The Experts below are selected from a list of 10437 Experts worldwide ranked by ideXlab platform
Helen Mcshane - One of the best experts on this subject based on the ideXlab platform.
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mucosal delivery of Tuberculosis Vaccines a review of current approaches and challenges
Expert Review of Vaccines, 2019Co-Authors: Elena Stylianou, Matthew J Paul, Rajko Reljic, Helen McshaneAbstract:Introduction: Tuberculosis (TB) remains a major health threat and it is now clear that the current vaccine, BCG, is unable to arrest the global TB epidemic. A new vaccine is needed to either replace or boost BCG so that a better level of protection could be achieved. The route of entry of Mycobacterium Tuberculosis, the causative organism, is via inhalation making TB primarily a respiratory disease. There is therefore good reason to hypothesize that a mucosally delivered vaccine against TB could be more effective than one delivered via the systemic route.Areas covered: This review summarizes the progress that has been made in the area of TB mucosal Vaccines in the last few years. It highlights some of the strengths and shortcomings of the published evidence and aims to discuss immunological and practical considerations in the development of mucosal Vaccines.Expert opinion: There is a growing body of evidence that the mucosal approach to vaccination against TB is feasible and should be pursued. However, further key studies are necessary to both improve our understanding of the protective immune mechanisms operating in the mucosa and the technical aspects of aerosolized delivery, before such a vaccine could become a feasible, deployable strategy.
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Insights and challenges in Tuberculosis vaccine development.
The Lancet. Respiratory medicine, 2019Co-Authors: Helen McshaneAbstract:Tuberculosis kills more people than any other pathogen and the need for a universally effective vaccine has never been greater. An effective vaccine will be a key tool in achieving the targets set by WHO in the End TB Strategy. Tuberculosis vaccine development is difficult and slow. Substantial progress has been made in research and development of Tuberculosis Vaccines in the past 20 years, and two clinical trial results from 2018 provide reason for optimism. However, many challenges to the successful licensure and deployment of an effective Tuberculosis vaccine remain. The development of new tools for vaccine evaluation might facilitate these processes, and continued collaborative working and sustained funding will be essential.
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tbvac2020 advancing Tuberculosis Vaccines from discovery to clinical development
Frontiers in Immunology, 2017Co-Authors: Stefan H. E. Kaufmann, Helen Mcshane, Hazel M Dockrell, Tom H M Ottenhoff, Nick Drager, Olivier Neyrolles, Brij Patel, Danielle Roordink, Francois Spertini, Steffen StengerAbstract:TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel Tuberculosis (TB) Vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel Vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel Vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal.
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Intracellular Cytokine Staining and Flow Cytometry: Considerations for Application in Clinical Trials of Novel Tuberculosis Vaccines.
PloS one, 2015Co-Authors: Steven G. Smith, Helen A. Fletcher, Kaatje Smits, Simone A. Joosten, Krista E. Van Meijgaarden, Iman Satti, Nadia Caccamo, Francesco Dieli, Françoise Mascart, Helen McshaneAbstract:Intracellular cytokine staining combined with flow cytometry is one of a number of assays designed to assess T-cell immune responses. It has the specific advantage of enabling the simultaneous assessment of multiple phenotypic, differentiation and functional parameters pertaining to responding T-cells, most notably, the expression of multiple effector cytokines. These attributes make the technique particularly suitable for the assessment of T-cell immune responses induced by novel Tuberculosis Vaccines in clinical trials. However, depending upon the particular nature of a given vaccine and trial setting, there are approaches that may be taken at different stages of the assay that are more suitable than other alternatives. In this paper, the Tuberculosis Vaccine Initiative (TBVI) TB Biomarker Working group reports on efforts to assess the conditions that will determine when particular assay approaches should be employed. We have found that choices relating to the use of fresh whole blood or peripheral blood mononuclear cells (PBMC) and frozen PBMC; use of serum-containing or serum-free medium; length of stimulation period and use of co-stimulatory antibodies can all affect the sensitivity of intracellular cytokine assays. In the case of sample material, frozen PBMC, despite some loss of sensitivity, may be more advantageous for batch analysis. We also recommend that for multi-site studies, common antibody panels, gating strategies and analysis approaches should be employed for better comparability.
