrucci, Luigi; Newman, Anne B et al. (2018) A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. Geroscience 40:419-436
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
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
Merani, Shahzma; Kuchel, George A; Kleppinger, Alison et al. (2018) Influenza vaccine-mediated protection in older adults: Impact of influenza infection, cytomegalovirus serostatus and vaccine dosage. Exp Gerontol 107:116-125
Ucar, Duygu; Márquez, Eladio J; Chung, Cheng-Han et al. (2017) The chromatin accessibility signature of human immune aging stems from CD8+ T cells. J Exp Med 214:3123-3144
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
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
Zhou, Xin; Hopkins, Jacob W; Wang, Chongkai et al. (2016) IL-2 and IL-6 cooperate to enhance the generation of influenza-specific CD8 T cells responding to live influenza virus in aged mice and humans. Oncotarget 7:39171-39183
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