March 2024

NIAID Strategic Plan for

Tuberculosis Research 

2024 Update
TB Research Strategic Plan Update

TABLE OF CONTENTS

EXECUTIVE SUMMARY ......................................................................................................................... 1

INTRODUCTION ................................................................................................................................... 3

Disease Manifestations.................................................................................................................... 3

Challenges with TB Infection ............................................................................................................ 4

Need for Improved Vaccines and Therapies...................................................................................... 4

Updated Research Priorities for TB................................................................................................... 5

STRATEGIC PRIORITY 1: Improve Fundamental Knowledge of TB.......................................................... 6

Objective 1.1 Enhance Understanding of Mycobacterium tuberculosis (Mtb) to Improve Options for 

Intervention..................................................................................................................................... 6

Objective 1.2 Characterize Immune Responses and Host Factors that Contribute to TB Progression 

and Pathology.................................................................................................................................. 7

Objective 1.3 Understand the Critical Drivers of TB Transmission..................................................... 8

Objective 1.4 Improve and Develop Animal and non-Animal Models of TB Disease .......................... 9

STRATEGIC PRIORITY 2: Advance Research to Improve Diagnosis of TB .............................................. 10

Objective 2.1 Develop and Improve Accurate and Rapid Diagnostics, Including Point of Care (POC) 

Diagnostics..................................................................................................................................... 10

Objective 2.2 Discover and Validate Novel TB Biomarkers and Biosignatures ................................. 12

STRATEGIC PRIORITY 3: Advance Research to Support TB Vaccine Development................................ 13

Objective 3.1 Identify Immune Correlates of Protection (COP) ....................................................... 13

Objective 3.2 Support Design and Development of Vaccine Candidates for Prevention of Infection 

and Prevention of Disease.............................................................................................................. 14

STRATEGIC PRIORITY 4: Support Research to Advance Strategies to Treat and Prevent TB ................. 15

Objective 4.1 Discover and Develop New TB Drug Targets and Interventions ................................. 15

Objective 4.2 Develop and Improve TB Preventative Treatment (TPT) Interventions...................... 16

Objective 4.3 Develop and Evaluate Shorter and/or Safer TB Treatment Regimens for All Patient

Populations and Forms of TB.......................................................................................................... 16

CONCLUSION ..................................................................................................................................... 18

APPENDICES....................................................................................................................................... 19

Appendix 1: NIAID TB Working Group Members............................................................................. 19

Appendix 2: NIH-Supported TB Research Resources....................................................................... 20

Appendix 3: Analysis of Public Comments to Request for Information (RFI) .................................... 23
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TB Research Strategic Plan Update

EXECUTIVE SUMMARY

Tuberculosis (TB) is the second leading cause of death from infectious disease in the world after COVID19. In 2022, TB caused nearly twice as many deaths as HIV. In the United States (U.S.), up to 13 million 

people are living with latent TB infection and have a 5-10% chance throughout their lives of developing 

active TB. 

Over the past decade, multiple global and domestic efforts have been established to accelerate the 

development of prevention strategies and treatments for TB. In 2015, the World Health Organization 

(WHO) established an End TB Strategy with a goal of a 90% reduction in TB incidence by 2035.

Domestically, the U.S. government’s Global TB Strategy and the National Action Plan for Combating 

Multidrug-resistant TB have outlined respective paths to end the TB pandemic. 

The COVID-19 pandemic impacted all facets of 

biomedical research and healthcare activities, 

including TB research and control programs. The 

resulting interruptions in TB diagnosis and treatment

lead to abrupt global reversals in what had been a 

trend of decreasing TB cases and deaths before 2020. 

As the world continues to emerge from the COVID-19 

pandemic, efforts to combat the longstanding TB 

pandemic need to be revisited and enhanced to end 

the global impact of this deadly disease. 

The National Institute of Allergy and Infectious 

Diseases (NIAID) released its first Strategic Plan for 

Tuberculosis Research in 2018, which was highlighted 

at the United Nations General Assembly High-level 

Meeting on TB in September 2018. This 2024 NIAID Strategic Plan for Tuberculosis Research Update

reaffirms the commitment of NIAID to accelerate basic and preclinical, translational, and clinical 

research and expedite the development of innovative tools and strategies to improve diagnosis, 

prevention, and treatment of TB. The updated plan is structured around four strategic priorities that are 

critical to the development and evaluation of the knowledge and tools needed to end TB globally (Figure 

1): 

1. IMPROVE FUNDAMENTAL KNOWLEDGE OF TB

2. ADVANCE RESEARCH TO IMPROVE THE DIAGNOSIS OF TB

3. ACCELERATE RESEARCH TO IMPROVE TB VACCINE DEVELOPMENT

4. SUPPORT RESEARCH TO ADVANCE THERAPEUTIC STRATEGIES TO TREAT AND PREVENT TB 

To accelerate research relevant to these four strategic priorities, NIAID will continue to leverage current 

resources and global collaborations, including existing NIAID-supported clinical trials networks 

(Appendix 2). NIAID continues to promote a multidisciplinary approach to TB research, drawing on 

expertise from fields within and outside of TB research to facilitate studies of complex biological

questions and encourage the application of state-of-the-art technologies. Efforts that connect the U.S. 

government to global health researchers and stakeholders have the potential to result in new and

improved global TB prevention and control strategies that advance efforts to end the TB pandemic. 

Strategic Plan Mission

To accelerate the end of the TB 

pandemic through:

Research Acceleration: Basic, 

translational, and clinical research and 

collaboration to better understand TB.

Innovation: Development of new tools 

and strategies to enhance diagnosis, 

prevention, and treatment.
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TB Research Strategic Plan Update

Figure 1: The NIAID Strategic Plan for TB Research Update proposes to advance four TB research priorities: 1) improving 

fundamental knowledge, 2) advancing research to improve diagnostics, 3) advancing research to improve vaccine development, 

and 4) supporting research to advance therapeutic strategies. Collectively, these priorities serve as primary approaches to 

achieve the overall mission of this plan.
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TB Research Strategic Plan Update

INTRODUCTION

Despite ongoing efforts to develop safe and effective countermeasures, tuberculosis (TB) remains the

second deadliest infectious disease in the world after COVID-19. In 2023, the World Health Organization 

(WHO) estimated that TB claimed the lives of 1.3 million people in the previous year, including 167,000 

people co-infected with HIV. The causative agent of TB, Mycobacterium tuberculosis (Mtb), is 

transmitted through the air and primarily infects the lungs (Figure 2). Mtb infection can result in a 

spectrum of outcomes: elimination or clearance of infection, latent TB infection, subclinical or 

asymptomatic TB disease, or active disease. 

Disease Manifestations

The most common outcome of infection is latency, which results 

from a balance between immunological control and bacterial 

persistence. Historically, the Mtb infection paradigm has been a 

binary one: individuals are either infected with Mtb but have a 

latent infection or individuals are actively sick from infection and 

are transmitting Mtb. The reality is a more nuanced spectrum of 

disease pathology that encompasses previously unrecognized 

disease states that were likely lumped into the ‘latent’ 

categorization. 

Asymptomatic or subclinical TB disease refers to active infection 

with Mtb but with no or minimal clinical symptoms. These 

categorizations present with abnormalities that can be detected 

using existing radiologic or microbiologic assays. Incipient TB is 

used to define cases of infection with Mtb that is likely to 

progress to active disease without treatment and may also be 

associated with no or few clinical symptoms. Latent TB refers to 

cases with immunological evidence of exposure to TB, for example, by a positive interferon-gamma 

release assay (IGRA) or Tuberculin Skin Test (TST), but without symptoms and without detection of the 

organism using radiologic or microbiologic assays. Individuals who are latently infected with Mtb have a 

5 - 10% risk of developing active TB at some point in their lives.

