A Narrative Review of the Regional Prospective Observational Research in Tuberculosis International Consortium: Sharing Diverse Data and Specimens in the Fight Against Tuberculosis

Abstract

Background.

Clinical tuberculosis (TB) research has been hampered by a lack of reliable predictors of Mycobacterium tuberculosis infection progression and active TB treatment’s cure, relapse, and failure. Given host and bacterial variability, large sample sizes from harmonized datasets are needed to study infrequent endpoints. Therefore, global observational research consortia, such as Regional Prospective Observational Research in Tuberculosis (RePORT) International (RI), can help make meaningful inroads into successful TB prevention, diagnosis, and treatment.

Methods.

RePORT International was created in 2012 by the US National Institute of Allergy and Infectious Diseases (NIAID) with bilateral country funding. The Consortium’s country networks (Brazil, India, Indonesia, Korea, Philippines, South Africa, and Uganda) use a common protocol to recruit for 2 participant cohorts (active TB and close contacts). A coordinating center, led by a multinational executive committee, provides early-stage investigator research and mentorship opportunities, guidance on quality-assured data and specimen collection, and scientific direction while allowing networks to pursue geographically relevant research and implementation.

Results.

Consortium biorepositories house 632 000+ specimens with associated epidemiological data from ~11 900 participants. There have been 67 country- and consortium-wide projects via multiple funding sources, resulting in about 200 publications covering epidemiology, drug resistance, biomarkers, comorbidities, transcriptomics, diagnostics, and immunology. Capacity building is conducted through research fellowships and collaborations with other consortia including with a public resource database and data/specimen dashboard.

Conclusions.

Public health research has had funding limitations on ideal patient enrollment and follow-up, as well as the maintenance of research infrastructure and personnel. However, RI is well prepared to meet these challenges while supporting better point-of-care diagnostics, screening for asymptomatic TB, post-TB care, and successful treatment outcomes.

BACKGROUND

Tuberculosis (TB) is an ancient disease that affects individuals globally. The World Health Organization indicates that annually, 10 million people become ill with TB. Despite it being a preventable and curable disease, over 1 million people affected by TB die from the disease [1]. Tuberculosis is also the world’s most deadly infectious disease. We know from epidemiological data that host factors, such as immunosuppression (eg, treatment with tumor necrosis factor-alpha (TNF-α) inhibitors) and the presence of comorbidities (eg, human immunodeficiency virus (HIV) infection and diabetes mellitus), affect the progression of infection to TB disease [2]. Given the scope of those affected by TB, it is clear that better and more accessible diagnostics, shorter and less toxic treatment regimens, and a deeper understanding of those at the highest risk of becoming infected with Mycobacterium (M.). tuberculosis and progressing to active TB disease are important. Therefore, studying TB epidemiology, biomarkers, diagnosis, and treatment outcomes is key to TB elimination.

Progress in TB clinical research has been slow due to a lack of reliable biomarkers that predict progression from M. tuberculosis exposure to active disease and subsequent cure, relapse, failure, or death. Local research on TB is hindered by the need for a large sample size to achieve sufficient numbers of infrequent outcomes, as well as the variability from population to population due to bacterial and host genetic factors. In addition, showing consistency of findings across geographic locations suggests invariance and generalizability, which increases their importance and relevance.

The Regional Prospective Observational Research in Tuberculosis (RePORT) International Consortium was established to address the barriers to developing tools and guidelines that would accelerate the elimination of TB. The Consortium’s broad geographic reach has resulted in a rich repository of genetically diverse biological samples with associated epidemiological data—both of which can be used to examine natural and environmental factors in how TB spreads, mutates, and influences short- and long-term treatment outcomes. Each RePORT network is designed to support local, in-country TB-specific data and specimen biorepositories, as well as associated research. It also enables geographically relevant implementation science.

This supplement will provide an overview of RePORT International (RI), highlighting its strengths as a consortium in 3 of its current priority areas of study: asymptomatic TB, post-TB sequelae, and factors related to TB transmission.

