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    [WHO Guidelines on Tuberculosis Infection Prevention and Control]. Christof Claudia,Nußbaumer-Streit Barbara,Gartlehner Gerald Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany)) BACKGROUND:Despite considerable progress in the fight against tuberculosis, it is still the most deadly bacterial infectious disease worldwide. Every year, up to 10 million people worldwide still die of tuberculosis. The World Health Assembly has set itself the goal of reducing the number of tuberculosis deaths by 90% and the number of new infections by 80% by 2030. Prevention and infection control measures in public health facilities and wherever the risk of transmission of the tuberculosis bacterium "Mycobacterium tuberculosis" is high are especially important. OBJECTIVE:The aim of the guideline is to provide updated and evidence-based recommendations for public health measures to prevent the spread of the tuberculosis bacterium in clinical settings and in tuberculosis management. METHODOLOGY:The World Health Organization (WHO) developed these recommendations according to the methods outlined in the WHO handbook for guideline development. This publication is a summary of the most important aspects of this guideline translated into German by members of the WHO Collaborating Centre at the Danube University Krems (Austria). RESULTS:This guideline takes into account the current evidence base and provides recommendations and comments on the implementation of tuberculosis prevention and control measures at the level of health care institutions and at the national level. 10.1055/a-1241-4321
    Global tuberculosis control: lessons learnt and future prospects. Lienhardt Christian,Glaziou Philippe,Uplekar Mukund,Lönnroth Knut,Getahun Haileyesus,Raviglione Mario Nature reviews. Microbiology Tuberculosis (TB) is an ancient disease, but not a disease of the past. After disappearing from the world public health agenda in the 1960s and 1970s, TB returned in the early 1990s for several reasons, including the emergence of the HIV/AIDS pandemic and increases in drug resistance. More than 100 years after the discovery of the tubercle bacillus by Robert Koch, what is the status of TB control worldwide? Here, we review the evolution of global TB control policies, including DOTS (directly observed therapy, short course) and the Stop TB Strategy, and assess whether the challenges and obstacles faced by the public health community worldwide in developing and implementing this strategy can aid future action towards the elimination of TB. 10.1038/nrmicro2797
    Tuberculosis control and elimination 2010-50: cure, care, and social development. Lönnroth Knut,Castro Kenneth G,Chakaya Jeremiah Muhwa,Chauhan Lakhbir Singh,Floyd Katherine,Glaziou Philippe,Raviglione Mario C Lancet (London, England) Rapid expansion of the standardised approach to tuberculosis diagnosis and treatment that is recommended by WHO allowed more than 36 million people to be cured between 1995 and 2008, averting up to 6 million deaths. Yet tuberculosis remains a severe global public health threat. There are more than 9 million new cases every year worldwide, and the incidence rate is falling at less than 1% per year. Although the overall target related to the Millennium Development Goals of halting and beginning to reverse the epidemic might have already been reached in 2004, the more important long-term elimination target set for 2050 will not be met with present strategies and instruments. Several key challenges persist. Many vulnerable people do not have access to affordable services of sufficient quality. Technologies for diagnosis, treatment, and prevention are old and inadequate. Multidrug-resistant tuberculosis is a serious threat in many settings. HIV/AIDS continues to fuel the tuberculosis epidemic, especially in Africa. Furthermore, other risk factors and underlying social determinants help to maintain tuberculosis in the community. Acceleration of the decline towards elimination of this disease will need invigorated actions in four broad areas: continued scale-up of early diagnosis and proper treatment for all forms of tuberculosis in line with the Stop TB Strategy; development and enforcement of bold health-system policies; establishment of links with the broader development agenda; and promotion and intensification of research towards innovations. 10.1016/S0140-6736(10)60483-7
    Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection. Rangaka Molebogeng X,Cavalcante Solange C,Marais Ben J,Thim Sok,Martinson Neil A,Swaminathan Soumya,Chaisson Richard E Lancet (London, England) The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes. 10.1016/S0140-6736(15)00323-2
