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

> **NIH NIH U01** · DANA-FARBER CANCER INST · 2022 · $1,238,693

## Abstract

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 def...

## Key facts

- **NIH application ID:** 10340603
- **Project number:** 1U01AI165442-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Wayne A. Marasco
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,238,693
- **Award type:** 1
- **Project period:** 2021-11-22 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10340603

## Citation

> US National Institutes of Health, RePORTER application 10340603, Identification of Metabolic and Immune Deficits in the Aged Population and Their Restoration to Achieve Youthful Anti-Influenza Vaccine Responsiveness (1U01AI165442-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10340603. Licensed CC0.

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