HISTORY

RePORT International began in 2012 as a collaborative effort funded partially by the US National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS to address the global epidemic of TB, including in people with HIV, who are at high risk for TB. Selected consortium countries also had to have an additional source of funding from host governments. Additionally, the countries had high rates of TB, including drug resistance, HIV, and comorbidities. Finally, country principal investigators had to commit to being able to recruit 2 specific cohorts of participants and maintain their related data and specimens.

Initially, the RI collaboration included investigators from India under the Indo–US Vaccine Action Program (2013). Additionally, a Brazilian network (2013) also arose, supported by the Brazilian Ministry of Health. Subsequently, the South African Medical Research Council TB research consortium (2016) and an Indonesian–NIAID (2017) initiative began enrolling participants. China and the Philippines signed memoranda of understanding in 2017 to join the Consortium. Enrollment under RePORT Philippines began in December 2018, with funding support from the Philippine Council for Health Research and Development, Department of Science and Technology. There are also nascent research partnerships with the Republic of Korea and Uganda, which are developing collaborative investigations and shared knowledge. Both countries have a productive history of enrollment in TB studies, data management, and important outcome discoveries.

The RePORT International Coordinating Center (RICC) coordinates RI’s multinational research and associated activities. The RICC can be viewed in 3 phases—RICC 1.0 (2015–2019) managed by FHI-360 [3]; RICC 2.0 (2020–2023) by Rutgers University; and RICC 3.0 (2023–present), which is an investigator-led coordinating center managed by Rutgers University, Vanderbilt University Medical Center, Johns Hopkins University, and Fiocruz in Brazil with the addition of a new partner, Frontier Science Foundation, which provides central data management and has worked to make data and resources more transparent and accessible to outside investigators.

REPORT INTERNATIONAL’S SIGNIFICANCE

To contribute to the prevention, care, and elimination of TB, the goals of RI include:

1. Identifying epidemiologic and clinical factors and associated biomarkers that predict TB outcomes

2. Measuring the accuracy of new tools to diagnose TB in multiple populations, including those with asymptomatic TB and atypical presentations of TB

3. Determining the prevalence and incidence of asymptomatic TB in diverse populations and identifying associated biomarkers that may be useful for screening

4. Characterizing post-TB pulmonary, cardiac, and other sequelae

5. Establishing which persons will progress from infection to active TB disease based on M. tuberculosis strain and host, sociodemographic, and environmental factors

6. Building the capacity of early-stage investigators to conduct TB research

The RI Consortium, now comprising 7 countries, conducts research that collectively addresses the goals above. The Consortium has 4 core countries with independently funded networks—Brazil, India, the Philippines, and South Africa—and 3 active associated members: Indonesia, the Republic of Korea, and Uganda. These 7 countries have unique patient populations, and the collective investigators have both distinct and complementary expertise. The scope of the program has allowed for TB research around drug-susceptible and drug-resistant TB, TB and comorbidities such as HIV infection and diabetes mellitus, and the progression of M. tuberculosis infection in contacts. An essential principle of RI is the use of a “common protocol” across sites and networks to facilitate harmonization of data and collection and storage of specimens.

Patients are recruited into 2 groups: Cohort A, which includes individuals with active pulmonary TB, and Cohort B, which includes contacts of individuals with active pulmonary TB. A variety of specimens from each cohort are stored in central biorepositories. Participant demographic and clinical data, measured at specific time points after initial recruitment, are associated with each specimen (Figures 1 and 2). Specimens include sputum, whole blood (paired box (Pax) Gene and deoxyribonucleic acid (DNA)), plasma, urine, peripheral blood mononuclear cells (PBMC), and M. tuberculosis isolates, which are collected at different time points. Sites may choose to collect additional specimens and data, maintaining their own datasets, which enrich the field of TB research. Considerations may include varying treatment regimens based on local guidelines, social determinants of health, and other comorbidities prevalent in the country. Examples of additional variables include pharmacokinetics (PK) and spirometry data, anthropometric measurements, income, dietary specifications and use of validated questionnaires, housing characteristics including crowding, fuel use, and occupation-related exposures. Finally, some consideration must be given for diagnostic variances in each setting, hence the need for expanded responses to account for these variables. Most sites use interferon gamma release assays (IGRA) to detect TB infection, but there is consideration for the tuberculin skin test (TST) on reporting forms. Another diagnostic difference between sites may be the bacterial confirmation of TB, which can be done using GeneXpert and/or culture with different types of media.