    Latent tuberculosis infection: the final frontier of tuberculosis elimination in the USA. LoBue Philip A,Mermin Jonathan H The Lancet. Infectious diseases Since 1989, the USA has been pursuing the goal of tuberculosis elimination. After substantial progress during the past two decades, the rate of tuberculosis cases in the USA each year has now levelled off and remains well above the elimination threshold. Both epidemiological data and modelling underline the necessity of addressing latent tuberculosis infection if further progress is to be made in eliminating the disease. In this Personal View we explore next steps towards elimination. Given the estimated prevalence of latent tuberculosis infection, compared with the limited testing and treatment that currently occur, a major new effort is required. This effort should consist of a surveillance system or registry to monitor progress, scale-up of targeted testing for latent tuberculosis infection in at-risk populations, scale-up of short-course treatment regimens, engagement of affected communities and medical providers who serve those communities, and increased public health staffing for implementation and oversight. Such an effort would benefit greatly from the development of new tools, such as tests that better indicate reactivation risk, and even shorter latent tuberculosis infection treatment regimens than currently exist. 10.1016/S1473-3099(17)30248-7
    Tuberculosis: epidemiology and control. Sulis Giorgia,Roggi Alberto,Matteelli Alberto,Raviglione Mario C Mediterranean journal of hematology and infectious diseases TUBERCULOSIS (TB) IS A MAJOR PUBLIC HEALTH CONCERN WORLDWIDE:despite a regular, although slow, decline in incidence over the last decade, as many as 8.6 million new cases and 1.3 million deaths were estimated to have occurred in 2012. TB is by all means a poverty-related disease, mainly affecting the most vulnerable populations in the poorest countries. The presence of multidrug-resistant strains of M. tuberculosis in most countries, with somewhere prevalence is high, is among the major challenges for TB control, which may hinder recent achievements especially in some settings. Early TB case detection especially in resource-constrained settings and in marginalized groups remains a challenge, and about 3 million people are estimated to remain undiagnosed or not notified and untreated. The World Health Organization (WHO) has recently launched a new global TB strategy for the "post-2015 era" aimed at "ending the global TB epidemic" by 2035. This strategy is based on the three pillars that emphasize patient-centred TB care and prevention, bold policies and supportive systems, and intensified research and innovation. This paper aims to provide an overview of the global TB epidemiology as well as of the main challenges that must be faced to eliminate the disease as a public health problem everywhere. 10.4084/MJHID.2014.070
    Transmission of drug-resistant tuberculosis in HIV-endemic settings. Khan Palwasha Y,Yates Tom A,Osman Muhammad,Warren Robin M,van der Heijden Yuri,Padayatchi Nesri,Nardell Edward A,Moore David,Mathema Barun,Gandhi Neel,Eldholm Vegard,Dheda Keertan,Hesseling Anneke C,Mizrahi Valerie,Rustomjee Roxana,Pym Alexander The Lancet. Infectious diseases The emergence and expansion of the multidrug-resistant tuberculosis epidemic is a threat to the global control of tuberculosis. Multidrug-resistant tuberculosis is the result of the selection of resistance-conferring mutations during inadequate antituberculosis treatment. However, HIV has a profound effect on the natural history of tuberculosis, manifesting in an increased rate of disease progression, leading to increased transmission and amplification of multidrug-resistant tuberculosis. Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis transmission. These interventions should include a combination of rapid molecular diagnostics and improved chemotherapy to shorten the duration of infectiousness, implementation of infection control measures, and active screening of multidrug-resistant tuberculosis contacts, with prophylactic regimens for individuals without evidence of disease. Development and improvement of the efficacy of interventions will require a greater understanding of the factors affecting the transmission of multidrug-resistant tuberculosis in HIV-endemic settings, including population-based molecular epidemiology studies. In this Series article, we review what we know about the transmission of multidrug-resistant tuberculosis in settings with high burdens of HIV and define the research priorities required to develop more effective interventions, to diminish ongoing transmission and the amplification of drug resistance. 10.1016/S1473-3099(18)30537-1
