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Sample records for defined tuberculosis vaccine

  1. A Defined Tuberculosis Vaccine Candidate Boosts BCG and Protects Against Multidrug Resistant Mycobacterium tuberculosis

    PubMed Central

    Bertholet, Sylvie; Ireton, Gregory C.; Ordway, Diane J.; Windish, Hillarie Plessner; Pine, Samuel O.; Kahn, Maria; Phan, Tony; Orme, Ian M.; Vedvick, Thomas S.; Baldwin, Susan L.; Coler, Rhea N.; Reed, Steven G.

    2011-01-01

    Despite the widespread use of Mycobacterium bovis bacillus Calmette-Guerin (BCG) childhood vaccine, tuberculosis (TB) remains a serious global health problem. A successful vaccine against TB that replaces or boosts BCG will include antigens that induce or recall appropriate T cell responses. Four Mycobacterium tuberculosis (Mtb) antigens, including members of the virulence factor families PE/PPE and EsX, or antigens associated with latency were produced as a single recombinant fusion protein. When administered with the adjuvant GLA-SE, a stable oil-in-water nanoemulsion, the fusion protein ID93 was immunogenic in mice, guinea pigs, and cynomolgus monkeys. In mice, ID93/GLA-SE combination induced polyfunctional CD4 TH1-cell responses characterized by antigen-specific IFN-gamma, tumor necrosis factor and interleukin-2, as well as a reduction in the number of bacteria in the lungs of animals subsequently infected with virulent or multidrug resistant Mtb strains. Furthermore, boosting BCG-vaccinated guinea pigs with ID93/GLA-SE resulted in reduced pathology and fewer bacilli, and prevented the death of animals challenged with virulent Mtb. Finally, ID93 elicited polyfunctional effector CD4 and CD8 T-cell responses in BCG-vaccinated or Mtb-exposed human peripheral blood mononuclear cells. This study establishes that the protein subunit vaccine ID93/GLA-SE protects against TB and MDR-TB in animals, and is a candidate for boosting the protective efficacy of the childhood BCG vaccine. PMID:20944089

  2. Defined tuberculosis vaccine, Mtb72F/AS02A, evidence of protection in cynomolgus monkeys

    PubMed Central

    Reed, Steven G.; Coler, Rhea N.; Dalemans, Wilfried; Tan, Esterlina V.; DeLa Cruz, Eduardo C.; Basaraba, Randall J.; Orme, Ian M.; Skeiky, Yasir A. W.; Alderson, Mark R.; Cowgill, Karen D.; Prieels, Jean-Paul; Abalos, Rodolfo M.; Dubois, Marie-Claude; Cohen, Joe; Mettens, Pascal; Lobet, Yves

    2009-01-01

    The development of a vaccine for tuberculosis requires a combination of antigens and adjuvants capable of inducing appropriate and long-lasting T cell immunity. We evaluated Mtb72F formulated in AS02A in the cynomolgus monkey model. The vaccine was immunogenic and caused no adverse reactions. When monkeys were immunized with bacillus Calmette–Guérin (BCG) and then boosted with Mtb72F in AS02A, protection superior to that afforded by using BCG alone was achieved, as measured by clinical parameters, pathology, and survival. We observed long-term survival and evidence of reversal of disease progression in monkeys immunized with the prime-boost regimen. Antigen-specific responses from protected monkeys receiving BCG and Mtb72F/AS02A had a distinctive cytokine profile characterized by an increased ratio between 3 Th1 cytokines, IFN-γ, TNF, and IL-2 and an innate cytokine, IL-6. To our knowledge, this is an initial report of a vaccine capable of inducing long-term protection against tuberculosis in a nonhuman primate model, as determined by protection against severe disease and death, and by other clinical and histopathological parameters. PMID:19188599