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Tuberculosis Vaccines beyond bacille calmette guerin
Philosophical Transactions of the Royal Society B, 2011Co-Authors: Helen McshaneAbstract:Tuberculosis (TB) disease caused by Mycobacterium Tuberculosis (M. tb) remains one of the leading infectious causes of death and disease throughout the world. The only licensed vaccine, Mycobacteri...
Stefan H. E. Kaufmann - One of the best experts on this subject based on the ideXlab platform.
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tbvac2020 advancing Tuberculosis Vaccines from discovery to clinical development
Frontiers in Immunology, 2017Co-Authors: Stefan H. E. Kaufmann, Helen Mcshane, Hazel M Dockrell, Tom H M Ottenhoff, Nick Drager, Olivier Neyrolles, Brij Patel, Danielle Roordink, Francois Spertini, Steffen StengerAbstract:TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel Tuberculosis (TB) Vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel Vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel Vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal.
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Tuberculosis Vaccines time to think about the next generation
Seminars in Immunology, 2013Co-Authors: Stefan H. E. KaufmannAbstract:Efforts over the last 2 decades have led to a rich research and development pipeline of Tuberculosis (TB) Vaccines. Although none of the candidates has successfully completed the clinical trial pipeline, many are under advanced clinical assessment. These Vaccines aim at prevention of active TB, with most of them being considered for preexposure with recent additions for postexposure or multistage administration. A few therapeutic Vaccines are under clinical assessment, as well. Preexposure vaccination with the licensed TB vaccine BCG prevents severe forms of TB in children but not in adolescents and adults. The current vaccine pipeline does not include strategies which prevent or eliminate infection with the causative agent Mycobacterium Tuberculosis (Mtb). Rather in a best-case scenario, they are quantitatively superior to BCG in preventing active TB over prolonged periods of time, ideally lifelong in the face of latent Mtb infection. Qualitatively superior Vaccines should be capable of preventing or eliminating Mtb infection, in this way eliminating the risk of TB reactivation. The time is now ripe to exploit radically new strategies to achieve this goal.
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Tuberculosis Vaccines--a new kid on the block.
Nature medicine, 2011Co-Authors: Stefan H. E. KaufmannAbstract:New Tuberculosis Vaccines are urgently needed to reduce the threat of this devastating disease. An approach consisting of a fusion protein of three Tuberculosis antigens provides significant protection in before- and after-exposure challenge mouse models, representing a crucial step forward in tackling Tuberculosis in latently infected individuals (pages 189–194).
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novel Tuberculosis Vaccines on the horizon
Current Opinion in Immunology, 2010Co-Authors: Shreemanta K Parida, Stefan H. E. KaufmannAbstract:Eleven new Tuberculosis (TB) Vaccines are in various phases of clinical trials. These include subunit Vaccines to improve the current vaccine BCG, and recombinant BCG to substitute for BCG, both given pre-exposure to prevent active disease. A plethora of potential candidates have reached various stages of the pre-clinical development pipeline, some ready to enter Phase I clinical trial soon. A boost vaccine to top up the immunity of existing BCG is on the horizon and will have to suffice until a better candidate to replace BCG is ready. The live mutants of Mycobacterium Tuberculosis show great promise, but face a myriad of regulatory challenges.
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recent findings in immunology give Tuberculosis Vaccines a new boost
Trends in Immunology, 2005Co-Authors: Stefan H. E. KaufmannAbstract:Tuberculosis remains a major health threat, solved by neither chemotherapy nor the current vaccine, BCG. Although a new generation of vaccine candidates is ready for field trials, further improvements will be required. A successful vaccination regime must stimulate memory T cells and, at the same time, avoid exhaustion of memory and suppression by regulatory mechanisms. The most probable scenario is priming with one vaccine candidate followed by boosting with a another vaccine candidate. For clinical trials, biomarkers need to be defined with T cells alternating between lung and periphery as prime indicator cells.
Alimuddin Zumla - One of the best experts on this subject based on the ideXlab platform.
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Do successful Tuberculosis Vaccines need to be immunoregulatory rather than merely Th1-boosting?