    Tuberculosis susceptibility and protection in children. Basu Roy Robindra,Whittaker Elizabeth,Seddon James A,Kampmann Beate The Lancet. Infectious diseases Children represent both a clinically important population susceptible to tuberculosis and a key group in whom to study intrinsic and vaccine-induced mechanisms of protection. After exposure to Mycobacterium tuberculosis, children aged under 5 years are at high risk of progressing first to tuberculosis infection, then to tuberculosis disease and possibly disseminated forms of tuberculosis, with accompanying high risks of morbidity and mortality. Children aged 5-10 years are somewhat protected, until risk increases again in adolescence. Furthermore, neonatal BCG programmes show the clearest proven benefit of vaccination against tuberculosis. Case-control comparisons from key cohorts, which recruited more than 15 000 children and adolescents in total, have identified that the ratio of monocytes to lymphocytes, activated CD4 T cell count, and a blood RNA signature could be correlates of risk for developing tuberculosis. Further studies of protected and susceptible populations are necessary to guide development of novel tuberculosis vaccines that could facilitate the achievement of WHO's goal to eliminate deaths from tuberculosis in childhood. 10.1016/S1473-3099(18)30157-9
    Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. Drain Paul K,Bajema Kristina L,Dowdy David,Dheda Keertan,Naidoo Kogieleum,Schumacher Samuel G,Ma Shuyi,Meermeier Erin,Lewinsohn David M,Sherman David R Clinical microbiology reviews Tuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium. 10.1128/CMR.00021-18
    Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design. Ernst Joel D Cell host & microbe Tuberculosis (TB) is a large global health problem, in part because of the long period of coevolution of the pathogen, Mycobacterium tuberculosis, and its human host. A major factor that sustains the global epidemic of TB is the lack of a sufficiently effective vaccine. While basic mechanisms of immunity that protect against TB have been identified, attempts to improve immunity to TB by vaccination have been disappointing. This Review discusses the mechanisms used by M. tuberculosis to evade innate and adaptive immunity and that likely limit the efficacy of vaccines developed to date. Despite multiple mechanisms of immune evasion, recent trials have indicated that effective TB vaccines remain an attainable goal. This Review discusses how knowledge from other systems can inform improvements on current vaccine approaches. 10.1016/j.chom.2018.06.004
    Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection. Simmons Jason D,Stein Catherine M,Seshadri Chetan,Campo Monica,Alter Galit,Fortune Sarah,Schurr Erwin,Wallis Robert S,Churchyard Gavin,Mayanja-Kizza Harriet,Boom W Henry,Hawn Thomas R Nature reviews. Immunology Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies. 10.1038/s41577-018-0025-3
    Antibodies and tuberculosis: finally coming of age? Li Hao,Javid Babak Nature reviews. Immunology Are antibodies important for protection against tuberculosis? The jury has been out for more than 100 years. B cell depletion in experimental Mycobacterium tuberculosis infection failed to identify a major role for these cells in immunity to tuberculosis. However, recent identification of naturally occurring antibodies in humans that are protective during M. tuberculosis infection has reignited the debate. Here, we discuss the evidence for a protective role for antibodies in tuberculosis and consider the feasibility of designing novel tuberculosis vaccines targeting humoral immunity. 10.1038/s41577-018-0028-0
    The global tuberculosis epidemic and progress in care, prevention, and research: an overview in year 3 of the End TB era. Floyd Katherine,Glaziou Philippe,Zumla Alimuddin,Raviglione Mario The Lancet. Respiratory medicine Tuberculosis is the number one cause of death from infectious disease globally and drug-resistant forms of the disease are a major risk to global health security. On the occasion of World Tuberculosis Day (March 24, 2018), we provide an up-to-date review of the status of the tuberculosis epidemic, recommended diagnostics, drug treatments and vaccines, progress in delivery of care and prevention, progress in research and development, and actions needed to accelerate progress. This Review is presented in the context of the UN Sustainable Development Goals and WHO's End TB Strategy, which share the aim of ending the global tuberculosis epidemic. In 2016, globally there were an estimated 10·4 million new cases of tuberculosis, and 600 000 new cases with resistance to rifampicin (the most powerful first-line drug). All countries and age groups are affected by tuberculosis, but most cases (90%) in 2016 were in adults, and almost two-thirds were accounted for by seven countries: India, Indonesia, China, Philippines, Pakistan, South Africa, and Nigeria. The sex ratio (male to female) was 1·9 and 10% of