Pulmonary TB is the most contagious active form of the disease and is characterized by an array of 

symptoms including cough, fever, weight loss, and night sweats. Left untreated, severe complications 

can develop that lead to death in about half of patients. Mtb can also cause extrapulmonary TB wherein 

disease affects organs outside of the lungs (e.g., heart, abdomen, skeletal, genito-urinary, and central 

nervous systems). Roughly 15 - 25% of overall cases are classified as extrapulmonary TB, and many of 

these Mtb infections cause high mortality. It is unclear why Mtb infection leads to such varying

outcomes in individuals. To reach the WHO End TB goal of reducing TB incidence by 90% and TB deaths

by 95% by 2035, a better understanding of the spectrum of pathology from Mtb infection must be 

achieved. 

Figure 2: Scanning electron micrograph of 

Mycobacterium tuberculosis, the bacterium 

that causes TB. Image credit: NIAID.
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TB Research Strategic Plan Update

Challenges with TB Infection

One of the challenges in addressing the TB pandemic is that an estimated 30% of individuals with active 

TB disease (approximately 3 million people) are not diagnosed, and thus are neither reported to public 

health authorities nor receiving treatment. Undiagnosed and untreated individuals account for a 

significant portion of TB deaths and continue to fuel the TB pandemic by acting as a reservoir for the 

pathogen. The development of rapid, accurate, cost-effective, and easy-to-use diagnostics for TB and 

drug resistant TB (DR-TB) remains a research priority and will help identify and facilitate prompt, 

effective treatment of TB patients. 

People living with HIV (PLWH) and Mtb experience additional challenges because they are 16 – 18 times

more likely to develop TB disease than people without HIV. While HIV positive individuals with low CD4 

T cell counts have the highest risk and higher rates of extrapulmonary TB, those with viral suppression 

and high CD4 T cell counts maintain TB risk that is higher than the general population. Additionally, TB 

drug regimens need to be compatible with HIV antiretroviral therapy (ART) and vice versa, which further 

complicates treatment. Despite significant efforts to improve the care of patients, TB continues to be

the leading cause of death in PLWH worldwide. 

Need for Improved Vaccines and Therapies

To change the trajectory of the TB pandemic, the development of a safe and effective preventive 

vaccine remains the most pivotal milestone. Although not employed for TB prevention in the U.S., the 

Bacillus Calmette–Guérin (BCG) vaccine is used in many countries with a high prevalence of TB to help 

prevent childhood TB, including TB meningitis (inflammation of the brain and spinal cord) and miliary TB

(disseminated disease through the circulatory system). The BCG vaccine does not sufficiently protect

adults and adolescents from disease, however. Therefore, ongoing research is needed to accelerate the 

development of additional safe and effective TB vaccines. 

While significant strides have been made towards improved, shorter course regimens to treat TB 

disease, availability of these new regimens remains limited. Currently, curative therapy for drugsensitive TB (DS-TB) typically requires a challenging six-month, four-drug regimen in most settings. In 

addition, large, dedicated public health programs are required to assure drug access and daily 

adherence to treatment to avoid recurrence or the development of drug resistance. In 2021, a 

collaboration supported by NIAID and the Centers for Disease Control and Prevention (CDC) reported 

that a new regimen of rifapentine (RPT), isoniazid (INH), pyrazinamide (PZA), and moxifloxacin (Mfx)

cured patients with DS-TB within four months of treatment. This accomplishment has demonstrated 

that shorter therapy for TB is possible and resulted in endorsement of the regimen by the WHO. 

CDC has provided guidance for the use of bedaquiline, pretomanid, and linezolid (BPaL) to treat DR-TB.

Multidrug-resistant TB (MDR-TB) occurs when Mtb becomes resistant to the two most effective anti-TB 

drugs, rifampin (RIF) and INH, and is much more difficult to treat than DS-TB. Traditional treatment of 

MDR-TB can take more than 2 years, sometimes including daily injections for 6 months, and is 

prohibitively expensive. Extensively drug-resistant TB (XDR-TB) is resistant to at least four of the core TB 

drugs. XDR-TB therapy is even more complex than MDR-TB therapy and often fails. Some of these 

treatments may also result in long-lasting or permanent side effects (e.g., deafness). The continued 

challenge of effectively and affordably treating DS-, MDR- and XDR-TB underpins the critical need for 
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TB Research Strategic Plan Update

shorter, safer, and more effective drug regimens that are well tolerated and can be delivered to patients 

in all care settings. 

Updated Research Priorities for TB

In 2020 and 2021, the COVID-19 pandemic impacted all aspects of global biomedical research and 

patient care. Shutdowns, quarantines, and the global effort to contain the pandemic resulted in limited 

access to medical providers, interruptions in the supply chain, and temporary refocus of resources and 

research from other infectious agents of concern to SARS-CoV-2. Due to the effects of the COVID-19

pandemic across the world, there was an 18% drop in the number of people newly diagnosed with TB 

and reported in 2020. Simultaneously, there was an increase in reported deaths from TB in 2021. 

Despite the global impact on biomedical research, the lessons learned and technological advances from 

the COVID-19 response, including the importance of understanding and addressing health disparities 

and social determinants, can be leveraged to bolster and enhance efforts to combat TB. 

In 2018, the NIAID TB Working Group developed a series of strategic priorities to advance research on 

TB and address the ongoing challenges of developing safe and effective countermeasures to TB. These 

priorities were described in the NIAID Strategic Plan for TB research. In 2023, the working group 

reconvened to update the plan. This effort included outlining critical research areas of focus and the 

solicitation of public input through a Request for Information (RFI). The updated plan emphasizes four 

strategic priorities that support basic and preclinical, translational, and clinical research focused on 

enhancing the fundamental knowledge, diagnosis, prevention, and treatment of TB. Advances guided by 

the four strategic priorities are expected to be interdependent and complementary. NIAID anticipates 

that this updated plan will serve as a foundation for its future research investments and guide 

comprehensive efforts toward the successful development of diagnostic, prevention, and treatment 

tools necessary to end the TB pandemic.
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TB Research Strategic Plan Update

STRATEGIC PRIORITY 1: Improve Fundamental Knowledge of TB

Mtb has evolved in parallel with the human immune system for millennia. Thus, Mtb is extraordinarily 

well-adapted to evade and exploit host immune responses to complete the cycle of infection 

establishment, replication, persistence, and, ultimately, transmission to uninfected individuals. 

Advancing efforts in basic TB bacteriology and immunology are central to our understanding of the Mtb

infection cycle and possible disease progression and outcomes. Identification of basic elements of Mtb

biology are interwoven into efforts to identify intervention strategies. Areas where continued research 

is needed to advance our fundamental knowledge of TB include Mtb virulence mechanisms; induction 

and maintenance of latency; and immune mechanisms associated with Mtb clearance, containment, and

disease pathogenesis. 

Objective 1.1 Enhance Understanding of Mycobacterium tuberculosis (Mtb) to 

Improve Options for Intervention

One of the major features of Mtb physiology is the presence of a unique lipid-dense cell envelope. The 

lipids organized between the inner and outer components of the Mtb cell envelope present a barrier to 

drugs and serve as a fundamental constituent of virulence. The bacterium also secretes virulence factors 

that can manipulate host cell proteins to make the environment more hospitable to Mtb by improving 

nutrient availability and modulating the immune response. Further characterization of such virulence 

mechanisms is critical to understanding how Mtb survives and evades the immune system. In addition, 

these secreted factors are potential targets for both anti-bacterial treatments and host directed 

therapies (HDTs) and may be utilized as diagnostic markers. 

Mtb may also respond to stressful environments and activate dormancy survival factors with important 

implications for immune evasion and persistence during treatment. A better understanding of this initial 

host-pathogen interaction may provide new insights into Mtb pathogenesis. Fundamental knowledge of 

Mtb metabolic systems is required to identify potential new drug targets. Thus, more research is needed 

on Mtb pathways for metabolism, catabolism, sequestration, and energy production and how these 

pathways change in response to host environments. 

