R01AI175315

Biomarker Signatures of TB Infection in Young Children with and without HIV

Per year, globally an estimated one million children develop tuberculosis (TB) and more than 15 million children are estimated to be exposed to Mycobacterium tuberculosis (MTB). The case fatality rate is high in children under 5 years of age. Current approaches to diagnosis and management of young children that are close contacts to a TB case are inadequate.

Those that are symptomatic may undergo sputum-based diagnostics that are not well tolerated (e.g., gastric aspirates), require access to a reference laboratory, and are not sensitive because TB may be paucibacillary or extrapulmonary. For that reason, empirical multidrug anti-TB treatment predominates in many locales. Management of the asymptomatics is sub-optimal as well.

Given the poor performance of interferon-gamma release assays (IGRAs) and tuberculin skin tests (TST) in this age group, most are treated with isoniazid preventive therapy (IPT). In adults, asymptomatic (subclinical TB) is at least as common as active TB and will not be detected by current symptom-based screening. We do not know how often this is the case in exposed children; however, IPT would be inadequate in them.

Furthermore, about 19% of children in this age group with latent TB infection (LTBI) will progress to active TB, usually within the next 3-6 years in the absence of IPT (and IPT is only 63% effective). The need, therefore, is to discover a biomarker or biomarkers that identify those children under 5 years of age with subclinical TB (likely to progress despite IPT) and those without subclinical TB that are likely to progress. These biomarkers would allow appropriate targeting of IPT and anti-TB treatment to those likely to benefit.

This consortium of investigators has ongoing diagnostic and cohort studies of child (< 5 years of age) close contacts of TB cases in Uganda that include a rigorous bacteriologic reference standard applied to asymptomatic as well as symptomatics and evaluation of novel diagnostics and discovery of non-sputum-based approaches. We propose now to evaluate in children under 5 years old that are close contacts of a TB case a diverse and complementary panel of bacterial, host-based, and imaging non-sputum biomarkers that have shown promise as predictors of progression in adults.

Furthermore, we will discover relevant biomarkers in this population through an unbiased multi-omics approach using proteomics, single-cell omics, T-cell activation markers, antigen-specific antibody profiling, MTB exosomal assays, computer-aided detection (CAD) for chest X-ray interpretation, and point-of-care ultrasound (POCUS). Our goal is to characterize a biomarker or group of biomarkers that meet a minimal target performance profile to identify children with subclinical TB and/or at high risk of progression.

We will apply advanced machine learning and integrative multiomics to identify combinations of these biomarker signatures alongside TB risk variables to improve the precision of predicting progression. These results will provide novel approaches to risk-stratify children under 5 years of age for targeting the administration of preventive therapy and anti-TB treatment.

Rutgers The State University Of New Jersey

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]

Newark, New Jersey 071032757 United States

Single Zip Code

Biomarker Signatures of TB Infection in Young Children With and Without HIV (R01 Clinical Trial Not Allowed) (RFA-AI-22-015)

Amendment Since initial award the total obligations have increased 1169% from $250,000 to $3,173,148.