Vaccine, 2005Co-Authors: Graham A W Rook, Keertan Dheda, Alimuddin ZumlaAbstract:Tuberculosis vaccine candidates are entering clinical studies in areas where BCG fails. This is a high-risk strategy. We suggest that geographical variation in the efficacy of BCG is related to the presence in developing countries of a cross-reactive background Th2-like response, probably attributable to exposure of mother and infant to helminths and environmental mycobacteria. Such Th2-like activity can stop Mycobacterium Tuberculosis from being pushed into a latent state by the Th1 response, impair bactericidal functions and cause toxicity of TNF-alpha and pulmonary fibrosis. A successful vaccine, rather than driving a Th1 response, might need to suppress this pre-existing subversive Th2-like component.
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Do successful Tuberculosis Vaccines need to be immunoregulatory rather than merely Th1-boosting?
VACCINE, 2005Co-Authors: Alimuddin ZumlaAbstract:Tuberculosis vaccine candidates are entering clinical studies in areas where BCG fails. This is a high-risk strategy. We suggest that geographical variation in the efficacy of BCG is related to the presence in developing countries of a cross-reactive background Th2-like response, probably attributable to exposure of mother and infant to helminths and environmental mycobacteria. Such Th2-like activity can stop Mycobacterium Tuberculosis from being pushed into a latent state by the Th1 response, impair bactericidal functions and cause toxicity of TNF-alpha and pulmonary fibrosis. A successful vaccine, rather than driving a Th1 response, might need to suppress this pre-existing subversive Th2-like component. (c) 2005 Elsevier Ltd. All rights reserved.
Carlos Martín - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic efficacy of pulmonary live Tuberculosis Vaccines against established asthma by subverting local immune environment
EBioMedicine, 2021Co-Authors: Raquel Tarancón, Dessislava Marinova, Carlos Martín, Elena Mata, Santiago Uranga, Ana Gomez, Isabel Otal, Nacho AguiloAbstract:Background Substantial recent advances in the comprehension of the molecular and cellular mechanisms behind asthma have evidenced the importance of the lung immune environment for disease outcome, making modulation of local immune responses an attractive therapeutic target against this pathology. Live attenuated mycobacteria, such as the Tuberculosis vaccine BCG, have been classically linked with a type 1 response, and proposed as possible modulators of the type 2 response usually associated with asthma. Methods In this study we used different acute and chronic murine models of asthma to investigate the therapeutic efficacy of intranasal delivery of the live Tuberculosis Vaccines BCG and MTBVAC by regulating the lung immune environment associated with airway hyperresponsiveness (AHR). Findings Intranasal administration of BCG, or the novel Tuberculosis vaccine candidate MTBVAC, abrogated AHR-associated hallmarks, including eosinophilia and lung remodeling. This correlated with the re-polarization of allergen-induced M2 macrophages towards an M1 phenotype, as well as with the induction of a strong allergen-specific Th1 response. Importantly, vaccine treatment was effective in a scenario of established chronic asthma where a strong eosinophil infiltration was already present prior to immunization. We finally compared the nebulization efficiency of clinical formulations of MTBVAC and BCG using a standard commercial nebulizer for potential aerosol application. Interpretation Our results demonstrate that pulmonary live Tuberculosis Vaccines efficiently revert established asthma in mice. These data support the further exploration of this approach as potential therapy against asthma. Funding Spanish Ministry of Science [grant numbers: BIO2014-5258P, RTI2018-097625-B-I00], Instituto de Salud Carlos III, Gobierno de Aragon/Fondo Social Europeo, University of Zaragoza [grant number: JIUZ-2018-BIO-01].
