U01AI165452

A Deep Longitudinal Analysis of Next Generation Influenza Vaccines in Older Adults - Project Summary

The World Health Organization estimates that annual epidemics of influenza result in 3-5 million cases of severe illness and 300,000-500,000 deaths. 90% of influenza-related deaths occur in older adults despite widespread vaccination programs with vaccines tailored for this high-risk group. The estimated effectiveness of the influenza vaccine in the U.S. for the 2018-2019 influenza season overall was 47%, but only 12-13% in older adults. There is therefore an urgent need to understand the mechanisms that are turned on/off in older adults that result in their limited response rate to the most commonly used influenza vaccine, FluZone® High-Dose. There is also a need to understand whether and why next-generation influenza vaccines might be more efficacious. Immunosenescence is known to be associated with declines in optimal B cell and T cell adaptive immunity, however, our overall understanding of the mechanisms of immunosenescence is incomplete. The central goal of this proposal is to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults through establishment of the 3Fluaging cohort of healthy older adults who will be vaccinated with three different influenza vaccines three years in a row. We hypothesize that aging impacts specific regulatory mechanisms of humoral immunity to reduce vaccine effectiveness.

In Aim 1, we will establish a cohort of 60 healthy older adults (≥65yrs) who will sequentially receive three different annual influenza vaccines, with serial blood and microbiome sample collection during three years of follow-up. Participants will undergo regular clinical assessments.

In Aim 2, we will decipher the magnitude and immunodominance pattern of the humoral response to influenza virus in healthy older individuals upon vaccination. For each vaccine, we will characterize antibody titer and quality and will define responders and non-responders.

In Aim 3, we will characterize the epigenome, transcriptome, cytokine production, and cell proportions of blood leukocytes in vaccinated healthy older participants. We will identify specific (epi)genomic and functional signatures, and their longevity, associated with vaccine response. We will also sequence all participants to uncover the role of genetic variation on influenza vaccine responses.

In Aim 4, we will assess the function of T helper cells and antigen presenting cells, specifically dendritic cells, in influenza vaccine responders and non-responders. By identifying responders and non-responders for each vaccine and integrating these data with baseline immune status multi-omic signatures, we will determine which immune features can predict vaccine responsiveness.

We expect to identify humoral immunity pathways that are altered in aging that can be used as the basis for designing novel approaches to boost efficacy of the most commonly used, as well as emerging, influenza vaccines.

Jackson Laboratory

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]

Farmington, Connecticut 060322374 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 401% from $1,622,607 to $8,127,184.