What is Tuberculosis?

Tuberculosis (TB) is a bacterial disease that most commonly affects the lungs (pulmonary TB). In otherwise healthy individuals, most infections are latent and therefore asymptomatic. About 5% of people infected with TB will develop active disease within the first year after exposure and an additional 5% are likely to develop active TB from latent infection over the course of their lifetime. In immunocompromised patients, such as those with HIV, the risk of developing active TB from an infection increases to ~10% per year.

Global Burden

Tuberculosis

TB is a worldwide health problem. 27% of the global population – about 1.9 billion people currently have latent TB. Interestingly, 80% of the global burden is borne by only 22 countries. In fact, India and China bear one-third of the total TB burden.1 The World Health Organization (WHO) estimated that 1.4 million people died from tuberculosis in 2010.2 An estimated 12% of incident cases occurred in patients who were HIV positive.

WHO Region Incidence TB (in thousands)1
Africa 2,800
Americas 270
Eastern Mediterranean 660
Europe 420
Southeast Asia 3,300
Western Pacific 3,300
Total: 10,750

Drug resistance and the growing global presence of drug resistant tuberculosis are alarming. Approximately 3% of cases are multidrug resistant (MDR – defined as resistant to both rifampin and isoniazid).

WHO Region Incidence MDR-TB (in thousands)1
Africa 69
Americas 8.2
Eastern Mediterranean 24
Europe 81
Southeast Asia 130
Western Pacific 120
Total: 432.2

The four countries with the highest incidence of MDR-TB were:

  1. China: 100,000 cases
  2. India: 99,000 cases
  3. The Russian Federation: 38,000 cases
  4. South Africa: 13,000 cases

In 2010, the estimated incidence increased to 650,000 cases of MDR-TB.2 The WHO reported that as of July 2010 58 countries reported as least one case of extensively drug-resistant TB (XDR-TB, defined as MDR + resistant to at least a fluoroquinolone and .an aminoglycoside).

Causative Agent

exampleTuberculosis is caused by the acid-fast Gram-positive bacterium Mycobacterium tuberculosis. The bacteria are most commonly spread by aerosol; when a person with active pulmonary disease exhales, coughs, sneezes, or even talks, tiny droplets containing bacteria are produced that can be inhaled by others. Inhalation of these droplets can result in infection.

Pathogenesis

Tuberculosis infection usually results in either asymptomatic disease, known as latent TB, or active pulmonary infection, known as active TB. In approximately 90% of infections, the M. tuberculosis bacteria invade macrophages in the host lung but are rapidly encapsulated in a granuloma in the lungs formed by the host’s immune response. The bacteria remain alive and are able to replicate within the granuloma but do not cause symptoms. This stage of disease is referred to as the latent stage. Because the bacteria are sequestered, latent TB is not transmissible.

People living with HIV and infected with TB are 21-34 times more likely to develop active disease compared to those without HIV.7 When children present with TB it is more disseminated with greater incidence of extra-pulmonary TB.8

In about 5% of new infections and in an additional 5% of the infected patient population over time, M. tuberculosis escapes the control of the immune system or granuloma and replicates within the lungs or other tissues of the body. Active replication of M. tuberculosis in the lungs leads to symptomatic or active pulmonary disease. Symptoms include a cough lasting more than two weeks, coughing up blood, fatigue, fever, chills, night sweats, weight loss, or appetite loss. Lung damage is primarily attributed to the host immune response mounted against the bacteria.

Current Control Strategy

The WHO has developed an integrated strategy for TB control called the Stop TB Strategy. This initiative has six core components, including:

  1. Expanding and enhancing access to directly observed treatment, short course (DOTS; standard of care for TB treatment)
  2. Addressing TB/HIV co-infection issues, MDR-TB, and the needs of vulnerable populations
  3. Strengthening health systems with a focus on primary care
  4. Engaging all providers to promote the standard of care for TB
  5. Empowering TB patients and communities
  6. Promoting and enabling research for new drugs, vaccines, and diagnostics as well as operational studies of current tools

The goal of the Stop TB Strategy is to significantly decrease the burden of TB by 2015 and ultimately eliminate TB as a public health concern by 2050. Funding for TB control efforts is estimated to reach nearly US$5 billion by 2011.3