As basic elements of Mtb biology continue to be elucidated, further characterization and understanding

of the impact of genetic variation within the different lineages of the organism may inform strategies to 

diagnose, prevent, and treat TB. For example, genetic variation, which depends on numerous factors, 

such as the ancestral lineage, fitness, and numerous host and environmental factors, can impact

virulence of DR strains. In the last several years, studies have shed light on bacterial molecular 

STRATEGIC PRIORITY 1: IMPROVE FUNDAMENTAL KNOWLEDGE OF TB

Objective 1.1: Enhance Understanding of Mycobacterium tuberculosis (Mtb) to Improve Options for 

Intervention 

Objective 1.2: Characterize Immune Responses and Host Factors that Contribute to TB Progression and 

Pathology

Objective 1.3: Understand the Critical Drivers of TB Transmission

Objective 1.4: Improve and Develop Animal and non-Animal Models of TB Disease
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

TB Research Strategic Plan Update 

mechanisms, host genetic predispositions underlying treatment failures, and emergence of drug 

resistance and tolerance. 

Another challenge to effectively control or eliminate TB disease is a subpopulation of Mtb organisms, 

referred to as bacterial persisters, that exhibit tolerance during exposure to therapeutic doses of 

antibiotics. Persisters are thought to contribute to the long treatment duration required for TB, but 

precisely how these persisters evolve is not clearly understood. 

NIAID will continue to leverage research activities and resources to expand the fundamental knowledge 

of circulating strains of Mtb and disease characteristics. Technological and methodological advances, 

such as CRISPR-based genetics and single cell RNA sequencing (scRNAseq), will facilitate interrogating 

the Mtb genome for relevant targets for therapeutic intervention. NIAID will continue to promote the 

development and use of state-of-the-art tools, including imaging technologies, multidisciplinary systems 

biology, computational modeling, and -omics approaches, to evaluate the dynamics of Mtb evolution, TB 

pathology, and the complicated interplay of pathogen with host factors that contribute to disease. 

Objective 1.2 Characterize Immune Responses and Host Factors that Contribute to TB 

Progression and Pathology 

Upon infection with Mtb, the human host mounts a series of innate and adaptive immune responses. 

However, the specific nature and interplay of the immune mechanisms required to limit disease 

progression remain unclear. There is evidence that immune mediators can contribute to pathology and, 

subsequently, to disease progression and post TB sequelae. In determining the underlying mechanisms 

of infection and immune responses, researchers may identify differences in those who become infected 

with Mtb but clear the infection, those who become 

latently infected, and those who develop active TB. It is 

also important to understand how co-morbidities in 

the host may impact these immune mechanisms. 

Following inhalation, Mtb infects innate immune cells, 

which subsequently stimulate the adaptive immune 

response by priming antigen-specific T cells. These T 

cells then migrate to the site of infection to control 

Mtb and prevent dissemination. The adaptive immune 

response takes some time to ramp up and is 

instrumental in the formation of granulomas (Figure 3). 

A granuloma is a structure consisting of an 

aggregation of immune cells that both limit growth of 

Mtb, but also provide a cache of sequestered, live Mtb 

that can perpetuate the infection cycle. Imaging 

technologies, such as positron emission tomography/computed tomography (PET/CT) are providing 

insights into the diversity of granuloma and disease dynamics (Figure 4). 

Each immune cell type involved in infection provides an opportunity for potential intervention—either 

to enhance protective mechanisms or prevent inflammation-induced pathology. However, mechanisms 

that prevent Mtb infection or lead to active disease are not fully understood. Efforts are underway using 

animal model systems to assess host factors that play a role in prevention of infection or disease 

Figure 3: Innate lymphoid cells (green) near and within a 

small area of inflammation, or granuloma, in a nonhuman primate infected with Mtb. Image credit: NIAID 

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TB Research Strategic Plan Update

progression. Major strides in analytical approaches offer new platforms to dissect such mechanisms on a 

cellular level in an experimental environment. This allows for the assessment of tissue and single cell 

transcriptional changes in specific cell types resulting from changes in host, environment, or microbial 

variables.

NIAID will continue to support research aimed at 

understanding host immune responses to Mtb

infection and identifying immune pathways that may 

be dysregulated and/or contribute to immune evasion

and pathogenesis. The identification of pathways that 

can be targeted by HDTs may augment antibiotic 

interventions, contribute to further efficiencies in 

therapy and vaccine development, and reduce lung 

inflammation and fibrosis that impairs lung function 

following treatment. To accomplish this task, NIAID 

will continue to prioritize research to further define 

the contribution of innate and adaptive immune cells 

in regulating host responses to Mtb. This effort will 

include more comprehensive evaluations of immune 

responses from individuals with active disease

including extrapulmonary disease, subclinical disease, 

or latent infection. Additionally, NIAID supports 

fundamental research grants and specialized programs such as the Tuberculosis Research Units Network 

(TBRU-N) , a multidisciplinary, collaborative effort focusing on understanding Mtb-host interactions.

Objective 1.3 Understand the Critical Drivers of TB Transmission

Mtb is highly contagious, and the TB transmission cycle is extremely complex with multiple contributing 

biological factors including host, pathogen, and micro-environments, as well as a broad array of 

socioeconomic and demographic factors. For example, TB incidence among historically marginalized 

communities is high, and these communities often have higher levels of risk factors for progression to TB 

disease. Recent evidence suggests that community spread may be as important as spread through 

household contacts. To better characterize factors that drive TB transmission, NIAID will support the 

development of tools for predictive modelling and advanced real-time mapping of infection clusters that 

can be used to identify key sites of transmission. These tools can be used to identify variables 

contributing to transmission and to improve community- and population-based strategies for prevention 

and active case finding. NAID also will continue to support research to characterize TB transmission, 

particularly within high-burden settings and high-risk populations. This may identify underlying 

pathogen and host factors that affect transmission and progression to disease. 

The previously understood model was that Mtb transmitted primarily by coughing. However, recent 

evidence suggests that Mtb may be transmitted through regular breath exhalations (tidal breathing) 

wherein Mtb is aerosolized and can be inhaled by nearby individuals. This model is particularly 

problematic given that prevalence studies demonstrate that many people with microbiologically 

confirmed TB have asymptomatic or subclinical TB infections. With that awareness, there is a need to 

understand what role people with asymptomatic or subclinical disease may have in TB transmission and 

Figure 4: Scanning electron micrograph of Mtb bacteria

(circular foreground image; bacteria are colorized gold) 

and a PET/CT scan showing TB infection (gold and 

yellow) in a patient’s lungs (background image). Image 

credit: NIAID.
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TB Research Strategic Plan Update

how to clinically manage these people most effectively. NIAID will support research to understand the 

dynamics of all TB disease manifestations and how they impact Mtb transmission. Other areas of 

research that are of high priority to NIAID are the impact of the immune response on TB transmission 

and how HIV infection (including viral suppression with ART) may affect intra-host Mtb burden, the 

likelihood of transmission, and the resulting population dynamics of TB among PLWH. 

There may be genetic factors present in the pathogen that promote transmission, including genes that 

induce host responses to Mtb infection with characteristics that increase transmissibility. Some 

responses that may be stimulated by Mtb include development of granulomas, production of higher 

bacterial burden in sputum, or increased coughing. Understanding the genetic, epigenetic, and microbial 

characteristics that help Mtb survive stressful conditions during transmission may also provide unique 

targets for interventions that can prevent TB transmission. 

Objective 1.4 Improve and Develop Animal and non-Animal Models of TB Disease

Currently, no models of TB disease exist that completely recapitulate all aspects of human Mtb infection 

and disease. Animal models, however, offer the most predictive information. The most common animal 

models used in TB research continue to be mice, guinea pigs, and non-human primates (NHPs), with 

rabbits and zebrafish being used less often. Mouse models are useful for the analysis of fundamental 

immunological studies and are valuable to examine basic mechanistic studies. Other small mammals, 

such as the guinea pig and the rabbit, adequately model some disease features, but their use is 

constrained by the limited availability of immunological tools and reagents. NHPs may offer additional 

insights into complex biological questions that are not accessible in small animals. It is still unknown how 

well any animal model mimics the dynamics of human host-pathogen interactions, pathology, and 

responses to vaccines and therapeutics. As a result, small and large animal models need further 

refinement and must be analyzed in parallel and iteratively with human clinical studies to validate 

hypotheses and endpoints and for testing new drug and vaccine candidates and regimen combinations. 

