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Tuberculosis (TB) remains a leading cause of death worldwide and is estimated to have caused 1.3 million deaths worldwide in 2022. Approximately one quarter of the world's population are infected with Mycobacterium tuberculosis, of whom up to 10% will progress to developing active TB disease. Achieving the World Health Organization End TB Strategy targets of a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide by 2035 remains a daunting task. The continuing spread of multidrug-resistant TB adds another obstacle to achieving global TB control. Larger funding pledges coupled with technological advances have recently enabled the enhancement of TB vaccine development efforts. These are yielding a pipeline of over 17 products currently in different stages of clinical trials. Emerging promising phase I and II trial results and advancement to phase III trials have necessitated "vaccine preparedness" in parallel so that a smooth transition from any positive clinical trial result to phase IV evaluation and implementation into policy and practice can follow. Promotion of a human rights-based approach, which recognizes and upholds the fundamental rights of all affected by the disease, is essential to ensure universal access to quality TB vaccines, regardless of their background or personal circumstances., Competing Interests: Declarations of competing interest All authors have an academic interest in TB. The authors have no competing interest to declare. The views expressed by the authors are their own and do not reflect those of their individual institutions., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Investments into 'Blue Skies' fundamental TB research in low- and middle-income countries (LMICs) have not been forthcoming. We highlight why blue skies research will be essential for achieving global TB control and eradicating TB., Methods: We review the historical background to early TB discovery research and give examples of where investments into basic science and fundamental 'blue skies research' are delivering novel data and approaches to advance diagnosis, management and holistic care for patients with active and latent TB infection., Findings: The COVID-19 pandemic has shown that making available adequate funding for priority investments into 'Blue skies research' to delineate scientific understanding of a new infectious diseases threat to global health security can lead to rapid development and rollout of new diagnostic platforms, treatments, and vaccines. Several advances in new TB diagnostics, new treatments and vaccine development are underpinned by basic science research., Conclusions: Blue Skies research is required to pave the way for a personalized medicine approach for management of TB and other Respiratory Tract Infections and preventing long-term functional disability. Transfer of skills and resources by wealthier nations is required to empower researchers in LMICs countries to engage in and lead Blue Skies research., Competing Interests: Declaration of Competing Interest All authors have an interest in TB. All authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.

