R01AI151173

Targeting TB Transmission Hotspots to Find Undiagnosed TB in South Africa: A Genomic, Geospatial, and Modeling Study (TARGET-TB) - Project Summary

Despite renewed public health efforts, including more effective treatment, tuberculosis (TB) incidence has reduced only incrementally, an effect driven by the inability to contain community TB transmission. Early identification and treatment of infectious individuals is central to breaking the chain of transmission and is limited by the fact that up to 40% of incident TB cases remain undiagnosed. The associated prolonged duration of infectiousness and delays in treatment initiation contribute significantly to ongoing TB transmission.

Undiagnosed cases comprise diseased individuals who have been missed by the healthcare system and those without symptoms (subclinical TB) where the ability to transmit TB is unknown. In our preliminary data, using active case finding and whole blood RNA biomarker, we identified subclinical TB disease at proportions that approach or exceed that of symptomatic active TB. These cases were associated with the presence of viable bacilli in the sputum, pointing to a large potentially infectious pool of individuals.

In high-transmission settings, highly targeted approaches like household contact investigation will capture only a small proportion of TB cases, yet general-population approaches are too inefficient to be practical. New case finding methods are needed that increase diagnostic yield through targeted screening in high-prevalence and high-transmission subpopulations. In low-incidence settings, standard mapping tools have been used to identify target populations for enhanced case-finding. Whether similar methods are sufficient in endemic settings is unknown and critical to advance new case-finding approaches.

To develop appropriate strategies, we must first understand the mechanisms and spatial patterns of community-level TB transmission that include subclinical TB. Advances in spatial and genomic statistical modeling coupled with sensitive diagnostics now enable evaluation of spatially targeted TB screening in high-burden communities. We hypothesize that transmission hotspots harbor a large number of individuals with undiagnosed and subclinical TB that, when targeted, can improve the efficiency of TB case finding.

In Aim 1, we determine the proportion of TB transmission that occurs within spatially organized hotspots. In Aim 2, we test whether spatially targeted case-finding will be more effective and efficient than broader approaches for identifying active and subclinical prevalent TB. To accomplish our aims, we incorporate innovative spatial statistical modeling with Bayesian phylogenetic methods to infer TB transmission using whole genome sequencing data, and use novel RNA biomarkers and Xpert Ultra with chest radiography to detect prevalent TB in the community.

If undetected prevalent TB, including subclinical forms, is, in fact, concentrated in locales of transmission, this would have important and practical implications for targeted community TB screening strategies as a means to identify infectious individuals early and interrupt transmission by early initiation of TB treatment.

The Trustees Of Columbia University In The City Of New York

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]

New York, New York 100323727 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 344% from $773,637 to $3,433,190.