Existing Products

Drugs

Standard treatment of active TB consists of combination treatment with four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol, substituting in streptomycin for ethambutol if meningitis is observed) daily for 2 months followed by two drugs (isoniazid and rifampicin) daily for 4 months.4

The WHO recommends that all treatment be provided using the DOTS method. DOTS in an acronym for directly observed therapy short-course and refers to the use of observers, generally community or health care worker volunteers, to observe patients as they take their daily TB medications. The strategy improves patient adherence and reduces the risk of the development of drug resistance. The DOTS program extends beyond its original acronym definition to encompass a greater strategic approach for the treatment of TB including five principles:5

  1. Political commitment with increased and sustained financing
  2. Case detection through quality-assured bacteriology
  3. Standardized treatment with supervision and patient support
  4. An effective drug supply and management system
  5. A monitoring and evaluation system, and impact measurement

From 1995-2009, the Stop TB Program was able to successfully treat 41 million cases of tuberculosis, saving approximately 6 million lives.

Latent TB is treated in the developed world using one of four regimes: isoniazid monotherapy for 6 or 9 months, isoniazid and rifapentine for six months or rifamin for four months. Latent TB is not treated in the developing world except in patients with HIV co-infection.9

Rifampicin which is used in TB treatment regimens induces cytochrome P450 and this leads to metabolism and reduction in systemic exposure and effectiveness of HIV protease inhibitors.10

Vaccines

The bacille Calmette-Guérin (BCG) vaccine is the only vaccine available for the prevention of tuberculosis. BCG is a live attenuated vaccine prepared from an attenuated strain of Mycobacterium bovisM. bovis is a bacterium that is related to human M. tuberculosis but primarily infects cows. In order to attenuate the live bacteria and produce the vaccine, the M. bovis was passaged in special media 230 times by a group of French scientists.

The BCG vaccine has been in use for more than 80 years and is known to protect newborn infants from TB-related meningitis and other systemic TB infections that can result from active disease. The reported vaccine efficacy in preventing primary TB infection, conversion of disease from latent to active forms, or pulmonary TB in adolescents or adults in the long-term is highly variable, with most studies showing little or no efficacy.

Diagnostics

Numerous diagnostic assays are available for TB, but each of the current assays has significant limitations for use in resource poor settings. The most commonly used diagnostics as well as their relative strengths and weaknesses are described below.

Test Strengths Weaknesses
Sputum smear microscopy (SSM; using acid-fast staining) Key component of the DOTS therapy strategy employed by WHO to control TB Requires extensive training for low throughput results

Lack of sensitivity: 70% sensitive in TB patients, <50% sensitive in HIV positive TB patients, and cannot detect extrapulmonary or latent TB

Lower limit of detection (10,000 bacteria per mL of sputum)
Bacterial culture from sputum Gold standard

Can be used to determine drug susceptibility
3-4 weeks to result

Cannot detect latent TB
Tuberculin skin test (Purified Protein Derivative, PPD, or Mantoux Test) Can detect latent TB Nonspecific

Patients with prior BCG vaccination have false positive

Cannot differentiate between latent and active TB

Does not work in HIV positive patients
Cellular assay from blood (Quantiferon-TB Gold, Cellestis Limited, Australia) Can detect latent TB even in patients with prior BCG vaccination Does not differentiate between latent and active TB
Nucleic acid amplification (Primarily used in research, one point of care test Xpert MTB/RIF by Cepheid available outside the US) Potential for use at the point of care

Can identify rifampicin-resistant infections without bacterial culture

Xpert MTB/RIF accurately diagnoses TB and MDR-TB in 100 minutes and is 26 countries are now using this system
Expensive

 In July 2011, the WHO released a recommendation against the use of rapid serological tests for active TB, calling them "inconsistent and imprecise," potentially leading to "misdiagnosis, mistreatment, and potential harm to public health."6

References

  1. WHO 2010 TB report.
  2. WHO 2011/2012 Tuberculosis Global Facts
  3. WHO Stop TB Factsheet.
  4. WHO (2010) Treatment of tuberculosis: guidelines – 4th ed.
  5. WHO (2006) The Stop TB Strategy: Building on and enhancing DOTS to meet the TB-related millennium development goals.
  6. WHO (2011) WHO warns against the use of inaccurate blood tests for active tuberculosis (News Release).
  7. WHO 2012 Tuberculosis Factsheet
  8. WHO Childhood Tuberculosis
  9. CDC, Treatment Regimens for Latent Tuberculosis Infections
  10. 10. Koul A. et al. (2011) “The challenge of new drug discovery for tuberculosis.” Nature, 469: 483-490