patients with newly diagnosed tuberculosis were also HIV-positive. There were 1·7 million deaths from tuberculosis in 2016, including 0·4 million deaths among people co-infected with HIV (officially classified as deaths caused by HIV/AIDS). Progress in care and prevention means that the global mortality rate (deaths per 100 000 people per year) is decreasing by 3·4% per year and incidence (new cases per 100 000 people per year) is decreasing by 1·9% per year. From 2000 to 2016, the annual global number of tuberculosis deaths decreased by 24% and the mortality rate declined by 37%. Worldwide, an estimated 53 million deaths were averted through successful treatment. Nonetheless, major gaps in care and prevention remain. For example, the 6·3 million new cases of tuberculosis reported globally in 2016 represented only 61% of the estimated incidence; only one in five of the estimated number of people with drug-resistant tuberculosis was enrolled in treatment. Pipelines for new diagnostics, drugs, and vaccines are progressing, but slowly. Actions needed to accelerate progress towards global milestones and targets for reductions in the burden of tuberculosis disease set for 2020, 2025, 2030, and 2035 include closing coverage gaps in testing, reporting of cases, and overall access to health care, especially in countries that account for the largest share of the global gap; multisectoral efforts to reduce prevalence of major risk factors for infection and disease; and increased investment in research and development. 10.1016/S2213-2600(18)30057-2
    Tuberculosis: advances and challenges in development of new diagnostics and biomarkers. Walzl Gerhard,McNerney Ruth,du Plessis Nelita,Bates Matthew,McHugh Timothy D,Chegou Novel N,Zumla Alimuddin The Lancet. Infectious diseases Tuberculosis remains the leading cause of death from an infectious disease worldwide. Early and accurate diagnosis and detection of drug-sensitive and drug-resistant tuberculosis is essential for achieving global tuberculosis control. Despite the introduction of the Xpert MTB/RIF assay as the first-line rapid tuberculosis diagnostic test, the gap between global estimates of incidence and new case notifications is 4·1 million people. More accurate, rapid, and cost-effective screening tests are needed to improve case detection. Diagnosis of extrapulmonary tuberculosis and tuberculosis in children, people living with HIV, and pregnant women remains particularly problematic. The diagnostic molecular technology landscape has continued to expand, including the development of tests for resistance to several antituberculosis drugs. Biomarkers are urgently needed to indicate progression from latent infection to clinical disease, to predict risk of reactivation after cure, and to provide accurate endpoints for drug and vaccine trials. Sophisticated bioinformatic computational tools and systems biology approaches are being applied to the discovery and validation of biomarkers, with substantial progress taking place. New data have been generated from the study of T-cell responses and T-cell function, serological studies, flow cytometric-based assays, and protein and gene expression studies. Alternative diagnostic strategies under investigation as potential screening and triaging tools include non-sputum-based detection with breath-based tests and automated digital radiography. We review developments and key achievements in the search for new tuberculosis diagnostics and biomarkers. We highlight gaps and challenges in evaluation and rollout of new diagnostics and biomarkers, and prioritise areas needing further investment, including impact assessment and cost-benefit studies. 10.1016/S1473-3099(18)30111-7
    Ecology and evolution of Mycobacterium tuberculosis. Gagneux Sebastien Nature reviews. Microbiology Tuberculosis (TB) is the number one cause of human death due to an infectious disease. The causative agents of TB are a group of closely related bacteria known as the Mycobacterium tuberculosis complex (MTBC). As the MTBC exhibits a clonal population structure with low DNA sequence diversity, methods (such as multilocus sequence typing) that are applied to more genetically diverse bacteria are uninformative, and much of the ecology and evolution of the MTBC has therefore remained unknown. Owing to recent advances in whole-genome sequencing and analyses of large collections of MTBC clinical isolates from around the world, many new insights have been gained, including a better understanding of the origin of the MTBC as an obligate pathogen and its molecular evolution and population genetic characteristics both within and between hosts, as well as many aspects related to antibiotic resistance. The purpose of this Review is to summarize these recent discoveries and discuss their relevance for developing better tools and strategies to control TB. 10.1038/nrmicro.2018.8