NIAID continues efforts to develop models that can replicate and/or predict findings in specific human 

target populations. In silico models, or computational models, and ex vivo models, including 3D lung 

models and organ-on-a-chip technologies, may serve as tools to bridge the results obtained in different 

animal models and humans. As part of this effort, NIAID will prioritize the harmonization of these 

models and standardization of approaches, including the establishment of benchmarks to allow for 

comparisons between these models and to determine their ability to predict outcomes in human clinical 

trials. 
TB Research Strategic Plan Update 

STRATEGIC PRIORITY 2: Advance Research to Improve Diagnosis of TB 

The development and optimization of sensitive, specific, and rapid diagnostics for Mtb infection is 

critical to ensure that individuals with TB receive proper and timely treatment. Currently, acid fast smear 

– microscopic analysis of sputum – is still used in many low resource settings, but it has poor sensitivity

and may miss cases, especially paucibacillary TB (TB disease with low levels of detectable Mtb bacteria).

Culture, where Mtb is grown in a laboratory, is the gold-standard; however, because Mtb is slow

growing, results from culture can take weeks to months. Ideally, newly developed or improved nucleic

acid amplification-based technologies (NAAT) and other molecular based technologies, including NextGeneration Sequencing (NGS), culture-based platforms, and other new diagnostic technologies would

allow testing directly on patient samples with minimal or no sample processing. These assays should be

low complexity to allow minimal operator expertise, yield results in a short time frame, and

accommodate easy to obtain samples. A diagnostic with these characteristics may even allow for

strategies to be developed for an at home or self-administered test to be integrated into TB control

programs. Although ideal TB diagnostics with the highest sensitivity and specificity should be made

available for all settings and for all people, a less sensitive test with greater accessibility could have a

significant impact on the overall TB pandemic and would allow more people to be diagnosed and

referred for treatment. Bringing TB diagnosis closer to the point of care (POC) and the patient may allow

more populations to be reached and increase the overall yield of cases identified and treated.

STRATEGIC PRIORITY 2: ADVANCE RESEARCH TO IMPROVE DIAGNOSIS OF TB 

 

 

 

 

 

 

Objective 2.1: Develop and Improve Accurate and Rapid Diagnostics, Including Point of Care (POC)

Diagnostics 

Objective 2.2: Discover and Validate Novel TB Biomarkers or Biosignatures 

Objective 2.1 Develop and Improve Accurate and Rapid Diagnostics, Including Point of 

Care (POC) Diagnostics 

There has been significant progress in developing molecular diagnostics that detect the presence of 

Mtb. Some examples of these diagnostics include GeneXpert MTB/Rif Ultra and MolBio TrueNat. The 

latter is both portable and battery-powered, which makes it more amenable to a POC setting. 

Molecular-based tests are recommended and preferred by the WHO; however, the currently available 

tests have limitations, particularly in low- and middle-income countries due to cost, required human 

resources, and infrastructure. Improved molecular-based tests for Mtb diagnosis and Mtb drug 

susceptibility testing (DST) are in development, including many that are suitable for POC or near POC 

use. The NIAID Feasibility of Novel Diagnostics for TB in Endemic Countries (FEND for TB) program 

supports the evaluation of early-stage diagnostics and novel diagnostic strategies for TB in endemic 

countries to address an urgent need for improved TB diagnostics. 

Most of the currently used diagnostics for active TB disease utilize sputum samples that can be difficult 

to obtain, particularly from young children and PLWH. These patients may also have low concentrations 

of Mtb in their sputum or may have paucibacillary disease wherein the sputum test will be negative, 

although samples from these individuals would be positive when analyzed via Mtb culture. Further, 

extra-pulmonary forms of TB cannot be detected in diagnostic tests that are based on sputum samples. 

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TB Research Strategic Plan Update 

Mtb diagnostic development areas should focus on the development of tests utilizing easy to obtain 

specimens and tests that are rapid, sensitive, and inexpensive (Figure 5). Innovative molecular based 

test development, including improved NAATs, NGS, and CRISPR, is underway. Additionally, there are 

continual advancements in developing tests that are breath-based or that utilize urine, blood/serum, or 

stool as these samples are often easier to obtain than sputum samples. Urine Lipoarabinomannan 

(uLAM), is a promising non-sputum based test which is low-cost, has high specificity, and can be used at 

the POC. The sensitivity of the currently available uLAM test is low, however, and is only recommended 

by the WHO as part of the diagnostic toolkit for PLWH with very low CD4 T cell counts. There is 

significant effort in the field to increase the sensitivity of uLAM assays for use in broader patient 

populations, as well as efforts to develop other urine based diagnostic assays. 

Other innovative diagnostic technologies include artificial intelligence (AI)-based tools to analyze images 

including chest X-ray (CXR) and computed tomography (CT) and AI-based tools for analysis of cough and 

lung sounds. Computer-aided detection software for automated interpretation of CXR is a useful tool 

that can assist in rapid and consistent CXR interpretation. CT is often only available in high-resource 

settings but can improve diagnosis of TB in more complex cases. Automated interpretation tools may 

expedite research, allow for more consistency between researchers, and enable comparisons of data 

between different research groups. 

Additionally, there is a need for improved DST, including DST for newly approved TB drugs. Current DST 

is used to determine which drugs are effective against Mtb and are performed when the patient is first 

found to have a positive Mtb culture. DST ensures that treatment can be initiated with the appropriate 

therapy. It is critical to develop the diagnostics for determining resistance to newly developed drugs as 

rapidly as new drugs are developed. This will ensure that as new drugs are rolled out, the tools are 

available to effectively use these drugs and reduce emergence of resistance. Ideally DST is molecularbased and drug-specific; however, phenotypic DST that is fast and accurate would be useful as new 

drugs are developed. Further, tests should 

be suitable to detect drug susceptibility in 

people with paucibacillary disease, children, 

and HIV seronegative and seropositive 

populations. 

NIAID will continue to support research on 

inexpensive screening diagnostics that can 

be paired with other more sophisticated 

technologies or can stand on their own and 

allow for cost-effective integration of these 

tools into TB control programs. These new 

diagnostics should be rapid, sensitive, and 

specific, useful at the POC or near care, costeffective and employ easy to obtain samples. 

NIAID will also continue to support the 

development of DST, especially for newly 

developed TB treatment drugs. 

Figure 5: Considerations for developing novel point of care (POC) 

diagnostics for TB. Currently, available tests are not widely accessible 

in most low- and middle-income countries and detection is difficult in 

children and people living with HIV (PLWH). New diagnostics should 

be low-complexity, affordable, and deployable in all settings. 

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TB Research Strategic Plan Update 

Objective 2.2 Discover and Validate Novel TB Biomarkers and Biosignatures 

Research efforts prioritize the identification of novel biomarkers or biosignatures, which may be able to 

identify recent infection, detect risk of disease progression from latent to active TB, monitor response to 

therapy, and predict disease relapse. Biomarkers may identify aspects of Mtb infection that precede 

active pulmonary disease or may be able to detect paucibacillary disease. Some approaches for studying 

early events in Mtb infection include the use of imaging probes and Mtb strains suitable for imaging 

studies in vivo, including tracking the presence, growth, and distribution of Mtb from infection through 

disease progression and treatment. Other comprehensive approaches such as multi-omics based studies 

are being advanced to identify biomarker signatures of clinical relevance. Omics based biomarkers that 

would be successful for diagnosing and managing TB in pediatric populations, PLWH, and for 

extrapulmonary TB are of particular interest. These biomarkers or biosignatures then need to be 

integrated into suitable technologies to provide accurate, reliable, and actionable information to 

clinicians. 

There are TB diagnostic assays currently in use that measure host biomarkers for Mtb infection or 

exposure, including the TST and IGRA, but these approaches only indicate prior infection or exposure to 

Mtb and cannot distinguish individuals with an immune memory of a prior infection from those with 

active TB disease and cannot predict those who may develop TB disease in the future. Further, the TST 

will test positive for those who received the BCG vaccination, whereas the IGRA will not. Improved 

diagnostics that can distinguish between people with TB disease and people with prior exposure to Mtb 

or BCG vaccination would be useful clinically. NIAID supports the identification and development of 

novel biomarkers or biosignatures to improve TB diagnostics, including biomarkers detectable in easy to 

obtain samples (e.g., urine, blood, serum, breath, or stool). 