Background: New tuberculosis (TB) drug treatment regimens are urgently needed. This study evaluated the potential of the histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the effects of first-line anti-TB drugs against intracellular Mycobacterium tuberculosis., Methods: M. tuberculosis H37Rv cultures were exposed to VPA or SAHA over 6 days, in the presence or absence of isoniazid (INH) and rifampicin (RIF). The efficacy of VPA and SAHA against intracellular M. tuberculosis with and without INH or RIF was tested by treating infected macrophages. Bactericidal activity was assessed by counting mycobacterial colony-forming units (CFU)., Results: VPA treatment exhibited superior bactericidal activity to SAHA (2-log CFU reduction), while both HDIs moderately improved the activity of RIF against extracellular M. tuberculosis. The bactericidal effect of VPA against intracellular M. tuberculosis was greater than that of SAHA (1-log CFU reduction) and equalled that of INH (1.5-log CFU reduction). INH/RIF and VPA/SAHA combination treatment inhibited intracellular M. tuberculosis survival in a shorter time span than monotherapy (3days vs. 6 days)., Conclusions: VPA and SAHA have adjunctive potential to World Health Organization-recommended TB treatment regimens. Clinical evaluation of the two drugs with regard to reducing the treatment duration and improving treatment outcomes in TB is warranted., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant., Methods: BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150μg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4 + T cell responses., Results: H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4 + T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4 + T cell expansion, IFN-γ production and multifunctional CD4 + Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50μg of H4 in combination with the 500nmol IC31 adjuvant dose., Conclusions: The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4 + T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50μg of H4 and 500nmol of IC31., Trial Registration: ClinicalTrials.gov, NCT02066428 and NCT02074956., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mycobacterium africanum comprises two phylogenetic lineages within the Mycobacterium tuberculosis complex (MTBC). M. africanum was first described and isolated in 1968 from the sputum of a Senegalese patient with pulmonary tuberculosis (TB) and it has been identified increasingly as an important cause of human TB, particularly prevalent in West Africa. The restricted geographical distribution of M. africanum, in contrast to the widespread global distribution of other species of MTBC, requires explanation. Available data indicate that M. africanum may also have important differences in transmission, pathogenesis, and host-pathogen interactions, which could affect the evaluation of new TB intervention tools (diagnostics and vaccines)-those currently in use and those under development. The unequal geographical distribution and spread of MTBC species means that individual research findings from one country or region cannot be generalized across the continent. Thus, generalizing data from previous and ongoing research studies on MTBC may be inaccurate and inappropriate. A major rethink is required regarding the design and structure of future clinical trials of new interventions. The West, Central, East, and Southern African EDCTP Networks of Excellence provide opportunities to take forward these pan-Africa studies. More investments into molecular, epidemiological, clinical, diagnostic, and immunological studies across the African continent are required to enable further understanding of host-M. africanum interactions, leading to the development of more specific diagnostics, biomarkers, host-directed therapies, and vaccines for TB., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Bacille Calmette-Guérin (BCG) is the world's most widely distributed vaccine, used against tuberculosis (TB), in cancer immunotherapy, and in autoimmune diseases due to its immunomodulatory properties. To date, the effect of BCG vaccination on antibody responses to host proteins has not been reported. High-content peptide microarrays (HCPM) offer a unique opportunity to gauge specific humoral immune responses., Methods: The sera of BCG-vaccinated healthy adults were tested on a human HCPM platform (4953 randomly selected epitopes of human proteins) to detect specific immunoglobulin gamma (IgG) responses. Samples were obtained at 56, 112, and 252 days after vaccination. Immunohistology was performed on lymph node tissue from patients with TB lymphadenitis. Results were analysed with a combination of existing and novel statistical methods., Results: IgG recognition of host peptides exhibited a peak at day 56 post BCG vaccination in all study subjects tested, which diminished over time. Primarily, IgG responses exhibited increased reactivity to ion transporters (sodium, calcium channels), cytokine receptors (interleukin 2 receptor β (IL2Rβ), fibroblast growth factor receptor 1 (FGFR1)), other cell surface receptors (inositol, somatostatin, angiopoeitin), ribonucleoprotein, and enzymes (tyrosine kinases, phospholipase) on day 56. There was decreased IgG reactivity to transforming growth factor-beta type 1 receptor (TGFβR1) and, in agreement with the peptide microarray findings, immunohistochemical analysis of TB-infected lymph node samples revealed an overexpression of TGFβR in granulomatous lesions. Moreover, the vesicular monoamine transporter (VMAT2) showed increased reactivity on days 112 and 252, but not on day 56 post-vaccination. IgG to interleukin 4 receptor (IL4R) showed increased reactivity at 112 days post-vaccination, while IgG to IL2Rβ and FGFR1 showed decreased reactivity on days 112 and 252 as compared to day 56 post BCG vaccination., Conclusions: BCG vaccination modifies the host's immune landscape after 56 days, but this imprint changes over time. This may influence the establishment of immunological memory in BCG-vaccinated individuals., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Understanding of humoral immune responses in tuberculosis (TB) is gaining interest, since B-cells and antibodies may be important in diagnosis as well as protective immune responses. High-content peptide microarrays (HCPM) are highly precise and reliable for gauging specific antibody responses to pathogens, as well as autoantigens., Methods: An HCPM comprising epitopes spanning 154 proteins of Mycobacterium tuberculosis was used to gauge specific IgG antibody responses in sera of TB patients from Africa and South America. Open source software for general access to this method is provided., Results: The IgG response pattern of TB patients differs from that of healthy individuals, with the molecular complexity of the antigens influencing the strength of recognition. South American individuals with or without TB exhibited a generally stronger serum IgG response to the tested M. tuberculosis antigens compared to their African counterparts. Individual M. tuberculosis peptide targets were defined, segregating patients with TB from Africa versus those from South America., Conclusions: These data reveal the heterogeneity of epitope-dependent humoral immune responses in TB patients, partly due to geographical setting. These findings expose a new avenue for mining clinically meaningful vaccine targets, diagnostic tools, and the development of immunotherapeutics in TB disease management or prevention., (Copyright © 2017. Published by Elsevier Ltd.)