    Tuberculosis. Furin Jennifer,Cox Helen,Pai Madhukar Lancet (London, England) Tuberculosis remains the leading cause of death from an infectious disease among adults worldwide, with more than 10 million people becoming newly sick from tuberculosis each year. Advances in diagnosis, including the use of rapid molecular testing and whole-genome sequencing in both sputum and non-sputum samples, could change this situation. Although little has changed in the treatment of drug-susceptible tuberculosis, data on increased efficacy with new and repurposed drugs have led WHO to recommend all-oral therapy for drug-resistant tuberculosis for the first time ever in 2018. Studies have shown that shorter latent tuberculosis prevention regimens containing rifampicin or rifapentine are as effective as longer, isoniazid-based regimens, and there is a promising vaccine candidate to prevent the progression of infection to the disease. But new tools alone are not sufficient. Advances must be made in providing high-quality, people-centred care for tuberculosis. Renewed political will, coupled with improved access to quality care, could relegate the morbidity, mortality, and stigma long associated with tuberculosis, to the past. 10.1016/S0140-6736(19)30308-3
    Building a tuberculosis-free world: The Lancet Commission on tuberculosis. Reid Michael J A,Arinaminpathy Nimalan,Bloom Amy,Bloom Barry R,Boehme Catharina,Chaisson Richard,Chin Daniel P,Churchyard Gavin,Cox Helen,Ditiu Lucica,Dybul Mark,Farrar Jeremy,Fauci Anthony S,Fekadu Endalkachew,Fujiwara Paula I,Hallett Timothy B,Hanson Christy L,Harrington Mark,Herbert Nick,Hopewell Philip C,Ikeda Chieko,Jamison Dean T,Khan Aamir J,Koek Irene,Krishnan Nalini,Motsoaledi Aaron,Pai Madhukar,Raviglione Mario C,Sharman Almaz,Small Peter M,Swaminathan Soumya,Temesgen Zelalem,Vassall Anna,Venkatesan Nandita,van Weezenbeek Kitty,Yamey Gavin,Agins Bruce D,Alexandru Sofia,Andrews Jason R,Beyeler Naomi,Bivol Stela,Brigden Grania,Cattamanchi Adithya,Cazabon Danielle,Crudu Valeriu,Daftary Amrita,Dewan Puneet,Doepel Laurie K,Eisinger Robert W,Fan Victoria,Fewer Sara,Furin Jennifer,Goldhaber-Fiebert Jeremy D,Gomez Gabriela B,Graham Stephen M,Gupta Devesh,Kamene Maureen,Khaparde Sunil,Mailu Eunice W,Masini Enos O,McHugh Lorrie,Mitchell Ellen,Moon Suerie,Osberg Michael,Pande Tripti,Prince Lea,Rade Kirankumar,Rao Raghuram,Remme Michelle,Seddon James A,Selwyn Casey,Shete Priya,Sachdeva Kuldeep S,Stallworthy Guy,Vesga Juan F,Vilc Valentina,Goosby Eric P Lancet (London, England) 10.1016/S0140-6736(19)30024-8
    The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda. Naidoo Charissa C,Nyawo Georgina R,Wu Benjamin G,Walzl Gerhard,Warren Robin M,Segal Leopoldo N,Theron Grant The Lancet. Respiratory medicine The diverse microbial communities within our bodies produce metabolites that modulate host immune responses. Even the microbiome at distal sites has an important function in respiratory health. However, the clinical importance of the microbiome in tuberculosis, the biggest infectious cause of death worldwide, is only starting to be understood. Here, we critically review research on the microbiome's association with pulmonary tuberculosis. The research indicates five main points: (1) susceptibility to infection and progression to active tuberculosis is altered by gut Helicobacter co-infection, (2) aerosol Mycobacterium tuberculosis infection changes the gut microbiota, (3) oral anaerobes in the lung make metabolites that decrease pulmonary immunity and predict progression, (4) the increased susceptibility to reinfection of patients who have previously been treated for tuberculosis is likely due to the depletion of T-cell epitopes on commensal gut non-tuberculosis mycobacteria, and (5) the prolonged antibiotic treatment required for cure of tuberculosis has long-term detrimental effects on the microbiome. We highlight knowledge gaps, considerations for addressing these knowledge gaps, and describe potential targets for modifying the microbiome to control tuberculosis. 10.1016/S2213-2600(18)30501-0
    Harnessing Biological Insight to Accelerate Tuberculosis Drug Discovery. de Wet Timothy J,Warner Digby F,Mizrahi Valerie Accounts of chemical research Tuberculosis (TB) is the leading cause of mortality globally resulting from an infectious disease, killing almost 1.6 million people annually and accounting for approximately 30% of deaths attributed to antimicrobial resistance (AMR). This despite the widespread administration of a neonatal vaccine, and the availability of an effective combination drug therapy against the causative agent, (Mtb). Instead, TB prevalence worldwide is characterized by high-burden regions in which co-epidemics, such as HIV, and social and economic factors, undermine efforts to control TB. These