Figure 1.

Cohort A specimen type with count and participant count. Abbreviations: DNA, deoxyribonucleic acid; PBMC, peripheral blood mononuclear cells; TB, tuberculosis.

Figure 2.

Cohort B specimen type with count and participant count. Abbreviations: DNA, deoxyribonucleic acid; PBMC, peripheral blood mononuclear cells; TB, tuberculosis.

ACCOMPLISHMENTS AND ALLIANCES

The contributions of the RI Consortium have provided important insights into TB treatment and transmission dynamics and have also been disseminated in guidelines and the peer-reviewed literature. A recent example can be found in the 2025 World Health Organization Consolidated Guidelines on TB, where, in the module on comorbidities, evidence from RePORT India demonstrated the critical role of undernutrition in TB progression and treatment failure [4, 5]. Since inception, there have been close to 200 publications resulting from about 70 funded projects, many spanning multiple collaborative sites and with varied funding sources, in the fields of pediatrics, biomarker discovery, local capacity building, enhanced diagnostics, TB outcomes with comorbidities, predictors of drug-resistant TB, federated data analysis, predictors of progression to TB, and data modeling (Figure 3). These projects have also given way for existing and future substudies to answer specific questions.

Figure 3.

RePORT International studies by focus areas (2013–present). Abbreviation: TB, tuberculosis.

Capacity Building

A formative role for RICC has been mentoring early- and midstage investigators to take on leadership roles in TB research. The RICC’s Post-Doctoral Fellowship, through a selective application process, is training 7 early-stage investigators to pursue independent research as well as professional development in research careers, immunology, data visualization, and global TB epidemiology. A second initiative, the Future Leaders Program, promotes and facilitates midstage investigators in conducting high-level, independent research using consortium samples and data, as well as in developing leadership and grant-writing skills. This program has 4 promising candidates, 1 from each of the 4 core countries. In addition, in late 2024, RICC addressed the issue of having a “1-stop shop” for global TB research education resources as well as current funding opportunities. Frontier Science and Johns Hopkins University have collaborated to create the Virtual Learning Room (VLR), a platform that collates and shares resources. The VLR currently contains 337 research tools, fellowship/grant opportunities, and training resources. The VLR continues to grow and evolve, with content updated regularly. Committed to transparency and broad public access, it remains freely available.

An area that warrants expansion within the Consortium is human resource development in the field of research capacity. Early-stage investigators, clinicians, laboratory scientists, and epidemiologists alike need mentoring, research opportunities, and funding. There is still much work to be done to eradicate TB, and the consortium continues to build capacity in independent research and explore opportunities to secure funding to support it. Partnerships with groups, such as the NIAID Tuberculosis Research Advancement Centers (TRACs), have been initiated to provide mentors to early-stage scientists.

Collaborations

Under RICC 3.0, the consortium has expanded, developing standards of practice for laboratories and biorepositories, as well as publicly available template documents, including data collection forms. Most importantly, the consortium has amassed over 632 000 specimens from approximately 6300 participants in Cohort A (active TB) and about 5600 participants in Cohort B (close contacts). Contacts are generally household contacts, identified by people with active TB, and thus, in most cases linked to a person in cohort A. These numbers are based on the RePORT International Data and Specimen Availability Dashboard (RADAR), which provides a quarterly update on the specimen availability of most sites by country, along with related participant characteristics. In Cohort A, retention has been about 65% (35% did not have TB, were lost to follow up, or died). For Cohort B, retention has been 73% (27% were lost to follow-up or died).

