U19AI168643

Immune Development in Early Life (IDEAL) Shapes Vaccine Response, Respiratory Infectious Disease, and Asthma - Project Summary

To date, efforts to define and apply precision endotyping have been limited to studies of adults. However, immune development in early life (IDEAL) is dynamic and varies between individuals, suggesting that endotypes corresponding to distinct pathophysiological mechanisms will be age-dependent. We propose, therefore, a novel approach in which we will study well-defined longitudinal childhood cohorts and use in silico integrative analyses of existing and prospectively collected data, coupled with age-specific human in vitro model systems, to identify agents that redirect IDEAL away from disease endotypes towards those associated with health.

We have selected three clinical endpoints to correlate with systems biology data to identify IDEAL endotypes:
A) Vaccine responsiveness, as vaccines are the most important biomedical intervention to reduce childhood disease;
B) Respiratory infection, which represents the greatest burden of childhood infectious disease; and
C) Asthma, an immune-mediated respiratory disease which manifests in childhood and results in substantial health burden.

Each of these endpoints demonstrates substantial inter-individual variability, enabling powerful systems biology tools to extract meaningful correlations. We will harmonize and study an IDEAL meta-cohort (IMC) comprised of longitudinal childhood cohorts enrolled in North America, Africa, and Australasia. Our clinical core in Rochester, NY, is nationally prominent in the study of childhood immune ontogeny.

Project (PR) 1 will employ cutting-edge, cross-platform integrative bioinformatics tools to identify endotypes associated with clinical endpoints. PR2 will apply epigenetic analysis tools to the same samples and translate to host immune parameters the in silico-derived signatures. In PR3, key endotype-associated biomarkers and pathways will be dissected in vitro to establish cause and effect and identify agents (e.g., proteins, metabolites, adjuvants, vaccines) that may redirect IDEAL away from unfavorable endotypes and towards favorable ones.

We have optimized sample-sparing assays to enable systems biology in infants, and our published preliminary data demonstrate feasibility, robust IDEAL, and suggest distinct signatures by clinical status. Our cross-platform validation and correlation with endotypes correlating with clinical phenotypes will identify predictive/actionable biomarkers by:
I) Characterizing IDEAL and microbiome in systemic/mucosal compartments (Overall Aim 1),
II) Identifying endotype-specific biomarkers (Overall Aim 2), and
III) Identifying in vitro interventions that re-direct IDEAL endotypes towards health (Overall Aim 3).

Overall, we will enhance and accelerate the discovery of new approaches to predict and prevent childhood disease.

Children's Hospital Corporation

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 021155724 United States

Single Zip Code

Immune Development in Early Life (IDEaL) (U19 Clinical Trial Not Allowed) (RFA-AI-20-078)

Amendment Since initial award the total obligations have increased 278% from $1,665,877 to $6,289,209.