Tuberculosis (TB) remains a global emergency, with an estimated 9.6 million new TB cases worldwide reported in 2014. Twenty-eight percent of these cases were in the World Health Organization (WHO) Africa Region, where the annual case detection rate was 281 per 100000 population-more than double the global average of 133 per 100000. Of the 9.6 million people who developed TB, an estimated 1.2 million (12%) were HIV-positive, and the Africa Region accounted for 74% of these cases. Three million people with TB remain undiagnosed and untreated. Globally, an estimated 480000 had multidrug-resistant TB (MDR-TB). Whilst of the African countries, only South Africa has reported a high prevalence of MDR-TB, it is likely that all of Sub-Saharan Africa has an unreported high load of drug-resistant TB. Tragically, in 2014, only 48% of individuals diagnosed with MDR-TB had successful treatment and an estimated 190000 people died of MDR-TB. Of the global TB funding gap of US$ 0.8 billion, the largest funding gap was in the Africa Region, amounting to US$ 0.4 billion in 2015. The MDR-TB pandemic in particular now threatens to devastate entire regions and may fundamentally alter the life-expectancy and demographic profile of many countries in Sub-Saharan Africa. The theme designated for this year's World TB Day, March 24, 2016, is 'Unite to End TB'. From the Africa Region, there is an urgent need to seriously address the political, economic, and social factors that influence host-Mycobacterium tuberculosis interactions and result in disease. Recent political and funder initiatives that provide renewed hope for the alleviation of Africa's TB and TB/HIV problems are discussed., (Copyright © 2016. Published by Elsevier Ltd.)

Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480,000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. A wide range of candidate host-directed therapies are being developed to accelerate eradication of infection, prevent new drug resistance, and prevent permanent lung injury. As these drugs have been approved for other clinical indications, they are now ready for repurposing for tuberculosis in phase 2 clinical trials. We assess risks associated with evaluation of new treatment regimens, and highlight opportunities to advance tuberculosis research generally through regulatory innovation in MDR tuberculosis. Progress in tuberculosis-specific biomarkers (including culture conversion, PET and CT imaging, and gene expression profiles) can support this innovation. Several global initiatives now provide unique opportunities to tackle the tuberculosis epidemic through collaborative partnerships between high-income countries and middle-income and low-income countries for clinical trials training and research, allowing funders to coordinate several national and regional programmes for greatest overall effect., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The protective role of B cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen Mycobacterium tuberculosis. However, B-cell-mediated immune responses in tuberculosis have recently been revisited in the context of B-cell physiology and antigen presentation. We discuss in this review the diverse functions of B cells in tuberculosis, with a focus on their biological and clinical relevance to progression of active disease. We also present the peptide microarray platform as a promising strategy to discover unknown antigenic targets of M. tuberculosis that could contribute to the better understanding of epitope focus of the humoral immune system against M. tuberculosis., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid-based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Despite the availability of effective diagnostics and curative treatment regimens for tuberculosis, millions of people die each year of this disease. The steady global increase in the number of tuberculosis cases caused by multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis are of major concern, especially in light of the thin tuberculosis drug pipeline. New tuberculosis drugs are undergoing clinical evaluation, and renewed hope comes from fresh approaches to improve treatment outcomes using a range of adjunct host-directed cellular and repurposed drug therapies. Current efforts in developing second-generation and new rapid point-of-care diagnostic assays take advantage of recent genetic and molecular advances. Slow progress in the development of prophylactic and therapeutic vaccines requires increased funding for basic as well as translational research. Although major challenges remain, these can be overcome by cementing our resolve, raising advocacy, bolstering global funder investments, and leveraging more effective collaborations through equitable public-private partnerships., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.