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TB Research Strategic Plan Update 

STRATEGIC PRIORITY 3: Advance Research to Support TB Vaccine 

Development 

Safe and effective preventive vaccine(s) and related vaccination strategies remain critical development 

milestones to combat the TB pandemic. The WHO End TB targets emphasize that a new vaccine 

effective for pre- and post- Mtb exposure is a critical piece of the effort to lower TB incidence. Studies 

have predicted that a TB vaccine targeting adolescents and adults could have a major beneficial impact 

on the epidemic. Although several vaccine candidates are in clinical development, ongoing research is 

needed to accelerate the development of additional safe and effective TB vaccines that prevent 

infection and disease. Identifying correlates of immune protection (COP) from Mtb disease/infection 

continues to be a research priority that would enable more efficient testing and advancement of TB 

vaccine candidates. In addition, given the significant burden of disease and risk of progression to active 

TB disease, it is crucial that the safety and performance of TB vaccines be evaluated in people with HIV 

and other co-morbidities. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

STRATEGIC PRIORITY 3: ADVANCE RESEARCH TO SUPPORT TB VACCINE DEVELOPMENT 

Objective 3.1: Identify Immune Correlates of Protection (COP) 

Objective 3.2: Support Design and Development of Vaccine Candidates for Prevention of Infection and

Prevention of Disease 

Objective 3.1 Identify Immune Correlates of Protection (COP) 

A COP is an immune marker that can substitute for a clinical end point and can be used to reliably 

predict vaccine efficacy. Although progress has been made in understanding the nature of Mtb-specific 

immune responses, mechanisms that prevent Mtb infection or disease progression are not fully 

understood. Identifying and assessing COP for TB will require building on in vitro studies, ex vivo or 

explant systems, and in silico modeling combined with animal model studies to characterize immune 

responses that predict a successful vaccine candidate. These findings will need to be corroborated by 

vaccine efficacy trials to demonstrate a positive correlate. 

NIAID has made investments in supporting research to gain an understanding of the immune responses 

and correlates required to prevent initial infection with Mtb, establishment of latent infection, and 

transition to active TB disease. Multidisciplinary research teams, supported by the IMPAc-TB program, 

are conducting immunological analyses of tissue-specific and systemic responses in small animals, NHPs, 

and humans to identify key correlates needed for protection against Mtb. These studies will also identify 

immunologic targets that can be used to improve TB vaccine strategies and determine the impact of HIV 

and nontuberculous mycobacteria infections on relevant immune responses to Mtb infection or TB 

vaccines. NIAID has supported intravenous BCG vaccination studies in NHPs, which demonstrated a 

significant level of protection against Mtb infection and enabled the study of COP. 

Another potential way to identify COP is through the use of Controlled Human Infection Models (CHIM). 

CHIMs are studies that utilize healthy adult volunteers who are intentionally exposed to pathogens (or 

attenuated forms of a pathogen) in a controlled environment to more closely study an infectious 

organism. In addition to providing insight into COP, CHIMs can be used to better understand hostpathogen interactions, determine host factors that contribute to infection, and accelerate the 

13 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

TB Research Strategic Plan Update 

development and testing of vaccines. The information gained from CHIMs can be compared to results 

from preclinical models and clinical trial results allowing for validation of model systems. 

NIAID is committed to continue studies to identify immune COP through comparative immunological 

analyses of tissue-specific and systemic responses in relevant animal models and clinical samples. 

Furthermore, immunological characterization of individuals with latent TB infection who do or do not 

progress to active disease will help researchers better understand the factors that impact progression to 

active disease vs. containment or resolution of infection. Similarly, a more thorough characterization of 

markers from individuals who resist Mtb infection (remain IGRA negative) despite high exposure will 

help researchers investigate the factors that determine the outcome of an infectious event. Learning 

about the immune responses of those individuals who resist infection with Mtb could be useful in the 

development of prophylactic vaccines or other protective treatments. 

Objective 3.2 Support Design and Development of Vaccine Candidates for Prevention 

of Infection and Prevention of Disease 

NIAID supports the discovery of new immunogens and immunogen/adjuvant combinations that can be 

tested in diverse vaccine expression and delivery platforms. Two NIAID initiatives, Innovation for 

Tuberculosis Vaccine Discovery and Advancing Vaccine Adjuvant Research for Tuberculosis (AVAR-T), 

support the design of novel TB vaccine candidates that exploit innovative approaches and the 

development of side-by-side comparisons of adjuvants in combination with Mtb immunogens, 

respectively. Additional areas of support focus on the design and development of vaccine candidates 

against both initial acquisition of Mtb infection (prevention of infection) and against the transition from 

latent TB infection to active TB disease (prevention of disease), as well as in the context of PLWH. Other 

investigations include trials of therapeutic TB vaccines (prevention of recurrence), administered to 

persons during or after treatment for active TB, with the objective to accelerate resolution and prevent 

recurrence. 

Currently, there are few TB vaccines candidates in early-stage clinical development. Given that, NIAID is 

committed to supporting preclinical and clinical development of novel TB vaccine approaches. To 

accomplish this goal, additional studies are needed to evaluate novel vaccine platforms, test different 

delivery routes, and support product development and manufacturing activities. Furthermore, given the 

different vaccine needs and epidemiologic patterns in key study populations, NIAID supports studies 

across the life span (infants, children, adolescents, adults) and in people living with co-morbidities such 

as HIV. 

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TB Research Strategic Plan Update

STRATEGIC PRIORITY 4: Support Research to Advance Strategies to Treat 

and Prevent TB 

The development of novel treatments and safe drug combinations, for both treatment and prevention,

is an important part of the strategy to end the TB pandemic. NIAID supports basic, preclinical, and 

clinical research investigations into therapeutic treatments for pulmonary and extrapulmonary disease 

caused by Mtb. These investigations include the use of in vivo, in vitro, or in silico model systems and 

clinical trials. Many clinical trials investigate the safety and effectiveness of new therapeutics often in

combinations with existing medications. The two-pronged approach: basic and preclinical research 

paired with clinical trials is an important bridge from bench to bedside. 

Objective 4.1 Discover and Develop New TB Drug Targets and Interventions

Research to develop more effective, shorter, and safer treatments and preventative treatment 

strategies for TB disease is a high priority. Discovery of new drug targets is crucial for developing 

innovative strategies for these priorities. New drug targets could include essential metabolic pathways, 

virulence factors, or components involved in drug resistance mechanisms (Figure 6). One approach that 

could be applied to TB includes using induced proximity therapeutics, a rapidly growing field featuring

small molecules that bring two proteins together thereby speeding up or instigating a molecular 

reaction. One example of this technology is 

Targeted Protein Degradation (TPD). TPD induces 

breakdown of a specific, or targeted, protein. 

PROteolysis TArgeting Chimeras (PROTAC) is a 

promising TPD; clinical trials of oncology 

therapeutics based on PROTAC approaches are 

ongoing, and its use has expanded to other

therapeutic areas. Another innovative approach 

involves the use of bacteriophages – viruses that 

infect and kill bacteria. For example, Mtbtargeting bacteriophages can be combined with 

antibiotics as an entirely new type of therapeutic 

intervention. 