  3. Tuberculosis vaccine types and timings.

    PubMed

    Orme, Ian M

    2015-03-01

    Traditionally, the design of new vaccines directed against Mycobacterium tuberculosis, the most successful bacterial pathogen on the planet, has focused on prophylactic candidates that would be given to individuals while they are still young. It is becoming more apparent, however, that there are several types of vaccine candidates now under development that could be used under various conditions. Thus, in addition to prophylactic vaccines, such as recombinant Mycobacterium bovis BCG or BCG-boosting vaccines, other applications include vaccines that could prevent infection, vaccines that could be given in emergency situations as postexposure vaccines, vaccines that could be used to facilitate chemotherapy, and vaccines that could be used to reduce or prevent relapse and reactivation disease. These approaches are discussed here, including the type of immunity we are trying to specifically target, as well as the limitations of these approaches.

  4. Tuberculosis Vaccine Types and Timings

    PubMed Central

    2014-01-01

    Traditionally, the design of new vaccines directed against Mycobacterium tuberculosis, the most successful bacterial pathogen on the planet, has focused on prophylactic candidates that would be given to individuals while they are still young. It is becoming more apparent, however, that there are several types of vaccine candidates now under development that could be used under various conditions. Thus, in addition to prophylactic vaccines, such as recombinant Mycobacterium bovis BCG or BCG-boosting vaccines, other applications include vaccines that could prevent infection, vaccines that could be given in emergency situations as postexposure vaccines, vaccines that could be used to facilitate chemotherapy, and vaccines that could be used to reduce or prevent relapse and reactivation disease. These approaches are discussed here, including the type of immunity we are trying to specifically target, as well as the limitations of these approaches. PMID:25540272

  5. What's new in tuberculosis vaccines?

    PubMed Central

    Ginsberg, Ann M.

    2002-01-01

    Over the past 10 years, tuberculosis (TB) vaccine development has resurged as an active area of investigation. The renewed interest has been stimulated by the recognition that, although BCG is delivered to approximately 90% of all neonates globally through the Expanded Programme on Immunization, Mycobacterium tuberculosis continues to cause over 8 million new cases of TB and over 2 million deaths annually. Over one hundred TB vaccine candidates have been developed, using different approaches to inducing protective immunity. Candidate vaccines are typically screened in small animal models of primary TB disease for their ability to protect against a virulent strain of M. tuberculosis. The most promising are now beginning to enter human safety trials, marking real progress in this field for the first time in 80 years. PMID:12132007

  6. Tuberculosis: from genome to vaccine.

    PubMed

    de Jonge, Marien I; Brosch, Roland; Brodin, Priscille; Demangel, Caroline; Cole, Stewart T

    2005-08-01

    The availability of mycobacterial genome sequences has paved the way to identifying potential tuberculosis vaccine candidates in order to replace the currently used bacillus Calmette-Guérin (BCG) vaccines that show variable protective efficacy in adults. Genomics provides the basis for bioinformatic, transcriptomic and proteomic analysis, increases screening efficiency and enables valuable information concerning the biology and virulence of the mycobacterial species to be extracted by comparative genomics. Although in silico results must be confirmed in vitro and in vivo, bioinformatic analysis of the genomes is highlighting candidates for testing. For designing subunit vaccines, attenuated or improved recombinant whole-cell live vaccines, information from the genomes of the human host and pathogenic mycobacterial species is of great help.

  7. Tuberculosis vaccines: hopes and hurdles.

    PubMed

    Ahsan, Mohamed J; Garg, Shiv K; Vashistha, Bharat; Sharma, Piush

    2013-10-01

    Tuberculosis (TB) remains as one of the most serious public health problems worldwide. It is one of the main causes of death in poor and developing countries, especially in sub-Saharan Africa, where it may be associated with the human immunodeficiency virus (HIV). It has been estimated that one third of the world population is infected by Mycobacterium tuberculosis (Mtb), and there were about 8.7 million new TB cases, and about 1.4 million yearly deaths due to TB in 2011. DOTS is the currently used drug therapy in TB but there is non-compliance which results in emergence of resistance. Bacille Calmette Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the only licensed TB vaccine, but not recommended in HIV-infected infants. There are 14 vaccine candidates that have entered clinical trials and over 35 candidates in discovery and preclinical development. Mycobacterium indicus pranii [Mw; MIP] and M. vaccae are in phase III clinical trial and the Drug Controller of India licensed MIP for human use in India.