THE FUTURE OF REPORT INTERNATIONAL: CHALLENGES AND OPPORTUNITIES

Observational cohorts, such as those within the RI Consortium, provide ready access to populations with diverse characteristics and environmental contexts with some constraints. Funding restricts follow-up beyond 12 months. This limits the ability to study post-TB relapse or sequelae and progression to active TB in contacts. However, RI is engaged in a specific protocol on post-TB sequelae with a subset of persons with HIV and without HIV, which is described in another paper. Additionally, host and bacteria-related factors, leading to progression to active disease in the 4% contacts in Cohort B, are also being studied throughout the consortium. In 2026, all of the Cohort B data will be harmonized into 1 unified dataset, which will lend itself to greater study of TB contacts. Lastly, much of what will also help strengthen RePORT’s research will be the ability to do whole-genome sequencing of specimens. This capability is not yet available at all sites but can be used for prediction of drug resistance, monitoring of transmission, and, of value in a geographically diverse participant pool, identification of M. tuberculosis lineage.

While TB remains prevalent at high levels globally, there will be an ongoing need to develop new drugs, more sensitive and specific diagnostic tests, and better vaccine candidates. Emerging pathogens, such as 2016 novel corona virus disease (COVID-19), provide new concerns that complicate the prognosis of a person with TB [6]. New pathogens, re-emerging health issues, and changing social and environmental factors will continue to present challenges that should be studied in relation to TB transmission, manifestation, and outcomes.

A vast amount of rich data and specimens should be accessed by scientists globally. Unfortunately, several countries have strict regulations governing the export of both data and specimens, and innovative approaches are needed for researchers to partner both onsite and through the use of technology to gather and share data. Commercial diagnostic and pharmaceutical companies should also utilize the Consortium’s biorepositories. Fostering mutually beneficial external partnerships is an area in which RI needs to focus more, especially with companies that already have existing international presence or the ability to build a presence.

Finally, while clinical trials and other types of interventional research are costly, observational research has its own financial constraints. Biorepositories require a substantial amount of infrastructure, including storage space, a reliable electrical supply, reliable quality control, and licenses for tracking specimen inventory [7–9]. Recruiting and retaining both new and experienced, talented research personnel is also challenging with fluctuations in the interest in science and public health and work in academic settings [10–12].

Finally, the application of research findings is key to sustaining funding and interest from governments together with donors in supporting science [13–15]. This includes continued support for ongoing cohort studies and data/specimen collection, maintaining valuable biorepositories and databases, and providing training fellowships and grants.

BROADENING RESEARCH IMPACT

RePORT International has been funded primarily to create the basis for new tools. However, to achieve an even greater impact, RI will be ramping up its undertaking of implementation science studies to ensure that research findings are effectively translated into real-world policy and guidelines. This includes compatibility in the field of point-of-service tests, screening algorithms for assessing transmission, use of modeling to make clinical decisions, barriers to uptake of tuberculosis preventive therapy, and a quality-of-life measure for persons post-TB treatment. This work will also promote future research relevant to challenges faced by affected countries, communities, and people [16].

Furthermore, many research groups have come to recognize the value of community advisory boards. Engaging stakeholders in research enhances the relevance of investigative questions, increases the transparency of the research process, and fosters buy-in from communities, creating a supportive environment for accelerating the implementation of findings. With the combination of implementation science and the creation of a community advisory board, RI can:

1. Increase research participation by providing practical feedback on procedures, recruitment materials, and incentives [17–19]

2. Assist with strategies for the dissemination of research findings

3. Build trust between academia, TB programs, and communities [20]

At the country level, community advisement is active from the creation of protocols to the dissemination of findings. The RICC is preparing to survey all levels of RI personnel to assess the level of patient-centered and community-centered interventions currently in place. The results will inform the development of more patient- and community-centric research designs and interventions that can be shared across the Consortium.

CONCLUSION

Building on current initiatives, RI will enhance global clinical research capacity in high-burden settings and increase local access to high-quality data and specimens for members of each network, as well as their domestic and international collaborators. As RI grows and evolves to meet new challenges, it will continue to be an important contributor in the fight against TB.

COLLABORATION WITH REPORT INTERNATIONAL

To explore research collaboration, capacity building, or other related opportunities, contact the RePORT International Coordinating Center at tbricc@njms.rutgers.edu and visit the webpage, https://reportinternational.org/collaborate-with-us.