Tuberculosis (TB) is an airborne infectious disease that kills almost two million individuals every year. Multidrug-resistant (MDR) TB is caused by strains of Mycobacterium tuberculosis (M. tb) resistant to isoniazid and rifampin, the backbone of first-line antitubercular treatment. MDR TB affects an estimated 500,000 new patients annually. Genetic analysis of drug-resistant MDR-TB showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. The need for new TB vaccines and faster diagnostics, as well as the development of new drugs, has recently been highlighted. The major problem in terms of current TB research and clinical demands is the increasing number of cases of extensively drug-resistant and 'treatment-refractory' TB. An emerging scenario of adjunct host-directed therapies is intended to target pulmonary TB where inflammatory processes can be deleterious and lead to immune exhaustion. 'Target-organ-saving' strategies may be warranted to prevent damage to infected tissues and achieve focused, clinically relevant and long-lasting anti-M. tb cellular immune responses. Candidates for such interventions may be biological agents or already approved drugs that can be 're-purposed' to interfere with biologically relevant cellular checkpoints. Here, we review current concepts of inflammation in TB disease and discuss candidate pathways for host-directed therapies to achieve better clinical outcomes., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Tuberculosis (TB) has been recognized as an important cause of morbidity and mortality in pregnancy for nearly a century, but research and efforts to roll out comprehensive TB screening and treatment in high-risk populations such as those with a high prevalence of HIV or other diseases of poverty, have lagged behind similar efforts to address HIV infection in pregnancy and the prevention of mother-to-child-transmission. Immunological changes during pregnancy make the activation of latent TB infection or de novo infection more likely than among non-pregnant women. TB treatment in pregnancy poses several problems that have been under-researched, such as contraindications to anti-TB and anti-HIV drugs and potential risks to the neonate, which are particularly important with respect to second-line TB treatment. Whilst congenital TB is thought to be rare, data from high HIV burden settings suggest this is not the case. There is a need for more studies screening for TB in neonates and observing outcomes, and testing preventative or curative actions. National tuberculosis control programmes (NTPs) should work with antenatal and national HIV programmes in high-burden populations to provide screening at antenatal clinics, or to establish functioning systems whereby pregnant women at high risk can drop in to routine NTP screening stations., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We review the history of TB in Sweden beginning in 1800, when 25% of mortality in Sweden was associated with TB. The Royal Family was involved in establishing dedicated sanatoria in Sweden to offer better diagnostics and clinical care. TB has declined in Sweden steadily, with some recent increases due to local spread of TB and challenging international and national socio-economical structures. Improved research and clinical knowledge is needed to diagnose and manage drug-susceptible as well as drug-resistant TB., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Anti-tuberculosis drug treatment is known to affect the number, phenotype, and effector functionality of antigen-specific T-cells. In order to objectively gauge Mycobacterium tuberculosis (MTB)-specific CD8+ T-cells at the single-cell level, we developed soluble major histocompatibility complex (MHC) class I multimers/peptide multimers, which allow analysis of antigen-specific T-cells without ex vivo manipulation or functional tests. We constructed 38 MHC class I multimers covering some of the most frequent MHC class I alleles (HLA-A*02:01, A*24:02, A*30:01, A*30:02, A*68:01, B*58:01, and C*07:01) pertinent to a South African or Zambian population, and presenting the following MTB-derived peptides: the early expressed secreted antigens TB10.4 (Rv0288), Ag85B (Rv1886c), and ESAT-6 (Rv3875), as well as intracellular enzymes, i.e., glycosyltransferase 1 (Rv2957), glycosyltransferase 2 (Rv2958c), and cyclopropane fatty acid synthase (Rv0447c). Anti-TB treatment appeared to impact on the frequency of multimer-positive CD8+ T-cells, with a general decrease after 6 months of therapy. Also, a reduction in the total central memory CD8+ T-cell frequencies, as well as the antigen-specific compartment in CD45RA-CCR7+ T-cells was observed. We discuss our findings on the basis of differential dynamics of MTB-specific T-cell frequencies, impact of MTB antigen load on T-cell phenotype, and antigen-specific T-cell responses in tuberculosis., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tuberculosis continues to kill 1·4 million people annually. During the past 5 years, an alarming increase in the number of patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has been noted, particularly in eastern Europe, Asia, and southern Africa. Treatment outcomes with available treatment regimens for drug-resistant tuberculosis are poor. Although substantial progress in drug development for tuberculosis has been made, scientific progress towards development of interventions for prevention and improvement of drug treatment outcomes have lagged behind. Innovative interventions are therefore needed to combat the growing pandemic of multidrug-resistant and extensively drug-resistant tuberculosis. Novel adjunct treatments are needed to accomplish improved cure rates for multidrug-resistant and extensively drug-resistant tuberculosis. A novel, safe, widely applicable, and more effective vaccine against tuberculosis is also desperately sought to achieve disease control. The quest to develop a universally protective vaccine for tuberculosis continues. So far, research and development of tuberculosis vaccines has resulted in almost 20 candidates at different stages of the clinical trial pipeline. Host-directed therapies are now being developed to refocus the anti-Mycobacterium tuberculosis-directed immune responses towards the host; a strategy that could be especially beneficial for patients with multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis. As we are running short of canonical tuberculosis drugs, more attention should be given to host-directed preventive and therapeutic intervention measures., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment., (Copyright © 2013 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd. All rights reserved.)

Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: A better understanding of the quality of cellular immune responses directed against molecularly defined targets will guide the development of TB diagnostics and identification of molecularly defined, clinically relevant M.tb vaccine candidates., Methods: Recombinant proteins (n = 8) and peptide pools (n = 14) from M. tuberculosis (M.tb) targets were used to compare cellular immune responses defined by IFN-γ and IL-17 production using a Whole Blood Assay (WBA) in a cohort of 148 individuals, i.e. patients with TB + (n = 38), TB- individuals with other pulmonary diseases (n = 81) and individuals exposed to TB without evidence of clinical TB (health care workers, n = 29)., Results: M.tb antigens Rv2958c (glycosyltransferase), Rv2962c (mycolyltransferase), Rv1886c (Ag85B), Rv3804c (Ag85A), and the PPE family member Rv3347c were frequently recognized, defined by IFN-γ production, in blood from healthy individuals exposed to M.tb (health care workers). A different recognition pattern was found for IL-17 production in blood from M.tb exposed individuals responding to TB10.4 (Rv0288), Ag85B (Rv1886c) and the PPE family members Rv0978c and Rv1917c., Conclusions: The pattern of immune target recognition is different in regard to IFN-γ and IL-17 production to defined molecular M.tb targets in PBMCs from individuals frequently exposed to M.tb. The data represent the first mapping of cellular immune responses against M.tb targets in TB patients from Honduras.

Frequently quoted statistics that tuberculosis and human immunodeficiency virus (HIV)/AIDS are the most important infectious causes of death in high-burden countries are based on clinical records, death certificates, and verbal autopsy studies. Causes of death ascertained through these methods are known to be grossly inaccurate. Most data from Africa on mortality and causes of death currently used by international agencies have come from verbal autopsy studies, which only provide inaccurate estimates of causes of death. Autopsy rates in most sub-Saharan African countries have declined over the years, and actual causes of deaths in the community and in hospitals in most sub-Saharan African countries remain unknown. The quality of cause-specific mortality statistics remains poor. The effect of various interventions to reduce mortality rates can only be evaluated accurately if cause-specific mortality data are available. Autopsy studies could have particular relevance to direct public health interventions, such as vaccination programs or preventive therapy, and could also allow for study of background levels of subclinical tuberculosis disease, Mycobacterium tuberculosis-HIV coinfection, and other infectious and noncommunicable diseases not yet clinically manifest. Autopsies performed soon after death may represent a unique opportunity to understand the pathogenesis of M. tuberculosis and the pathogenesis of early deaths after initiation of antiretroviral therapy. The few autopsies performed so far for research purposes have yielded invaluable information and insights into tuberculosis, HIV/AIDS, and other opportunistic infections. Accurate cause-specific mortality data are essential for prioritization of governmental and donor investments into health services to reduce morbidity and mortality from deadly infectious diseases such as tuberculosis and HIV/AIDS. There is an urgent need for reviving routine and research autopsies in sub-Saharan African countries.