  8. Vaccination Against Tuberculosis With Whole-Cell Mycobacterial Vaccines.

    PubMed

    Scriba, Thomas J; Kaufmann, Stefan H E; Henri Lambert, Paul; Sanicas, Melvin; Martin, Carlos; Neyrolles, Olivier

    2016-09-01

    Live attenuated and killed whole-cell vaccines (WCVs) offer promising vaccination strategies against tuberculosis. A number of WCV candidates, based on recombinant bacillus Calmette-Guerin (BCG), attenuated Mycobacterium tuberculosis, or related mycobacterial species are in various stages of preclinical or clinical development. In this review, we discuss the vaccine candidates and key factors shaping the development pathway for live and killed WCVs and provide an update on progress. PMID:27247343

  9. Novel approaches to tuberculosis prevention: DNA vaccines.

    PubMed

    Rivas-Santiago, Bruno; Cervantes-Villagrana, Alberto R

    2014-03-01

    It is estimated that there are approximately eight million new cases of active tuberculosis (TB) worldwide annually. There is only 1 vaccine available for prevention: bacillus Calmette-Guérin (BCG). This has variable efficacy and is only protective for certain extrapulmonary TB cases in children, therefore new strategies for the creation of novel vaccines have emerged. One of the promising approaches is the DNA vaccine, used as a direct vaccination or as a prime-boost vaccine. This review describes the experimental data obtained during the design of DNA vaccines for TB.

  10. Tuberculosis vaccines in clinical trials

    PubMed Central

    Rowland, Rosalind; McShane, Helen

    2011-01-01

    Effective prophylactic and/or therapeutic vaccination is a key strategy for controlling the global TB epidemic. The partial effectiveness of the existing TB vaccine, bacille Calmette–Guérin (BCG), suggests effective vaccination is possible and highlights the need for an improved vaccination strategy. Clinical trials are evaluating both modifications to the existing BCG immunization methods and also novel TB vaccines, designed to replace or boost BCG. Candidate vaccines in clinical development include live mycobacterial vaccines designed to replace BCG, subunit vaccines designed to boost BCG and therapeutic vaccines designed as an adjunct to chemotherapy. There is a great need for validated animal models, identification of immunological biomarkers of protection and field sites with the capacity for large-scale efficacy testing in order to develop and license a novel TB vaccine or regimen. PMID:21604985

  11. Tuberculosis vaccine: time to look into future.

    PubMed

    Chawla, Sumit; Garg, Dinesh; Jain, Ram Bilas; Khanna, Pardeep; Choudhary, Satvinder; Sahoo, Soumya; Singh, Inderjeet

    2014-01-01

    Global burden of tuberculosis is nearly 12 million. As per the WHO Global TB Report 2013, there were an estimated 8.6 million incident cases of TB globally in 2012. Tuberculosis is an issue that affects development through its effect on the health of individuals and families. In humans, neither prior latent infection nor recovery from active TB confers reliable protection against reinfection or reactivation disease. The power of vaccines as a public health intervention lies in their ability to reduce onward transmission of disease as much as in their ability to protect vaccinated individuals; a feature generally referred to as "herd immunity." MVA85A is a booster vaccine, used in con-junction with BCG as part of a prime-boost strategy. BCG serves as the prime vaccination and MVA85A as the boost, operating under the theory that the addition of MVA85A will produce a better immune response and more protection against TB than BCG vaccination alone. There is a critical need to raise the profile of TB vaccine research at the community, national, regional, and global levels in order to generate support and political will, increase investment, create an enabling and supportive environment for clinical trials, and lay the groundwork for acceptance and adoption of new TB vaccines once licensed.