Targeting specific host-pathogen interactions or 

exploiting the immune response or other host 

metabolic pathways offer alternative avenues for 

HDTs that may help protect the lungs, improve 

STRATEGIC PRIORITY 4: SUPPORT RESEARCH TO ADVANCE STRATEGIES TO TREAT AND

PREVENT TB 

Objective 4.1: Discover and Develop New TB Drug Targets and Interventions

Objective 4.2: Develop and Improve TB Preventive Treatments (TPT) Interventions

Objective 4.3: Develop and Evaluate Shorter and/or Safer TB Treatment Regimens for All Patient 

Populations and Forms of TB

Figure 6: Therapeutic targets could include components 

involved in drug resistance mechanisms, host-pathogen 

interactions, virulence factors, and metabolic pathways.
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TB Research Strategic Plan Update

long term survival, and shorten treatment duration. Innovative research to identify new targets for HDTs 

and to evaluate novel immune modulating treatments, and therapeutic vaccines are needed to improve 

the effectiveness of immune responses to Mtb. Novel treatments should also aim to reduce tissue 

destruction caused by Mtb infection. Basic and preclinical research is required to identify these hostpathogen interactions for further refinement and testing. The preclinical work supported by NIAID is 

foundational for the eventual development of novel drugs to treat pulmonary and extrapulmonary Mtb

infections. 

Some existing TB drugs are associated with adverse events such as myelosuppression, anemia, 

neuropathy, hearing loss, and kidney damage that can present during the long treatment period

necessary for MDR- and XDR-TB. Safer therapeutics with less severe adverse events during treatment

are needed. Additionally, research is needed to determine the mechanisms of TB drug toxicities and to 

develop improved methods to detect these toxicities earlier in treatment. 

Objective 4.2 Develop and Improve TB Preventative Treatment (TPT) Interventions 

Significant strides have been made in developing improved TB Preventative Treatment (TPT) strategies. 

For example, a 2019 study showed that a TPT strategy that included a 1-month treatment of RPT and 

INH can effectively prevent progression from latent to active TB infection among adult PLWH. The 

efficacy of this regimen is being evaluated further in children and in people not infected with HIV. 

Another TPT trial, the Protecting Households on Exposure to Newly Diagnosed Index Multidrug-resistant 

Tuberculosis Patients (PHOENIx), co-funded by NIAID and the National Institute of Child Health and 

Human Development (NICHD), is investigating the ability of a new TB drug (delamanid) to prevent TB 

disease among household contacts of individuals with MDR-TB. This trial represents a collaboration 

between the Advancing Clinical Therapeutics Globally for HIV and other Infections (ACTG) Network and 

the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. 

With advances in formulation technologies and the discovery of more potent drugs with activity against 

Mtb, it is possible to further simplify TPT regimens into shorter, safer, and more effective courses. As 

research in these diverse fields advances, NIAID will continue to support platforms to integrate these 

efforts into combined interventions so maximal benefit is achieved at individual and population levels. 

Objective 4.3 Develop and Evaluate Shorter and/or Safer TB Treatment Regimens for

All Patient Populations and Forms of TB

As TB treatments are advanced through the research and development pipeline, they must be evaluated 

for their interactions with other TB treatment regimens, in various disease states, and in persons with 

co-infections or co-morbidities. The anticipated result is that new regimens will enable patients to 

adhere to TB treatment more easily, ensure better patient outcomes, and reduce forward transmission

(Figure 7). As such, NIAID is prioritizing rational design of new TB drug regimens. New drug combinations 

may result in improved efficacy and shorter treatment schedules, thereby improving implementation of 

these regimens in various settings. Importantly, safety and tolerability of new treatments are important 

characteristics for new regimen development. 

NIAID supports TB research tools such as the TB Portals, a collaborative and open access platform to

provide clinical investigators with outcome data on a global scale. Other translational work and clinical 
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TB Research Strategic Plan Update

trials investigate potential therapeutics for treating TB in combination with drugs for co-morbidities, 

particularly PLWH. 

The development of quantitative measures of

Mtb burden in all populations, as well as 

microbiologic studies to characterize the 

sterilizing activity of existing drugs, will 

contribute to advancing novel drug candidates. 

Continued investigation of the impact of HIV 

infection on TB disease and treatment 

outcomes should be prioritized to ensure that 

PLWH benefit from advances in TB treatments. 

Clinical evaluations of promising regimens 

must consider the spectrum of populations 

affected by TB including pregnant women, 

pediatric populations, and those with disease 

modifying co-morbidities. NIAID will continue 

to support development and evaluation of 

treatment regimens against both DS and DR TB as improved TB therapeutic interventions are critical to 

enhancing efficacy, shortening treatment duration, overcoming drug resistance, and ultimately reducing 

the global burden of TB. 

As part of this effort to develop and test promising drug candidates, NIAID will build on existing 

investments in clinical research infrastructure and resources (Appendix 2). These efforts will be directed 

both within and outside of the U.S. where TB is endemic to facilitate the development of therapeutics 

for people with TB, including PLWH and in people with other co-morbidities (e.g., diabetes, 

cardiovascular disease, and other lung conditions). 

Extrapulmonary TB, especially TB meningitis, continues to exact a substantial toll in morbidity and 

mortality. Thus, improvements in therapies to treat these conditions are greatly needed. Research has 

shown that treatments that work well for pulmonary TB may not have the same level of efficacy for TB 

meningitis due to several factors, including limited penetration through the blood-brain-barrier. 

Research to fully understand the factors impacting treatment efficacy in TB meningitis and development 

of improved strategies should be prioritized. 

In addition to HIV, it is known that other co-morbidities, including diabetes, hypertension, malnutrition, 

and tobacco smoking, are risk factors for TB and for poor TB treatment outcomes. Co-morbidities 

complicate patient health status by affecting local or systemic immune responses, drug metabolism, 

hormonal balances, or nutrient malabsorption. It is therefore important to understand how comorbidities impact TB progression to improve co-management and treatment strategies. Collaborative 

research conducted in TB-endemic countries provides novel insights into the impact of co-infections and 

co-morbidities on Mtb infection. To begin to address these issues, NIAID created the Regional 

Prospective Observational Research in Tuberculosis (RePORT) International program to foster 

collaborations between bench and clinical researchers. Each international cohort is designed to support 

local, in-country, TB and TB/HIV-specific data and specimen biorepositories and associated research and 

NIAID will continue to support building global clinical research capacity in high burden settings and share 

common protocols and data and specimen collection to address research needs. 

Figure 7: Continued development of novel treatment regimens for TB 

can lead to shorter treatment times that can enable better patient 

adherence; improved outcomes for all, including those with coinfections or co-morbidities; and decreased transmission.
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TB Research Strategic Plan Update

CONCLUSION

This updated 2024 NIAID Strategic Plan for TB Research builds on the momentum generated from highprofile, international reports and meetings, including the WHO End TB Strategy, 1st WHO Global 

Ministerial Conference on TB, and UN General Assembly High-Level Meeting on Ending TB. The updated

plan also aligns with the global goals and supports the objectives delineated in the U.S. Government 

Global TB Strategy and the National Action Plan for Combating Multidrug-resistant TB. These reports 

and meetings highlight the importance of biomedical research as a critical component of a global 

strategy to end TB and underscore the need to continue efforts to improve knowledge and tools to 

prevent, diagnose, and treat TB. NIAID aims to address these needs through a comprehensive scientific 

agenda and infrastructure expansion that are geared towards strengthening TB research. 

To continue the advancement of efforts to end the TB pandemic, it is important to continue recruiting

experienced, as well as new investigators to the field of TB research and increase collaborative,

multidisciplinary research that includes researchers from all backgrounds. In 2022, NIAID established

new TB Research Advancement Centers (TRACs) to promote these goals and support mentoring and 

funding of new investigators and researchers new to TB. NIAID will draw on expertise from diverse 

disciplines, including but not limited to virology, immunology, microbiology data science, genetics, and 

epidemiology, to drive the research that will increase fundamental knowledge and the development of 

new diagnostics, preventative measures, and treatments. 

NIAID continues to leverage its existing portfolio of resources and investments in biomedical research to 

expand and modernize its TB research program. These efforts are expected to reinvigorate TB research 

and accelerate the development and evaluation of new and improved methods to diagnose, prevent, 

and treat TB. By advancing fundamental TB research, resource development, and training of the next 

generation of researchers, NIAID will accelerate the development of a comprehensive toolkit to end TB. 
 