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.

To prevent the global spread of tuberculosis (TB) infection, a novel vaccine that triggers potent and long-lived immunity is urgently required. A plasmid-based vaccine has been developed to enhance activation of major histocompatibility complex (MHC) class I-restricted CD8⁺ cytolytic T cells using a recombinant Bacille Calmette-Guérin (rBCG) expressing a pore-forming toxin and the Mycobacterium tuberculosis (Mtb) antigens Ag85A, 85B and TB10.4 followed by a booster with a nonreplicating adenovirus 35 (rAd35) vaccine vector encoding the same Mtb antigens. Here, the capacity of the rBCG/rAd35 vaccine to induce protective and biologically relevant CD8⁺ T-cell responses in a nonhuman primate model of TB was investigated. After prime/boost immunizations and challenge with virulent Mtb in rhesus macaques, quantification of immune responses at the single-cell level in cryopreserved tissue specimen from infected organs was performed using in situ computerized image analysis as a technological platform. Significantly elevated levels of CD3⁺ and CD8⁺ T cells as well as cells expressing interleukin (IL)-7, perforin and granulysin were found in TB lung lesions and spleen from rBCG/rAd35-vaccinated animals compared with BCG/rAd35-vaccinated or unvaccinated animals. The local increase in CD8⁺ cytolytic T cells correlated with reduced expression of the Mtb antigen MPT64 and also with prolonged survival after the challenge. Our observations suggest that a protective immune response in rBCG/rAd35-vaccinated nonhuman primates was associated with enhanced MHC class I antigen presentation and activation of CD8⁺ effector T-cell responses at the local site of infection in Mtb-challenged animals.

Background: There is a need for reliable markers to diagnose active and latent tuberculosis (TB). The interferon gamma release assays (IGRAs) are compared to the tuberculin skin test (TST) more specific, but cannot discriminate between recent or remote TB infection. Here the Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA), which quantifies expanded T-lymphoblasts by flow-cytometric analysis after long-term antigen stimulation of whole blood, is combined with cytokine/chemokine analysis in the supernatant by multiplex technology for diagnosis of Mycobacterium tuberculosis (Mtb) infection., Methods and Findings: Consecutive patients with suspected TB (n = 85), with microbiologically verified active pulmonary TB (n = 33), extra pulmonary TB (n = 21), clinical TB (n = 11), presumed latent TB infection (LTBI) (n = 23), patients negative for TB (n = 8) and 21 healthy controls were studied. Blood samples were analyzed with FASCIA and multiplex technology to determine and correlate proliferative responses and the value of 14 cytokines for diagnosis of Mtb infection: IFN- γ, IL-2, TNF-α, IP-10, IL-12, IL-6, IL-4, IL-5, IL-13, IL-17, MIP-1β, GM-CSF, IFN-α2 and IL-10. Cytokine levels for IFN-γ, IP-10, MIP-1β, IL-2, TNF-α, IL-6, IL-10, IL-13 and GM-CSF were significantly higher after stimulation with the Mtb specific antigens ESAT-6 and CFP-10 in patients with active TB compared to healthy controls (p<0.05) and correlated with proliferative responses. IP-10 was positive in all patients with verified TB, if using a combination of ESAT-6 and CFP-10 and was the only marker significantly more sensitive in detecting active TB then IFN-γ (p = 0.012). Cytokine responses in patients with active TB were more frequent and detected at higher levels than in patients with LTBI., Conclusions: IP-10 seems to be an important marker for diagnosis of active and latent TB. Patients with active TB and LTBI responded with similar cytokine profiles against TB antigens but proliferative and cytokine responses were generally higher in patients with active TB.