  12. Post-exposure vaccination against Mycobacterium tuberculosis

    PubMed Central

    Henao-Tamayo, Marcela; Palaniswamy, Gopinath S.; Smith, Erin E.; Shanley, Crystal A.; Wang, Baolin; Orme, Ian M.; Basaraba, Randall J.; DuTeau, Nancy M.; Ordway, Diane

    2009-01-01

    Summary Enhancing immunity to tuberculosis in animal models after exposure to the infection has proved difficult. In this study we used a newly described flow cytometric technique to monitor changes in cell populations accumulating in the lungs of guinea pigs challenged by low dose aerosol infection with Mycobacterium tuberculosis and vaccinated ten days later. On day forty after infection the fusion protein F36 and a pool of Ag85A and ESAT-6 vaccines had significant effects on the bacterial load, showed increased expression of the activation marker CD45+ on CD4+ T cells, and reduced numbers of heterophils. Lung pathology and pathology scores were marginally improved in animals given these vaccines, but lymph node pathology was not influenced. Despite early effects no changes in long term survival were seen. These results suggest that a single post-exposure vaccination can initially slow the disease process. However, this effect is transient, but this could be of use in an multidrug resistant/extremely drug resistant outbreak situation because it could potentially slow the infection long enough to complete drug susceptibility testing and initiate effective chemotherapy. PMID:19264552

  13. Vaccine development for tuberculosis: current progress.

    PubMed

    Orme, Ian M

    2013-07-01

    Very substantial efforts have been made over the past decade or more to develop vaccines against tuberculosis. Historically, this began with a view to replace the current vaccine, Bacillus Calmette Guérin (BCG), but more recently most candidates are either new forms of this bacillus, or are designed to boost immunity in children given BCG as infants. Good progress is being made, but very few have, as yet, progressed into clinical trials. The leading candidate has advanced to phase IIb efficacy testing, with disappointing results. This article discusses the various types of vaccines, including those designed to be used in a prophylactic setting, either alone or BCG-boosting, true therapeutic (post-exposure) vaccines, and therapeutic vaccines designed to augment chemotherapy. While there is no doubt that progress is still being made, we have a growing awareness of the limitations of our animal model screening processes, further amplified by the fact that we still do not have a clear picture of the immunological responses involved, and the precise type of long-lived immunity that effective new vaccines will need to induce.

  14. Vaccine development for tuberculosis: current progress

    PubMed Central

    Orme, Ian M.

    2013-01-01

    Very substantial efforts have been made over the past decade or more to develop vaccines against tuberculosis. Historically, this began with a view to replace the current vaccine, BCG, but more recently most candidates are either new forms of this bacillus, or are designed to boost immunity in children given BCG as infants. Good progress is being made, but very few have as yet progressed into clinical trials. The leading candidate has advanced to Phase IIb efficacy testing, with disappointing results. This article discusses the various types of vaccines, including those designed to be used in a prophylactic setting, either alone or BCG-boosting, true therapeutic [post-exposure] vaccines, and therapeutic vaccines designed to augment chemotherapy. While there is no doubt that progress is still being made, we have a growing awareness of the limitations of our animal model screening processes, further amplified by the fact that we still do not have a clear picture of the immunological responses involved, and the precise type of long lived immunity we will need effective new vaccines to induce. PMID:23794129

  15. The Importance of Animal Models in Tuberculosis Vaccine Development

    PubMed Central

    Acosta, Armando; Norazmi, Mohd Nor; Hernandez-Pando, Rogelio; Alvarez, Nadine; Borrero, Reinier; Infante, Juan F; Sarmiento, Maria E

    2011-01-01

    Research, development, and production of vaccines are still highly dependent on the use of animal models in the various evaluation steps. Despite this fact, there are strong interests and ongoing efforts to reduce the use of animals in vaccine development. Tuberculosis vaccine development is one important example of the complexities involved in the use of animal models for the production of new vaccines. This review summarises some of the general aspects related with the use of animals in vaccine research and production, as well as achievements and challenges towards the rational use of animals, particularly in the case of tuberculosis vaccine development. PMID:22589668

  16. Tuberculosis Vaccines and Prevention of Infection

    PubMed Central

    Day, Tracey A.; Scriba, Thomas J.; Hatherill, Mark; Hanekom, Willem A.; Evans, Thomas G.; Churchyard, Gavin J.; Kublin, James G.; Bekker, Linda-Gail; Self, Steven G.