 

 

TB Research Strategic Plan Update 

APPENDICES 

Appendix 1: NIAID TB Working Group Members 

Last Name First Name Position 

Azeez Olumayowa Health Science Policy Analyst; Policy, Planning and Evaluation 

Branch, OD 

Boggiano Cesar Chief; Preclinical Research and Development Branch, DAIDS 

Boyce Jim Program Officer, Tuberculosis and Other Mycobacterial 

Diseases Section, DMID 

Bushar Nicholas Branch Chief; Policy, Planning and Evaluation Branch, OD 

Dang Que Program Officer; Preclinical Research and Development 

Branch, DAIDS 

Darrah Patricia Staff Scientist; Cellular Immunology Section, VRC 

Deckhut Alison Branch Chief; Basic Immunology Branch, DAIT 

Deschamps Anne 

Senior Health Science Policy Analyst; Policy, Planning and 

Evaluation Branch, OD 

Drew Jessi Scientific Policy Analyst (Contractor); Policy, Planning and 

Evaluation Branch, OD 

Eichelberg Katrin Program Officer; Tuberculosis and Other Mycobacterial 

Diseases Section, DMID 

Grace Beth Senior Financial Analyst, DCR 

Hutter Julia Medical Officer; Vaccine Clinical Research Branch, DAIDS 

Kim Peter Director; Therapeutics Research Program, DAIDS 

Lacourciere Karen Program Officer; Tuberculosis and Other Mycobacterial 

Diseases Section, DMID 

Laughon Barbara Program Officer; Tuberculosis and Other Mycobacterial 

Diseases Section, DMID 

Leitner Wolfgang Section Chief; Innate Immunity Section, DAIT 

Mendez Susana Program Officer; Tuberculosis and Other Mycobacterial 

Diseases Section, DMID 

Miers Sarah Program Analyst, Office of Scientific Coordination and Program 

Operations, DMID 

Ramachandra Lakshmi Section Chief; Tuberculosis and Other Mycobacterial Diseases 

Section, DMID 

Robinson Richard Program Officer; Tuberculosis and Other Mycobacterial 

Diseases Section, DMID 

Read Sarah Deputy Director; DAIDS 

Schmit Ginny Health Science Policy Analyst; Policy, Planning and Evaluation 

Branch, OD 

Shaffer Meredith Scientific Program Specialist; DIR 

Vázquez-Maldonado Nancy Program Officer; Innate Immunity Section, DAIT 

Vernon Andrew Branch Chief; Tuberculosis Clinical Research Branch, DAIDS 

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TB Research Strategic Plan Update 

Appendix 2: NIH-Supported TB Research Resources 

Resource Name Description 

Adjuvant Development Program 

The goal of the adjuvant development program is to establish and 

expand the availability of novel vaccine adjuvants that 

researchers can use for preclinical vaccine development in 

infectious and immune mediated diseases. 

Adjuvant Discovery Program 

NIAID plays a leading role in the discovery, development, and 

characterization of new vaccine adjuvants that may be used to: 

improve the efficacy of current vaccines; design new or improved 

vaccines for existing and emerging infectious diseases; and 

develop vaccines to treat allergies, autoimmune diseases, and 

cancer. 

AIDS Reagent Program 

Acquires, develops, and produces state of the art reagents and 

provides these reagents at no cost to qualified investigators 

throughout the world. 

Advancing Vaccine Adjuvant

Research for Tuberculosis (AVAR-T) 

The AVAR-T program will provide support to further the 

development of preventive, including post-exposure, TB vaccines 

through side-by-side comparisons of adjuvants in combination 

with Mtb immunogens and to establish immunological profiles of 

adjuvants that work through different mechanisms. 

Bacterial and Viral Bioinformatics 

Resource Center (BV-BRC) 

Information system that integrates bacterial pathogen 

information with rich data and analysis tools to support work on 

infectious diseases. 

BEI Resources Repository 

Central repository that supplies organisms and reagents to the 

broad community of microbiology and infectious diseases 

researchers. 

Bioinformatics Resource Centers Collects, archives, updates, and integrates research data with 

user-friendly interfaces and computational analysis tools. 

Centers for Research on Structural 

Biology of Infectious Diseases 

(CRSTAL-ID) 

Applies state-of-the-art technologies/methodologies to 

characterize 3-D atomic structures of molecules to support 

infectious disease research. 

Clinical Genomics Program Provides centralized resources to be used for genomics and 

related research. 

Cooperative Centers on Human

Immunology 

Translates immunology research into clinical applications in 

infectious disease. 

Early Phase Clinical Trial Units 

Supports design, development, implementation, and conduct of 

Phase I clinical trials against viral (other than HIV), bacterial, 

parasitic, and fungal pathogens. 

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TB Research Strategic Plan Update 

Resource Name Description 

Finding TB Cases Actively,

Separating safely and Treating -

effectively (FAST-TB) 

FAST-TB is an approach to preventing TB spread in congregate 

settings. The acronym FAST focuses on effective treatment which 

is the most important TB transmission intervention. 

Feasibility of Novel Diagnostics for 

TB in Endemic Countries (FEND for

TB) 

The FEND for TB program supports the evaluation of early-stage 

diagnostics and novel diagnostic strategies for TB in TB endemic 

countries to address an urgent need for improved TB diagnostics. 

Genomic Centers for Infectious 

Disease (GCID) Resources 

Provides innovative application of genomic technologies and 

rapid, cost-efficient production of high-quality genome sequences 

for pathogens and hosts. 

HIV/AIDS Clinical Trials Network Group of clinical trials networks addressing HIV scientific 

priorities including vaccines and therapeutics for co-infection. 

HIV, Opportunistic Infection and TB

Therapeutics Database (ChemDB) 

Extracts from the scientific literature structure / activity 

information on compounds tested against HIV, opportunistic 

infections, and TB. 

Human Immunology Project

Consortium (HIPC) 

Uses modern tools to examine the human immune system before 

/ after infection, vaccination, or adjuvant treatment. 

Infectious Disease Clinical Research 

Consortium 

A clinical trials research consortium that prioritizes vaccines, 

diagnostics, and other interventions to test in clinical trials. 

International Epidemiology

Databases to Evaluate AIDS (IeDEA)

Cohort Consortium 

Generates large, harmonized HIV/AIDS datasets from seven 

international regional data centers to help address high priority 

research questions. 

In-Vitro Assessment for 

Antimicrobial Activity Program 

Tests for antimicrobial activity of products against microbial 

pathogens and vectors. Strains and panels include those derived 

from clinical specimens. 

ImmPort Platform to share and analyze immunology data generated from 

human and animal models. 

Immune Epitope Database (IEDB) 

and Analysis Resource 

Database with detailed information for more than 1,000,000 

unique immune epitopes (antibody/B cell and T cell) related to 

infectious and immune mediated diseases. 

Immune Mechanisms of Protection 

Against Mycobacterium

tuberculosis Centers (IMPAc-TB) 

The IMPAc-TB program is an initiative established by NIAID in 

2019 to elucidate the immune responses needed to protect 

against infection with Mtb. The program will lead to a better 

understanding of TB immunology which is critical to guide the 

design and development of new and improved TB vaccines. 

ImmuneSpace 

Powerful data management and analysis engine for the HIPC 

program that enables integrative analyses and visualization of 

human immunological data. 

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TB Research Strategic Plan Update 

Resource Name Description 

Preclinical Models of Infectious 

Disease Program 

Provides development, screening, and efficacy testing in 

preclinical infectious diseases models, including traditional lab 

species, non-human primates, and non-traditional models. 

Regional Prospective Observational

Research in Tuberculosis (RePORT)

International 

Supports the establishment of regional RePORT consortia in 

cooperation with host countries for future combined or 

comparative data analysis and is a resource to bridge 

collaborations between bench and clinical researchers. 

Tetramer Core Facility Produces and distributes major histocompatibility complex 

tetramers and related reagents to the research community. 

TB Portals Advancing TB research through open-access, multi-domain, 

global TB data and tools. 

Tuberculosis Research Units 

Network (TBRU-N) 

The Tuberculosis Research Units operate as a collaborative 

network designed to improve the understanding of Mtb host 

interactions. 