There is a large and growing worldwide need for reliable tests to diagnose active and latent tuberculosis (TB). Improved methodology for identifying individuals with true latent TB (LTBI), particularly those with a recent infection, would pave the way for targeted prophylactic treatment. The traditionally used tuberculin skin test (TST) is unspecific and impractical. Interferon gamma release assays (IGRA) are more specific than the TST but, like that test, cannot discriminate either between recent and remote TB infection, or between these and a mere immunological memory of previous TB infection. The Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) combines long-term antigen stimulation of whole blood and flow-cytometric analysis with quantification of the expanded T-lymphoblasts and can also be employed for measurement of cytokine responses., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Global eradication of tuberculosis (TB) depends on identification and treatment of all active TB cases and of the two billion people who are estimated to be latently infected with Mycobacterium tuberculosis. The past decade has seen a renaissance of scientific activities and funder investment into development of new TB drugs, diagnostics, biomarkers and vaccines. This viewpoint critically summarises the promising portfolio of more accurate TB diagnostics, new TB drugs and vaccines that have been endorsed by the STOP TB Partnership. Increasing numbers of Phase 2 and 3 drug, vaccine and diagnostic clinical trials in high-TB endemic areas reflect substantial progress towards attaining Global STOP-TB Partnership targets. Achievement of STOP-TB Partnership goals will crucially depend on political will and serious investment by funders and developing country governments into improving delivery of better health services and living conditions for their people. Long-term sustainability of any newer tools implemented at point of care is essential., (© 2011 Blackwell Publishing Ltd.)

Prisons have long been associated with rapid transmission of infectious diseases. The HIV/AIDS epidemic in sub-Saharan Africa (SSA) has fuelled the spread of TB and HIV in prisons. The poor living conditions and ineffective health services in prisons in SSA are a major breeding ground of Mycobacterium tuberculosis (Mtb). The spread of TB between prisoners, prison staff and visitors and the emergence of drug-resistant TB in prisons now poses a threat to control efforts of national TB programmes in SSA. Accurate data required to develop appropriate interventions to tackle the ominous problem of TB in African prisons are scanty and unreliable. The health of prisoners is by default a neglected political issue. This article reviews the available literature on TB and drug-resistant TB in prisons from SSA countries, discusses the risk factors for acquiring TB and highlights the priorities for further translational research in prisons. Ethical issues pertaining to research on captive African populations are discussed. Scientific, political and funder attention is required urgently to improve prison health services., (Copyright © 2010. Published by Elsevier Ltd.)

Background: Research suggests a positive association between coeliac disease and tuberculosis (TB), but that research has often been limited to in-patients and small sample size. We examined the relationship between TB and coeliac disease., Aim: To examine the association of TB and coeliac disease., Methods: We collected biopsy data from all pathology departments in Sweden (n=28) to identify individuals who were diagnosed with coeliac disease between 1969 and 2007 (Marsh 3: villous atrophy; n=29,026 unique individuals). Population-based sex- and age-matched controls were selected from the Total Population Register. Using Cox regression, we calculated hazard ratios (HRs) for TB from data in the Swedish national health registers., Results: Individuals with coeliac disease were at increased risk of TB (HR=2.0; 95% CI=1.3-3.0) (during follow-up, 31 individuals with coeliac disease and 74 reference individuals had a diagnosis of TB). The absolute risk of TB in patients with coeliac disease was 10/100,000 person-years with an excess risk of 5/100,000. Risk estimates were the highest in the first year. Restricting our outcome to a diagnosis of TB confirmed by (I) a record of TB medication (HR=2.9; 95% CI=1.0-8.3), (II) data in the National Surveillance System for Infectious Diseases in Sweden (HR=2.6; 95% CI=1.3-5.2) or (III) positive TB cultivation (HR=3.3; 95% CI=1.6-6.8) increased risk estimates. The positive association between coeliac disease and TB was also observed before the coeliac disease diagnosis (odds ratio=1.6; 95% CI=1.2-2.1)., Conclusion: We found a moderately increased risk of tuberculosis in patients with coeliac disease., (© 2011 Blackwell Publishing Ltd.)