elements additionally ensure conditions that favor the emergence of drug-resistant Mtb strains, which further threaten prospects for future TB control. To address this challenge, significant resources have been invested in developing a TB drug pipeline, an initiative given impetus by the recent regulatory approval of two new anti-TB drugs. However, both drugs have been reserved for drug-resistant disease, and the seeming inevitability of new resistance plus the recognized need to shorten the duration of chemotherapy demands continual replenishment of the pipeline with high-quality "hits" with novel mechanisms of action. This represents a massive challenge, which has been undermined by key gaps in our understanding of Mtb physiology and metabolism, especially during host infection. Whereas drug discovery for other bacterial infections can rely on predictive in vitro assays and animal models, for Mtb, inherent metabolic flexibility and uncertainties about the nutrients available to infecting bacilli in different host (micro)environments instead requires educated predictions or demonstrations of efficacy in animal models of arguable relevance to human disease. Even microbiological methods for enumeration of viable mycobacterial cells are fraught with complication. Our research has focused on elucidating those aspects of mycobacterial metabolism that contribute to the robustness of the bacillus to host immunological defenses and applied antibiotics and that, possibly, drive the emergence of drug resistance. This work has identified a handful of metabolic pathways that appear vulnerable to antibiotic targeting. Those highlighted, here, include the inter-related functions of pantothenate and coenzyme A biosynthesis and recycling and nucleotide metabolism-the last of which reinforces our view that DNA metabolism constitutes an under-explored area for new TB drug development. Although nonessential functions have traditionally been deprioritized for antibiotic development, a common theme emerging from this work is that these very functions might represent attractive targets because of the potential to cripple mechanisms critical to bacillary survival under stress (for example, the Rel-dependent stringent response) or to adaptability under unfavorable, potentially lethal, conditions including antibiotic therapy (for example, DnaE2-dependent SOS mutagenesis). The bar, however, is high: demonstrating convincingly the likely efficacy of this strategy will require innovative models of human TB disease. In the concluding section, we focus on the need for improved techniques to elucidate mycobacterial metabolism during infection and its impact on disease outcomes. Here, we argue that developments in other fields suggest the potential to break through this barrier by harnessing chemical-biology approaches in tandem with the most advanced technologies. As researchers based in a high-burden country, we are impelled to continue participating in this important endeavor. 10.1021/acs.accounts.9b00275
    Tuberculosis Vaccine Development: Progress in Clinical Evaluation. Sable Suraj B,Posey James E,Scriba Thomas J Clinical microbiology reviews Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the bacille Calmette-Guérin (BCG) vaccine. A safer and more effective vaccine than BCG is urgently required. More than a dozen TB vaccine candidates are under active evaluation in clinical trials aimed to prevent infection, disease, and recurrence. After decades of extensive research, renewed promise of an effective vaccine against this ancient airborne disease has recently emerged. In two innovative phase 2b vaccine clinical trials, one for the prevention of infection in healthy adolescents and another for the prevention of TB disease in -infected adults, efficacy signals were observed. These breakthroughs, based on the greatly expanded knowledge of the infection spectrum, immunology of TB, and vaccine platforms, have reinvigorated the TB vaccine field. Here, we review our current understanding of natural immunity to TB, limitations in BCG immunity that are guiding vaccinologists to design novel TB vaccine candidates and concepts, and the desired attributes of a modern TB vaccine. We provide an overview of the progress of TB vaccine candidates in clinical evaluation, perspectives on the challenges faced by current vaccine concepts, and potential avenues to build on recent successes and accelerate the TB vaccine research-and-development trajectory. 10.1128/CMR.00100-19