Therapeutic Development Services:

Biopharmaceutical Product

Development Services 

Offers services for biotechnology products, such as planning, 

product characterization, process development, formulation, 

Good Manufacturing Practice, and Chemistry, Manufacturing and 

Control documentation. 

Therapeutic Development Services:

Interventional Agent Development

Services 

Facilitates development of therapeutics, including lead 

identification and development, chemistry and manufacturing, 

toxicology, and pharmacokinetics. 

Tuberculosis Research 

Advancement Centers (TRACs) 

Centers will support the development of a next generation of TB 

researchers by providing focused mentoring and funding support 

for new investigators, opportunities for multidisciplinary and 

collaborative research; and training in laboratory and clinical 

settings. 

Tuberculosis Information for 

Researchers 

Through the information offered here, researchers can learn 

about the science being conducted at NIAID and by NIAID funded 

researchers. 

Vaccine Adjuvant Compendium 

Displays adjuvant characteristics or metadata defined through 

NIAID-supported adjuvant studies, helps vaccine developers 

identify suitable adjuvants for vaccine indications. 

Vaccine and Treatment Evaluation 

Units 

Supports efforts to develop new and improved vaccines and 

therapies against infectious diseases. 

Vaccine Development Services 

Offers services for vaccine and adjuvant development such as 

assay development, non-clinical immunogenicity and efficacy 

studies, clinical and non-clinical sample testing and safety and 

toxicity testing, and for manufacturing. Manufacturing services 

include gap analysis and product development plan support as 

well as product optimization and other assistance. 

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TB Research Strategic Plan Update 

Appendix 3: Analysis of Public Comments to Request for Information (RFI) 

NIAID sought input from stakeholders in the scientific research community and the public regarding the 

proposed priorities for the NIAID Strategic Plan for Tuberculosis Research Update through a Request 

for Information (RFI). The RFI (NOT-AI-23-052) was open for comments from June 13, 2023 to August 22, 

2023. Submissions were received through a web-based form or by email. Input was requested on, but 

was not limited to, the following five topics regarding tuberculosis (TB) research: 

 IMPROVING FUNDAMENTAL KNOWLEDGE OF TB 

 ADVANCING RESEARCH TO IMPROVE DIAGNOSIS OF TB 

 ACCELERATING RESEARCH TO IMPROVE TB PREVENTION 

 SUPPORTING RESEARCH TO ADVANCE STRATEGIES TO TREAT TB 

 DEVELOPING TOOLS AND RESOURCES TO ADVANCE TB RESEARCH 

NIAID received 16 responses to the RFI, mostly from those in academia and from professional 

organizations. The submissions largely supported the priorities outlined in the plan, while offering 

specific input on gaps, resources necessary to advance TB research, and emerging technologies. A 

summary of themes based on an analysis of the RFI responses is provided. 

Specific Themes 

TB Biology and Disease 

Commenters noted several gaps related to TB biology and disease. Some indicated that more support is 

necessary to improve the fundamental knowledge of TB, including how microbial physiology and 

genetics impact disease phenotype. Host factors that are associated with risk of TB infection, 

progression, transmission, and treatment response must also be better understood. Additionally, there 

is a need to define sub-phenotypes of TB disease more precisely. 

Gaps also remain in understanding the biology of lung tissue damage and repair in TB disease. These 

gaps extend from mediators of matrix destruction and cavity formation to the subsequent remodeling 

that occurs in response. Other post-TB sequelae that should be more thoroughly investigated include 

recurrent infections and long-term co-morbidities. 

Tools, Resources, and Models of TB 

Respondents noted the need to use natural, minimally cultured patient isolates of Mtb rather than the 

more widely used in vitro passaged laboratory strains. Doing so would expand knowledge into the 

natural biological diversity of TB on both the host and microbe. 

Commenters stressed the need for continued development of TB disease models, including animal and 

non-animal alternatives (e.g., ex vivo human tissue models). These models should have increased 

complexity that allow for mechanistic studies and enable the detection of immune COP. Robust 

validation strategies must accompany these new models. In addition, a dedicated resource sharing 

database, widely accepted definitions, and standards as they pertain to complex immunological TB 

studies are needed. Multimodal and whole-body imaging technologies (PET/CT/MRI) can provide 

detailed insights regarding the dynamics and pathophysiology of TB disease and can assist in 

development of novel host-directed therapies, biomarkers, and can provide cross-species analyses. 

Surveillance, Screening, and Diagnostics 

Many respondents identified a need for TB case-finding and tracking outbreaks, especially among 

pediatric populations, people living with HIV (PLWH), pregnant women, and migrants. To address better 

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TB Research Strategic Plan Update 

screening and surveillance activities, more sensitive diagnostic tests are needed. These tests should be 

suitable for mass screening measures using non-sputum sampling (e.g., exhaled breath, blood, or urine) 

and should be capable of deployment in remote settings. Commenters also stated that development of 

point of care diagnostics and home-based testing assays should be prioritized and should leverage 

successes developed during the COVID-19 pandemic. With that, better diagnostic laboratory capabilities 

and capacities are also needed. 

TB Prevention and Treatment Strategies 

Several comments stressed the necessity for advances in host-directed immunomodulatory or 

immunotherapeutic treatments. Host-directed therapies could improve the efficacy of antibiotic 

treatment, shorten required treatment durations, reduce pressures driving antibiotic resistance, and 

enhance immune protection against secondary infection. Continued development of shorter regiments 

for drug-sensitive and drug-resistant forms of TB, including in children and PLWH, is especially 

warranted, commenters stated. 

Respondents also noted that technology advances can assist in the development of TB therapies. AI or 

machine learning may be useful in development of TB treatments and could be employed to predict 

treatment response. Additionally, mobile apps to trace contacts and monitor patients’ treatment 

compliance and response would be a useful area for development. 

Cross-cutting Themes 

TB Workforce 

Support for early career investigators and physician-scientists focused on TB research warrants 

emphasis, commenters noted. Dedicated funding strategies to support the next generation of early 

career TB researchers is especially needed. NIH should also encourage innovative and high-risk projects, 

especially cross-disciplinary collaborations that could bring in expertise from other fields. 

U.S. based researchers conducting global health research should have strong ties and collaborations 

with the partner institutions and communities where the work is based. Comments also indicated that 

more specialist inputs from TB endemic regions through collaborations between the NIH and other 

federal agencies would facilitate research. Professional development and training for researchers and 

clinicians from TB endemic regions through collaborations between the NIH and other federal agencies 

would also be beneficial. 

TB Research Funding and Infrastructure 

Respondents noted that a boost in TB research funding, as called for by the Stop TB Partnership, would 

produce dramatic results in achieving the goal of ending TB. Increased investment in TB Research 

Advancement Centers (TRAC) could also generate successes in TB research similar to that of the Centers 

for AIDS Research (CFAR) program. Investment in an NIH core or other funding mechanism for T cell and 

B cell antigen discovery platforms for infectious disease research, including TB, would be welcomed. 

Respondents also commented that there is a need for dedicated mechanisms of support for BSL3 

facilities, as they are difficult to maintain via typical grant mechanisms. 

At-risk Populations 

Commenters indicated that TB research should account for social and economic factors that 

fundamentally drive the epidemic. All populations of patients including pediatric populations, PLWH, 

pregnant women, migrants, and asylum seekers should be integrated into all aspects of TB research, 

treatment, and management. Transmission, diagnosis, and treatment can be partially addressed 

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TB Research Strategic Plan Update

through effective public health education provided in a linguistically competent manner among minority 

populations. Investigations into the social determinants of health that drive TB transmission should also 

be prioritized. Increasing the numbers of trained professionals to support TB prevention and treatment 

activities in communities at the highest risk for TB would be beneficial to the field and would further

positive public health interactions with diverse populations.

Clinical Research

Respondents indicated that research should refocus on the natural history of tuberculosis disease, 

especially in high-burden countries, by developing large multi-country cohorts. Increased clinical 

research capacity, particularly for pediatric populations, should also be prioritized. Additionally, 

advancing TB drug regimens necessitates the development of standardized, patient-centered endpoints 

incorporated into clinical trials.