Tuberculosis is a life-threatening infection worldwide. Despite improvements in therapy, it results in 2 million deaths and 9 million new cases annually. This study evaluated the use of the QuantiFERON-TB GOLD enzyme-linked immunosorbent assay in a high HIV/TB burden setting in an ARV clinic at the Tshwane District Hospital, South Africa. The sensitivity and specificity of the QF assay in the clinic were 30% (9/30) and 63% (19/30), respectively, when compared with the gold standard culture results. Analysis also suggested that the sensitivity of the QuantiFERON assay is determined by a limiting patient CD4 value between 150 and 200.

Both antigen-presenting cells and immune effector cells are required to effectively eradicate or contain Mycobacterium tuberculosis-infected cells. A variety of cytokines are involved to ensure productive "cross talk" between macrophages and T lymphocytes. For instance, infection of macrophages with mycobacteria leads to effective interleukin-7 (IL-7) and IL-15 secretion, and both cytokines are able to maintain strong cellular immune responses of alpha/beta and gamma/delta T cells. Here we show that either cytokine is able to enhance survival of M. tuberculosis-infected BALB/c mice significantly compared to application of IL-2, IL-4, or phosphate-buffered saline (as a control). Enhanced survival could be achieved only when IL-7 or IL-15 was delivered as a treatment (i.e., 3 weeks postinfection), not when it was administered at the time of infection. Increased survival of M. tuberculosis-infected animals was observed following passive transfer of spleen cells harvested from M. tuberculosis-infected, IL-7- or IL-15-treated animals, but not after transfer of spleen cells obtained from mice which received either cytokine alone. Histological examination revealed that IL-7 and IL-15 failed to significantly impact on the number and composition of granulomas formed or the bacterial load. Our data indicated that administration of IL-7 or IL-15 to M. tuberculosis-treated animals resulted in a qualitatively different cellular immune response in spleen cells as reflected by increased tumor necrosis factor alpha and decreased gamma interferon secretion in response to M. tuberculosis-infected antigen-presenting cells.

Challenged by scattered understanding of protective immunity to Mycobacterium tuberculosis (MTB), we have mapped peptide epitopes to human leukocyte antigen (HLA)-A*0101, A*0201, A*1101, A*2402, B*0702, B*0801 and B*1501 of the secreted mycobacterial antigen Ag85B, a vaccine candidate that may be associated with immune protection. Affinity (ED50) and half-life (t1/2, off-rate) analysis for individual peptide species on HLA-A and HLA-B molecules revealed binding ranges between 10−3 and 10−7 M. After selection of the best matches, major histocompatibility complex class I/peptide tetramer complexes were constructed to measure the CD8+ T-cell responses directly ex vivo in peripheral blood mononuclear cells (PBMC) derived from 57 patients with acute pulmonary tuberculosis. Three patterns of (allele-) specific CD8+ recognition were identified: (a). Focus on one dominant epitope with additional recognition of several subdominant T-cell epitopes (HLA-A*0301, A*2402, B*0801 and B*1501); (b). Co-dominant recognition of two distinct groups of peptides presented by HLA-B*0702; and (c). Diverse and broad recognition of peptides presented by HLA-A*0201. Peptides that bound with slow off-rates to class I alleles, that is HLA-A*0201, were associated with low frequency of CD8+ T cells in PBMCs from patients with tuberculosis. HLA-B alleles showed fast off-rates in peptide binding and restricted high numbers (up to 6%) of antigen-specific CD8+ T cells in patients with pulmonary tuberculosis.Genes and Immunity (2007) 8, 334–343; doi:10.1038/sj.gene.6364392; published online 12 April 2007 [ABSTRACT FROM AUTHOR]

A response from J.F. Ludvigsson and colleagues to a letter to the editor about their article related to tuberculosis (TB) in coeliac disease in the May 2011 issue is presented.