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Drugs

Analysis

Drug development for TB is rapidly expanding and improving. Several recent events have helped encourage this process including:1

  • 2008-2009: Significant pledges of funding from the U.S. and U.K. governments to support TB drug development through TB Alliance.
  • June 2009: First program for parallel development of a novel TB drug for both drug sensitive and MDR-TB launched by TB Alliance and Tibotec for the development of TMC207.
  • March 2010: Launch of the Critical Path to TB Drug Regimens (CPTR) Initiative to reduce the time for development of novel TB drugs to <6 years, joint project between the Bill & Melinda Gates Foundation, TB Alliance, and the Critical Path Institute with support from the U.S. Food & Drug Administration (FDA).
  • October 2010: The first proof of concept clinical trial (phase II) to evaluate new combination therapies for TB was initiated. This is the first evaluation in over 50 years of entirely novel drug combinations for TB, as opposed to substituting single new products into existing drug combination regimens.

Beyond government, non-profit, and product development partnership participation, TB drug development benefits from significant participation by the pharmaceutical and biotech industries. Companies participating in TB drug development include Anacor Pharmaceuticals, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline (GSK), Lupin Pharmaceuticals, Novartis, Pfizer, Otsuka, Sanofi-aventis, Sequella, and Tibotec.

Tuberculosis has the largest and most diverse discovery and pre-clinical stage pipelines of the neglected diseases. Products span multiple drug target classes including, but not limited to:

  • Nucleic acid synthesis
  • Lipid biosynthesis
  • Energy metabolism 
  • Proteases
  • Kinases
  • Protein synthesis

Additionally, multiple whole cell screens and projects to identify and develop natural products as inhibitors are underway.

 StrengthsWeaknessesOpportunitiesRisks
Fluoroquinolones (Nucleic acid synthesis)
Most advanced program:  Moxifloxicin, Phase III (Additional phase III product currently on hold)Known antibiotic FDA approved for other indications since 1999 Most advanced stage product  Unique mechanism of action, inhibition of DNA gyrase, compared to on market products reducing risk for cross resistance and increasing potential for efficacy in MDR-TBLike existing TB products, known risks for liver toxicity or side effects in patients with hepatoinsufficiencyCombination therapies with existing products and with other new products in development Potential to shorten treatment course through new combination developmentLow potential for safety improvement over existing drugs (related molecule, gatifloxicin, is on hold for TB development and is no longer being produced for use in the US for other indications due to adverse events) There is pre-existing drug resistance due to wide use of this class of antibiotics for non TB indications.
Nitroimidazoles
Most advanced program:  PA-824 and OPC-67683, Phase II (Additional programs in pre-clinical development)Unique mechanism of action compared to on market products reducing risk for cross resistance and increasing potential for efficacy in MDR-TB Related molecules are FDA approved for other indications Phase II data for PA-824 showed early bactericidal activity at lower drug concentrations than expectedNitroimidazole analogs in use or in development for other diseases are known to have side effectsNitroimidazoles are in use or in development for multiple NTDS, so potential for overlap and data sharing among developers  Combination therapies with existing products and with other new products in development Potential to shorten treatment course through new combination development
Diarylquinolines (Energy metabolism)
Most advanced program: TMC207, Phase II (Additional programs in discovery stage development)Unique mechanism of action compared to on market products reducing risk for cross resistance and increasing potential for efficacy in MDR-TB Related molecules are FDA approved for other indications Phase II data for PA-824 showed early bactericidal activity at lower drug concentrations than expectedCaused significantly more nausea relative to current standard of care for MDR-TB in a phase II trial but did not result in discontinuation of treatmentMost advanced product with clinical evidence for efficacy against MDR-TB Combination therapies with existing products and with other new products in development Potential to shorten treatment course through new combination developmentLow potential for safety improvement over existing drugs
Oxazolidinones (Protein synthesis)
Most advanced program: PNU-100480, Phase II (Additional programs in phase I and discovery stages of development)Related to linezolid, an oxazolidinone used for the treatment of other bacterial infections Unique mechanism of action, 70S ribosome inhibition, compared to on market products for TB reducing risk for cross resistance and increasing potential for efficacy in MDR-TBThe related oxazolidinone, linezolid, has been reported to have serious neurologic, ophthalmologic, and hematologic toxicities associated with inhibition of mitochondrial protein synthesis. However, phase I data with PNU-100480 suggests the toxicities are within tolerable limitsCombination therapies with existing products and with other new products in development Potential to shorten treatment course through new combination developmentSafety profile in patients with TB, as compared to currently used drugs and other products in clinical development, remains to be determined Not currently part of novel drug combination trials

