U01AI165442

Identification of Metabolic and Immune Deficits in the Aged Population and Their Restoration to Achieve Youthful Anti-Influenza Vaccine Responsiveness - 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 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 vaccine cohort of 153 participants (ages 21-76, including 15 individuals ≥ 65 years) 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 (≤ 40 years, 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.

Dana-Farber Cancer Institute

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 022155418 United States

Single Zip Code

Cohort Studies To Improve Our Understanding of Influenza Immunity, Vaccine Response and Effectiveness in Older Adults (65 years and older) (U01 Clinical Trial Not Allowed) (RFA-AI-20-060)

Amendment Since initial award the total obligations have increased 284% from $1,238,693 to $4,757,817.