    Tuberculosis, HIV, and viral hepatitis diagnostics in eastern Europe and central Asia: high time for integrated and people-centred services. Dara Masoud,Ehsani Soudeh,Mozalevskis Antons,Vovc Elena,Simões Daniel,Avellon Calvo Ana,Casabona I Barbarà Jordi,Chokoshvili Otar,Felker Irina,Hoffner Sven,Kalmambetova Gulmira,Noroc Ecatarina,Shubladze Natalia,Skrahina Alena,Tahirli Rasim,Tsertsvadze Tengiz,Drobniewski Francis The Lancet. Infectious diseases Globally, high rates (and in the WHO European region an increasing prevalence) of co-infection with tuberculosis and HIV and HIV and hepatitis C virus exist. In eastern European and central Asian countries, the tuberculosis, HIV, and viral hepatitis programmes, including diagnostic services, are separate vertical structures. In this Personal View, we consider underlying reasons for the poor integration for these diseases, particularly in the WHO European region, and how to address this with an initial focus on diagnostic services. In part, this low integration has reflected different diagnostic development histories, global funding sources, and sample types used for diagnosis (eg, typically sputum for tuberculosis and blood for HIV and hepatitis C). Cooperation between services improved as patients with tuberculosis needed routine testing for HIV and vice versa, but financial, infection control, and logistical barriers remain. Multidisease diagnostic platforms exist, but to be used optimally, appropriate staff training and sensible understanding of different laboratory and infection control risks needs rapid implementation. Technically these ideas are all feasible. Poor coordination between these vertical systems remains unhelpful. There is a need to increase political and operational integration of diagnostic and treatment services and bring them closer to patients. 10.1016/S1473-3099(19)30524-9
    The status of tuberculosis vaccine development. Schrager Lewis K,Vekemens Johan,Drager Nick,Lewinsohn David M,Olesen Ole F The Lancet. Infectious diseases Tuberculosis represents the leading global cause of death from an infectious agent. Controlling the tuberculosis epidemic thus represents an urgent global public health priority. Epidemiological modelling suggests that, although drug treatments for tuberculosis continue to improve, WHO timelines to control the spread of the disease require a new vaccine capable of preventing tuberculosis, particularly in adolescents and adults. The spread of strains resistant to multiple drugs adds additional urgency to the vaccine development effort yet attempts to develop new vaccines with wider applicability and better, longer-lasting efficacy than BCG-the only tuberculosis vaccine licensed for use globally-have proven challenging. Results from clinical efficacy trials, particularly a completed, phase 2b trial for preventing tuberculosis disease in people infected with Mycobacterium tuberculosis using the adjuvanted protein subunit vaccine M72/AS01E give hope. We review the current status of tuberculosis vaccine candidates and outline the diversified vaccine development that are underway. 10.1016/S1473-3099(19)30625-5
    Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health. Fries Chelsea N,Curvino Elizabeth J,Chen Jui-Lin,Permar Sallie R,Fouda Genevieve G,Collier Joel H Nature nanotechnology Despite the overwhelming success of vaccines in preventing infectious diseases, there remain numerous globally devastating diseases without fully protective vaccines, particularly human immunodeficiency virus (HIV), malaria and tuberculosis. Nanotechnology approaches are being developed both to design new vaccines against these diseases as well as to facilitate their global implementation. The reasons why a given pathogen may present difficulties for vaccine design are unique and tied to the co-evolutionary history of the pathogen and humans, but there are common challenges that nanotechnology is beginning to help address. In each case, a successful vaccine will need to raise immune responses that differ from the immune responses raised by normal infection. Nanomaterials, with their defined compositions, commonly modular construction, and length scales allowing the engagement of key immune pathways, collectively facilitate the iterative design process necessary to identify such protective immune responses and achieve them reliably. Nanomaterials also provide strategies for engineering the trafficking and delivery of vaccine components to key immune cells and lymphoid tissues, and they can be highly multivalent, improving their engagement with the immune system. This Review will discuss these aspects along with recent nanomaterial advances towards vaccines against infectious disease, with a particular emphasis on HIV/AIDS, malaria and tuberculosis. 10.1038/s41565-020-0739-9