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bridging the gap between efficacy trials and model based impact evaluation for new Tuberculosis Vaccines
Nature Communications, 2019Co-Authors: Mario Tovar, Dessislava Marinova, Carlos Martín, Sergio Arregui, Joaquín Sanz, Yamir MorenoAbstract:In Tuberculosis (TB), given the complexity of its transmission dynamics, observations of reduced epidemiological risk associated with preventive interventions can be difficult to translate into mechanistic interpretations. Specifically, in clinical trials of vaccine efficacy, a readout of protection against TB disease can be mapped to multiple dynamical mechanisms, an issue that has been overlooked so far. Here, we describe this limitation and its effect on model-based evaluations of vaccine impact. Furthermore, we propose a methodology to analyze efficacy trials that circumvents it, leveraging a combination of compartmental models and stochastic simulations. Using our approach, we can disentangle the different possible mechanisms of action underlying vaccine protection effects against TB, conditioned to trial design, size, and duration. Our results unlock a deeper interpretation of the data emanating from efficacy trials of TB Vaccines, which renders them more interpretable in terms of transmission models and translates into explicit recommendations for vaccine developers. One measurement of Tuberculosis vaccine efficacy in clinical trials is prevention of disease, but different mechanisms can underlie disease prevention. Here, the authors develop a mathematical model that allows to identify mechanisms of action of a vaccine preventing TB disease.
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On the impact of masking and blocking hypotheses for measuring the efficacy of new Tuberculosis Vaccines
PeerJ, 2016Co-Authors: Sergio Arregui, Dessislava Marinova, Carlos Martín, Joaquín Sanz, Yamir MorenoAbstract:Over the past 60 years, the Mycobacterium bovis bacille Calmette–Guerin (BCG) has been used worldwide to prevent Tuberculosis (TB). However, BCG has shown a very variable efficacy in different trials, offering a wide range of protection in adults against pulmonary TB. One of the most accepted hypotheses to explain these inconsistencies points to the existence of a pre-existing immune response to antigens that are common to environmental sources of mycobacterial antigens and Mycobacterium Tuberculosis. Specifically, two different mechanisms have been hypothesized to explain this phenomenon: the masking and the blocking effects. According to masking hypothesis, previous sensitization confers some level of protection against TB that masks vaccine’s effects. In turn, the blocking hypothesis postulates that previous immune response prevents vaccine taking of a new TB vaccine. In this work we introduce a series of models to discriminate between masking and blocking mechanisms and address their relative likelihood. We apply our methodology to the data reported by BCG-REVAC clinical trials, which were specifically designed for studying BCG efficacy variability. Our results yield estimates that are consistent with high levels of blocking (41% in Manaus -95% CI [14–68]- and 96% in Salvador -95% CI [52–100]-). Moreover, we also show that masking does not play any relevant role in modifying vaccine’s efficacy either alone or in addition to blocking. The quantification of these effects around a plausible model constitutes a relevant step towards impact evaluation of novel anti-Tuberculosis Vaccines, which are susceptible of being affected by similar effects, especially if applied on individuals previously exposed to mycobacterial antigens.
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On the impact of Masking and Blocking Hypotheses for measuring efficacy of new Tuberculosis Vaccines
arXiv: Populations and Evolution, 2015Co-Authors: Sergio Arregui, Dessislava Marinova, Carlos Martín, Joaquín Sanz, Yamir MorenoAbstract:Over the past 60 years, the Mycobacterium bovis bacille Calmette-Gu\'erin (BCG) has been used worldwide to prevent Tuberculosis (TB). However, BCG has shown a very variable efficacy in different trials, showing a wide range of protection in adults against pulmonary TB. Previous studies indicate that this failure is related to pre-existing immune response to antigens that are common to environmental sources of mycobacterial antigens and Mycobacterium Tuberculosis. Specifically, two different mechanisms have been hypothesized: the masking, (previous sensitization confers some level of protection against TB), and the blocking (previous immune response prevent vaccine taking of a new TB vaccine), effects. In this work we introduce a series of models to discriminate between masking and blocking mechanisms and address their relative likelihood. The application of our models to interpret the results coming from the BCG-REVAC clinical trials, specifically designed for the study of sources of efficacy variability yields estimates that are consistent with high levels of blocking (41% in Manaus -95% C.I. [14%-68%]- and 96% in Salvador -95% C.I. [52%-100%]-), and no support for masking to play any relevant role in modifying vaccine efficacy either alone or aside blocking. The quantification of these effects around a plausible model constitutes a relevant step towards impact evaluation of novel anti-Tuberculosis Vaccines, which are susceptible of being affected by similar effects if applied on individuals previously exposed to mycobacterial antigens.
