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Identification of Metabolic and Immune Deficits in the Aged Population and Their Restoration to Achieve Youthful Anti-Influenza Vaccine Responsiveness

Award Number: U01AI165442
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Influenza is a leading cause of death in the elderly and current vaccines only protect a fraction of this population despite widespread vaccination programs and specialized formulations. A better understanding of the molecular mechanisms that control immunological aging is urgently needed so that newly designed vaccines, adjuvants and pharmacologic interventions can be employed to restore youthful antibody (Ab) responses in the older population. Our overarching goals are focused on determining the effects of aging on immune cells that mediate the anti-influenza Ab vaccine response. We will perform an integrated and comprehensive evaluation of circulating T follicular helper (Tfh), T follicular regulatory (Tfr) cells and B cells as well as their subsets from young and older individuals prior to and after seasonal influenza vaccination. We will test the hypothesis that a consequence of advancing age is an altered distribution of individual subsets of Tfh/Tfr cells resulting in metabolic reprogramming and defective B cell elicited influenza vaccine responses. Our integrated analysis includes studies to investigate at the organismal and cellular level age-related declines in metabolic pathways, such as defective mitochondrial biogenesis and one carbon metabolism and to determine if these changes contribute to the immune dysfunction. Finally, knowledge gained from these studies will be used to perform proof of concept rescue experiments in vitro to restore optimal influenza vaccine responsiveness. To support these studies, samples will be used from a seasonal influenza vaccinee cohort of 153 participants (ages 21-76, including 15 individuals = 65yr) who have donated blood at days 0, 7 and 32 after quadrivalent hemagglutinin (HA) vaccination. We plan a targeted expansion of this cohort to recruit an additional 100 donors = 65 years of age and a group of 25 younger adults (= 40yr, n=25) for single cell genomic and metabolomic studies that require fresh blood samples. We will temporally follow the influenza vaccine response and compare young and older groups. Specifically, in Aim 1 we will examine alterations in subset composition and metabolic reprogramming in follicular T cells in young and aged individuals. The completion of these studies will allow us to understand whether defects in humoral immunity associated with aging are mediated by changes in Tfh and Tfr subsets, intrinsic functionality, or both. In Aim 2 we will assess characteristics of the Ab response and determine composition and metabolic changes in B cell populations in young and aged individuals. At the completion of these studies we will also understand changes that result in immune imprinting. In Aim 3 we will analyze age- related dysfunction of Tfh, Tfr and B cells in vitro in response to influenza vaccine antigens. Tfh/B cell co-cultures will be treated with immune modulators and small molecules to restore immunologic and metabolic function to overcome age-related defects in vaccine responses. We have assembled a highly accomplished team to carry out these studies with the goal of testing new paradigms and establishing an actionable roadmap on how to improve vaccine responsiveness in the elderly.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $1,176,696 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	10/31/2022	NON-COMPETING CONTINUATION	$1,176,696


Issue Date FY: 2022 ( Subtotal = $1,238,693 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	11/22/2021	NEW	$1,238,693


Grand Total All Awards = $2,415,389

Sum of Action Amount is $2,415,389;

Grand Total = $2,415,389

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Identification of Metabolic and Immune Deficits in the Aged Population and Their Restoration to Achieve Youthful Anti-Influenza Vaccine Responsiveness

Award Number: U01AI165442

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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