R01AI157807

Defining Adaptive Immune Responses to MTB-Infection and TB Disease Among Young Children with and without HIV-Exposure - Project Summary

Tuberculosis disease (TB), caused by Mycobacterium tuberculosis (MTB), is a leading cause of morbidity and mortality in young children <5 years old. The vulnerability of young children to develop TB following primary infection is not understood; this critical knowledge gap hampers efforts to develop a more effective vaccine and improved diagnostic tests for this high-risk population.

HIV-exposed (HEU) children are the majority of children living in the homes of HIV+ adults, where they are more likely than HIV-unexposed-uninfected (HUU) children to be TB exposed. Clinical, epidemiologic, and immunologic findings support that young, HEU children will exhibit distinctive immune responses following MTB-exposure; however, immune responses to MTB-infection have not been characterized in this high-risk population.

Our proposal will comprehensively define adaptive immune responses to MTB-exposure and TB in children <5 years old using a pediatric TB household contact (HHC) study based in Kampala, Uganda, where up to 20% of children are HEU. Our approach will identify unique immunologic biosignatures driven by where the child sits on the TB disease spectrum, as well as by HIV-exposure status.

We hypothesize that immune biosignatures of MTB-exposed asymptomatic HEU children will more closely resemble those observed among children with TB, as compared to asymptomatic HUU children. If proven, this would suggest that MTB-exposed HEU children are more likely to be experiencing a pre-clinical rather than quiescent or latent MTB-infection. Such findings would have implications for the development of immune-based diagnostics for MTB-infection and TB disease that may perform differently in HIV-exposed and unexposed children, as well as clinical management and monitoring of HEU-children following TB exposure.

Working with a biorepository of samples obtained from Ugandan children <5 years old, and a proposed prospective cohort of Ugandan children <5 years old who are TB HHC, we will address three specific aims that:

1) Define longitudinal, functional and phenotypic MTB-specific adaptive immune responses among young children who developed TB or remained asymptomatic;
2) Develop a pool of novel MTB-epitopes and focused flow cytometry-based assay customized to detect MTB-specific T cell responses in young children; and
3) Establish a unique MTB-specific antibody FC profile that defines children with TB.

Our proposal will advance pediatric global health by:
1) Identification of immunologic signatures reflecting successful containment of primary MTB infection that can serve as correlates of protective immunity for novel vaccine trials;
2) Development of novel blood-based assays that discriminate between young children with TB and those who have been exposed but successfully contained their infection.

Oregon Health & Science University

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]

Portland, Oregon 972393011 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 395% from $713,382 to $3,527,794.