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Recent developments in Tuberculosis Vaccines
Expert review of vaccines, 2013Co-Authors: Dessislava Marinova, Jesús Gonzalo-asensio, Nacho Aguilo, Carlos MartínAbstract:Substantial efforts have been made over the past decade to develop Vaccines against Tuberculosis. We review recent developments in Tuberculosis Vaccines in the global portfolio, including those designed for use in a prophylactic setting, either alone or as boosts to Bacille Calmette–Guerin, and therapeutic Vaccines designed to improve chemotherapy. While there is no doubt that progress is still being made, there are limitations to our animal model screening processes, which are further amplified by the lack of understanding of the immunological responses involved and the precise type of long-lived immunity that new Vaccines need to induce. The challenge ahead is to optimize the planning for advanced clinical trials in poor endemic settings, which could be greatly facilitated by identifying correlates of protection.
Ian M. Orme - One of the best experts on this subject based on the ideXlab platform.
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Tuberculosis Vaccines
Drugs, 2005Co-Authors: Ian M. OrmeAbstract:Tuberculosis continues to be a major cause of disease and death throughout the developing world. Chemotherapy is the current method of control but with the continuing emergence of drug resistance, coupled with the reticence of major drug companies to invest in drug discovery, the identification of new Vaccines to combat Tuberculosis is a pressing need. Rational vaccine design requires knowledge of the protective immune response and, while this is not fully understood, it is clear that induction of a T-helper-1 type of immunity is critical to host resistance. A variety of animal models, but especially the mouse and guinea pig, can be used to determine the protective efficacy of new Vaccines. These mostly consist of relatively short-term prophylactic models in which animals are vaccinated and then challenged by the aerosol infection route to determine their capacity to reduce the lung bacterial load. Several promising vaccine types have emerged, including subunit Vaccines, DNA Vaccines and Vaccines based upon living vectors, such as recombinant bacillus Calmette-Guérin (BCG) Vaccines and auxotrophic or gene disrupted mutants of Mycobacterium Tuberculosis. A few of these have already entered early stage clinical trials.
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immunopathogenesis of pulmonary granulomas in the guinea pig after infection with mycobacterium Tuberculosis
Infection and Immunity, 2003Co-Authors: Oliver C Turner, Randall J Basaraba, Ian M. OrmeAbstract:Pulmonary Tuberculosis in guinea pigs is similar to the disease in humans and is accordingly widely used as a model to test Tuberculosis Vaccines. The primary site of expression of acquired immunity and the hallmark of Tuberculosis is the granuloma. Granuloma morphology is well described, but there is limited information regarding T-cell subset influx. We monitored the course of pulmonary Tuberculosis in guinea pigs and observed four distinct immunohistopathological stages. In all stages there were similar numbers and arrangement of CD4 and CD8 T cells. There were only small numbers of apoptotic lymphocytes, scattered around and within the necrotic core, and acid-fast bacilli were visible both within macrophages and free within airway debris. A key finding of the study was the observation that the development of the necrotic core was an early event and almost certainly preceded the emergence of the acquired immune response. This in turn suggests that innate mechanisms are the basis of the early lesions and that subsequent acquired responses are unable to moderate them. This hypothesis differs from the current dogma that excessive activity of T cells mediates delayed-type hypersensitivity and that cellular cytolysis is the root cause of the necrosis.
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effective preexposure Tuberculosis Vaccines fail to protect when they are given in an immunotherapeutic mode
Infection and Immunity, 2000Co-Authors: Joanne Turner, Elizabeth Rhoades, Marc A Keen, John T Belisle, Anthony A Frank, Ian M. OrmeAbstract:Two vaccine formulations previously shown to induce protective immunity in mice and prevention of long-term necrosis in guinea pigs were tested as potential immunotherapeutic Vaccines in mice earlier infected by aerosol with Mycobacterium Tuberculosis. Neither vaccine had any effect on the course of the infection in the lungs, but both reduced the bacterial load in the spleen. Similarly, inoculation with Mycobacterium bovis BCG had no effect whatsoever and, if given more than once, appeared to induce an increasingly severe pyogranulomatous response in the lungs of these mice.