Vaccines

Analysis

For some diseases, full sterilizing immunity is essential to warrant the development and use of a vaccine. For tuberculosis, however, there are a variety of potential vaccination strategies that could have a significant impact on the control of TB. These include:3

  • Pre-exposure vaccination (especially valuable if it works in HIV positive patients) to
    • Prevent or at least delay TB reactivation from the latent form
    • Achieve sterile immunity to M. tuberculosis
  • Post-exposure vaccination
    • To delay TB reactivation from the latent form (especially in HIV positive patients)
    • As a therapeutic vaccine to kill M. tuberculosis (including prevention of latent infections)

Vaccines currently in development primarily focus on pre-exposure prevention of tuberculosis disease, although studies relating to prevention of reactivation of TB are also underway. The majority of studies rely on a heterologous prime-boost approach that uses combinations of vaccines based on different technologies and antigens to provide a more comprehensive immune response to infection. Studies of new vaccines as boosters in individuals with prior childhood BCG vaccination are the cornerstone of this approach.

Vaccination strategies for TB in the future will most likely include:

  • New prime-boost studies using improved recombinant BCG vaccines as the “prime” component replacing the current BCG vaccine
  • More extensive evaluation of clinical stage vaccines in alternate vaccination strategies (i.e., therapeutic, prevention of reactivation, safety, and efficacy in HIV positive populations)
 StrengthsWeaknessesOpportunitiesRisks
Inactivated
Most advanced program: M. vaccaevaccine (Preventive, Boost following BCG prime), Phase III Additional product in phase II as a therapeutic vaccineBased on well accepted strategy for vaccine development Traditionally, inactivated whole cell vaccines primarily induce humoral immunity which may be less relevant for TB as it is an intracellular pathogenNew recombinant BCG strains for improved prime are in development and provide potential for improved immune response in prime-boost combinations Potential role in novel heterologous primer-boost combinationsMultiple components of the immune response are important for mediating TB immunity but mechanisms of protection not fully understood Immune stimulation through vaccination could worsen immune response-related damage
Recombinant/purified protein
Most advanced program: M72 (Preventive, Boost following BCG prime), Phase II Additional products in phase I developmentBased on well accepted strategy for vaccine development M72 is being developed by GlaxoSmithKline (GSK) and has access to GSK’s proprietary adjuvants M72 induces CD4+ T-cell responseUnlikely to be sufficient for vaccine alone  Traditionally, recombinant protein vaccines primarily induce humoral immunity which may be less relevant for TB as it is an intracellular pathogenNew recombinant BCG strains for improved prime are in development and provide potential for improved immune response in prime-boost combinations Potential role in novel heterologous primer-boost combinations Multiple components of the immune response are important for mediating TB immunity but mechanisms of protection not fully understood  Immune stimulation through vaccination could worsen immune response-related damage
Viral vector
Most Advanced Program: AERAS-402/Crucell Ad35 and MVA85A/AERAS-485 (Preventive, Boost following BCG prime), Phase II Additional product in phase I developmentAERAS-402/CrucellAd35 induces CD8+ T-cell response whereas MVA85A/AERAS-485 induces polyfunctional CD4+ T-cells, suggesting viral vector strategy can be used to simulate different components of the immune responseNew recombinant BCG strains for improved prime are in development and provide potential for improved immune response in prime-boost combinations  Potential to be first approved viral vector vaccine Potential role in novel heterologous prime-boost combinationsThere are no FDA approved viral vector vaccines on market Termination of adenovirus-based HIV vaccine trial in 2005 raised safety concerns which may lead to increased regulatory scrutiny Multiple components of the immune response are important for mediating TB immunity but mechanisms of protection not fully understood Immune stimulation through vaccination could worsen immune response-related damage
Live attenuated
Most advanced program:  AERAS-422 (Preventive, recombinant BCG to replace current BCG strain for priming vaccinations), Phase I Additional product in discovery stage developmentPotential to replace current BCG for newborn vaccination as well as serve as the new prime for prime-boost vaccination strategiesFinding populations with no history of BCG vaccination for later stage clinical efficacy studies may be challenging Risk for causing symptoms in high risk populations (i.e., HIV positive) if attenuation is not sufficientCurrent BCG vaccine is highly variable in quality and efficacy, so improved rBCG has a high probability of replacing the existing vaccine Potential role in novel heterologous primer-boost combinationsEfficacy studies in newborns to replace current BCG entirely may be difficult

