Summary Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability ...arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen–host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Tuberculosis is still one of the most important causes of death worldwide. The 2010 Lancet tuberculosis series provided a comprehensive overview of global control efforts and challenges. In this ...update we review recent progress. With improved control efforts, the world and most regions are on track to achieve the Millennium Development Goal of decreasing tuberculosis incidence by 2015, and the Stop TB Partnership target of halving 1990 mortality rates by 2015; the exception is Africa. Despite these advances, full scale-up of tuberculosis and HIV collaborative activities remains challenging and emerging drug-resistant tuberculosis is a major threat. Recognition of the effect that non-communicable diseases—such as smoking-related lung disease, diet-related diabetes mellitus, and alcohol and drug misuse—have on individual vulnerability, as well as the contribution of poor living conditions to community vulnerability, shows the need for multidisciplinary approaches. Several new diagnostic tests are being introduced in endemic countries and for the first time in 40 years a coordinated portfolio of promising new tuberculosis drugs exists. However, none of these advances offer easy solutions. Achievement of international tuberculosis control targets and maintenance of these gains needs optimum national health policies and services, with ongoing investment into new approaches and strategies. Despite growing funding in recent years, a serious shortfall persists. International and national financial uncertainty places gains at serious risk. Perseverance and renewed commitment are needed to achieve global control of tuberculosis, and ultimately, its elimination.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
3.
New vaccines for tuberculosis Kaufmann, Stefan HE, Prof; Hussey, Gregory, Prof; Lambert, Paul-Henri, MD
The Lancet (British edition),
06/2010, Volume:
375, Issue:
9731
Journal Article
Peer reviewed
Summary New vaccines are urgently needed if we want to reach the goal of substantially reducing the incidence of tuberculosis by 2050. Despite a steady increase in funding over the past decade, there ...is still a striking financial shortfall for vaccine research and development for tuberculosis. Yet, around ten vaccine candidates have left the laboratory stage and entered clinical trials. These vaccines are either aimed at replacing the present vaccine, BCG, or at enhancing immunity induced by BCG. However, these pre-exposure candidates are designed for prevention of disease and will therefore neither eradicate the pathogen, nor prevent stable infection. Long-term vaccination strategies need to target these more ambitious goals. Even though vaccine development will have a price, the return of investment will greatly exceed original costs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat ...the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. Methods In this prospective cohort study, we followed up healthy, South African adolescents aged 12–18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex quantitative real-time PCR (qRT-PCR), the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease. Findings Between July 6, 2005, and April 23, 2007, we enrolled 6363 participants from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in the 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill & Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union, and the South African Medical Research Council.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Summary The Millennium Development Goal target for tuberculosis control is to halt the spread of tuberculosis by 2015, and begin to reverse the worldwide incidence. After the introduction of standard ...control practices in 1995, 36 million people were cured and about 6 million deaths were averted. However, substantial scientific advances and innovative solutions are urgently needed together with creative new strategies. Strong international and national political commitment is essential. Urgent action is needed by national governments to fund their own programmes, and for the G8 countries and other donor governments and organisations to support governmental and non-governmental efforts. To foster the global need for urgent action to control the tuberculosis epidemic, The Lancet , in collaboration with the Stop TB Partnership, WHO, Global Fund to Fight AIDS, Tuberculosis and Malaria, and the experts participating in this Series, is launching The Lancet TB Observatory, which will assess and monitor progress in tuberculosis control and research, assess domestic and global financing, regularly disseminate information, and advocate for intensified efforts with stakeholders at all levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
7.
Neue Impfstoffe gegen Tuberkulose Kaufmann, Stefan H. E.
Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz,
2020/1, Volume:
63, Issue:
1
Journal Article
Peer reviewed
Open access
Zusammenfassung
Mit ca. 10 Mio. Erkrankungen und 1,5 Mio. Todesfällen im Jahr 2018 gehört die Tuberkulose (TB) weiterhin zu den bedrohlichsten Infektionskrankheiten weltweit. Dennoch erwartet die ...Weltgesundheitsorganisation (WHO), dass bis 2035 im Vergleich zu 2015 die Morbidität um 90 % und die Mortalität um 95 % gesenkt werden kann. Zwar stehen uns Diagnostika, Therapeutika und ein Impfstoff zur Verfügung, es besteht aber kein Zweifel, dass bessere Interventionsmaßnahmen benötigt werden, um dieses ehrgeizige Ziel zu erreichen. Der vorhandene Impfstoff Bacille Calmette-Guérin (BCG) schützt Kleinkinder teilweise gegen TB, ist aber weitgehend wirkungslos gegen Lungen-TB bei Jugendlichen und Erwachsenen. Die Möglichkeiten dieses Impfstoffs scheinen jedoch noch nicht voll ausgeschöpft zu sein. Zudem gibt es neue Impfstoffkandidaten, die sich derzeit in klinischer Überprüfung befinden.
Da ein Viertel der Menschheit mit
Mycobacterium tuberculosis
(
Mtb
) latent infiziert ist, müssen neue Impfstoffe nicht nur vor der Infektion (präexpositionell), sondern auch danach (postexpositionell) gegen die Erkrankung wirken. Als klinische Endpunkte werden Schutz vor Infektion, Schutz vor Erkrankung und Schutz vor Wiederauftreten (Rekurrenz) überprüft. Der Schutz gegen TB wird wesentlich von T‑Zell-Antworten getragen, weshalb in der Impfstoffentwicklung der Schwerpunkt hierauf gelegt wird. In der klinischen Überprüfung befinden sich Protein-Adjuvans-Impfstoffe, virale Vektoren, Tot- und Lebendimpfstoffe. Auch die Möglichkeit einer therapeutischen Impfung wird untersucht, um besonders bei multiresistenten TB-Fällen die Chemotherapie zu unterstützen. Es ist wahrscheinlich, dass ein einziger Impfstoff die verschiedenen Zielstellungen nicht erfüllen kann und unterschiedliche Impfstrategien benötigt werden.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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