    The escalating tuberculosis crisis in central and South American prisons. Walter Katharine S,Martinez Leonardo,Arakaki-Sanchez Denise,Sequera Victor G,Estigarribia Sanabria G,Cohen Ted,Ko Albert I,García-Basteiro Alberto L,Rueda Zulma Vanessa,López-Olarte Rafael A,Espinal Marcos A,Croda Julio,Andrews Jason R Lancet (London, England) In the past decade, tuberculosis incidence has declined in much of the world, but has risen in central and South America. It is not yet clear what is driving this reversal of progress in tuberculosis control. Since 2000, the incarcerated population in central and South America has grown by 206%, the greatest increase in the world. Over the same period, notified tuberculosis cases among the incarcerated population (hereinafter termed persons deprived of their liberty [PDL], following the Inter-American Commission on Human Rights) have risen by 269%. In both central and South America, the rise of disease among PDL more than offsets tuberculosis control gains in the general population. Tuberculosis is increasingly concentrated among PDL; currently, 11% of all notified tuberculosis cases in central and South America occur among PDL who comprise less than 1% of the population. The extraordinarily high risk of acquiring tuberculosis within prisons creates a health and human rights crisis for PDL that also undermines wider tuberculosis control efforts. Controlling tuberculosis in this region will require countries to take urgent measures to prioritise the health of PDL. 10.1016/S0140-6736(20)32578-2
    100 years of Mycobacterium bovis bacille Calmette-Guérin. Lange Christoph,Aaby Peter,Behr Marcel A,Donald Peter R,Kaufmann Stefan H E,Netea Mihai G,Mandalakas Anna M The Lancet. Infectious diseases Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination. 10.1016/S1473-3099(21)00403-5
    Latent Tuberculosis Infection. The New England journal of medicine 10.1056/NEJMcp2108501
    Accelerating research and development of new vaccines against tuberculosis: a global roadmap. The Lancet. Infectious diseases To eliminate tuberculosis globally, a new, effective, and affordable vaccine is urgently needed, particularly for use in adults and adolescents in low-income and middle-income countries. We have created a roadmap that lists the actions needed to accelerate tuberculosis vaccine research and development using a participatory process. The vaccine pipeline needs more diverse immunological approaches, antigens, and platforms. Clinical development can be accelerated by validated preclinical models, agreed laboratory correlates of protection, efficient trial designs, and validated endpoints. Determining the public health impact of new tuberculosis vaccines requires understanding of a country's demand for a new tuberculosis vaccine, how to integrate vaccine implementation with ongoing tuberculosis prevention efforts, cost, and national and global demand to stimulate vaccine production. Investments in tuberculosis vaccine research and development need to be increased, with more diversity of funding sources and coordination between these funders. Open science is important to enhance the efficiency of tuberculosis vaccine research and development including early and freely available publication of study findings and effective mechanisms for sharing datasets and specimens. There is a need for increased engagement of industry vaccine developers, for increased political commitment for new tuberculosis vaccines, and to address stigma and vaccine hesitancy. The unprecedented speed by which COVID-19 vaccines have been developed and introduced provides important insight for tuberculosis vaccine research and development. 10.1016/S1473-3099(21)00810-0
    The intersecting pandemics of tuberculosis and COVID-19: population-level and patient-level impact, clinical presentation, and corrective interventions. The Lancet. Respiratory medicine The global tuberculosis burden remains substantial, with more than 10 million people newly ill per year. Nevertheless, tuberculosis incidence has slowly declined over the past decade, and mortality has decreased by almost a third in tandem. This positive trend was abruptly reversed by the COVID-19 pandemic, which in many parts of the world has resulted in a substantial reduction in tuberculosis testing and case notifications, with an associated increase in mortality, taking global tuberculosis control back by roughly 10 years. Here, we consider points of intersection between the tuberculosis and COVID-19 pandemics, identifying wide-ranging approaches that could be taken to reverse the devastating effects of COVID-19 on tuberculosis control. We review the impact of COVID-19 at the population level on tuberculosis case detection, morbidity and mortality, and the patient-level impact, including susceptibility to disease, clinical presentation, diagnosis, management, and prognosis. We propose strategies to reverse or mitigate the deleterious effects of COVID-19 and restore tuberculosis services. Finally, we highlight research priorities and major challenges and controversies that need to be addressed to restore and advance the global response to tuberculosis. 10.1016/S2213-2600(22)00092-3