Diagnostics

Analysis

The potential for successful development of point of care diagnostics for tuberculosis is increasing. Although the Cepheid GeneXpert nucleic acid amplification device is now available outside the U.S., significant price reduction will be necessary before this or other molecular devices can be used effectively in resource poor settings.

Alternative inexpensive rapid diagnostic tests for use at the point of care in resource poor settings have been explored. Point-of-care rapid diagnostic tests are available for HIV, malaria, and a limited number of other diseases for use in resource poor settings. The majority of these tests are immune-based disposable lateral flow devices that are inexpensive and easy to use. An independent evaluation of 19 commercially available TB rapid diagnostic tests conducted by the WHO/TDR demonstrated that these products were far inferior to microscopic evaluation of sputum smears with sensitivity and specificity ranging from 0.97% to 59.7% and 53% to 98.7%, respectively.4 New biomarker innovation is needed before improved lateral flow rapid tests will be feasible.

Additional new tuberculosis diagnostic test development is ongoing through support of the Foundation for Innovative New Diagnostics (FIND) and other multilateral partnerships. Additional information on TB diagnostics in development is available through the Evidence-Based Tuberculosis Diagnosis site.

References

  1. TB Alliance (2010) 2010 Annual Report: More than ever it’s time for a faster cure.
  2. Schwalbe NR et al. (2008) “Estimating the market for tuberculosis drugs in industrialized and developing nations.” The International Journal of Tuberculosis and Lung Disease 12: 1173–1181.
  3. Kaufmann, SHE (2010) “Future vaccination strategies against tuberculosis: thinking outside the box.” Immunity 33: 567-577.
  4. WHO (2008) Laboratory-based evaluation of 19 commercially available rapid diagnostic tests for tuberculosis (Diagnostics evaluation series, 2).

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The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for TB. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for TB are generally well developed.  However, the BSL3 laboratory safety conditions needed to work with virulent M. tuberculosis as well as the slow growth of M. tuberculosis are factors that limit the use of these tools.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome: Sequenced and annotated 

Key databases: GenoList Genome BrowserTARGETTBDB

In vitro culture: Solid media or liquid culture, BSL3 laboratory facilities required

Gene knock-outs: Yes

Conditional gene knock-outs: Yes 

Transposon mutagenesis: Yes 

RNAi: Host factors only

Other antisense technology:  Yes

Viability assays: Yes 

Transcription microarrays: Yes

Proteomics: Yes 

Crystal structures: Extensive, available through the TB Structural Genomics Consortium

Whole-cell screening assays: Yes, but for safety reasons M. smegmati or BCG are commonly used as a model organism in place of M. tuberculosis

Enzymatic screening assays: Yes

Animal models: Yes Mouse for acute and chronic disease Guinea pig, rabbit, and primate models also available

Monitoring treatment efficacy: Yes, reduction in bacteremia in sputum 

Availability of endpoints: Yes, reduction in bacteremia in sputum 

Availability of surrogate endpoints: No 

Access to clinical trial patients/sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: No, animal models primarily used to evaluate safety not potential efficacy

Detection of endogenous antigen specific response in clinical samples: Yes

Natural immunity well characterized: Currently being evaluated, polyfunctional CD4+ memory T-cells and CD8+ effector T-cells both appear to be important

Surrogate markers of protection: No

Challenge studies possible: No

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes

Access to clinical samples: Yes, including the TDR Specimen Bank

Possible sample types: Sputum, blood

Access to clinical trial patients/sites: Yes

Treatment available if diagnosed: Yes

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.