    2014-01-01

    SUMMARY Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation. PMID:25428938

  17. How far have we reached in tuberculosis vaccine development?

    PubMed

    Kumar, Himanshu; Malhotra, Dheeraj; Goswami, Sanjeev; Bamezai, R N K

    2003-01-01

    Tuberculosis, a bacterial disease prevalent since ancient times, continues to cause the most deaths globally compared with all other diseases. The causative agent Mycobacterium tuberculosis is responsible for different types of tuberculosis in humans; however, pulmonary tuberculosis is the most common and causes the most deaths. Mycobacterium tuberculosis is an intracellular pathogenic bacterium, which has developed sophisticated mechanisms to survive inside host mononuclear phagocytes and thus evade the host immune system. This is attributed primarily to an inadequate immune response toward infecting bacteria, which results in temporary growth inhibition rather than death and subsequently allows the bacteria to multiply immensely, leading to full-blown disease in an individual. This disease has become a challenge due to poor diagnosis, a low-efficiency tuberculosis vaccine (Mycobacterium bovis Bacillus Calmette-Guerin [BCG]), a long-term antibacterial chemotherapy regimen (approximately 6 months), and an emergence of multiple drug resistant strains of Mycobacterium tuberculosis especially in people with human immune deficiency virus (HIV) infection, for whom researchers worldwide must develop effective short-term chemotherapy and an effective vaccine. In this review different aspects of vaccines in tuberculosis are discussed, and these include the traditional BCG vaccine, the modern auxotrophic vaccine, the subunit or acellular vaccine; and a DNA vaccine. We discuss also the potential of mycobacterial lipids as a vaccine or as an adjuvant in the future. Since complete genome information of Mycobacterium tuberculosis H37Rv and bioinformatics tools are available, it is possible to develop new strategies for a better and effective tuberculosis vaccine, which can replace the traditional BCG vaccine.

  18. Development of vaccines to control the worldwide tuberculosis pandemic.

    PubMed

    Hoft, Daniel F

    2014-01-01

    Mycobacterium tuberculosis (Mtb) infection and tuberculosis (TB) disease are major public health problems. Available BCG vaccines are partially effective against severe disease, but have not reduced the overall prevalence of TB infection and disease. A third of the world's population is latently infected with Mtb, and therefore more effective prophylactic and therapeutic vaccines are urgently needed. The Hoft laboratory and the Saint Louis University Center for Vaccine Development (SLUCVD) are actively pursuing these important goals.

  19. Drying a tuberculosis vaccine without freezing.

    PubMed

    Wong, Yun-Ling; Sampson, Samantha; Germishuizen, Willem Andreas; Goonesekera, Sunali; Caponetti, Giovanni; Sadoff, Jerry; Bloom, Barry R; Edwards, David

    2007-02-20

    With the increasing incidence of tuberculosis and drug resistant disease in developing countries due to HIV/AIDS, there is a need for vaccines that are more effective than the present bacillus Calmette-Guérin (BCG) vaccine. We demonstrate that BCG vaccine can be dried without traditional freezing and maintained with remarkable refrigerated and room-temperature stability for months through spray drying. Studies with a model Mycobacterium (Mycobacterium smegmatis) revealed that by removing salts and cryoprotectant (e.g., glycerol) from bacterial suspensions, the significant osmotic pressures that are normally produced on bacterial membranes through droplet drying can be reduced sufficiently to minimize loss of viability on drying by up to 2 orders of magnitude. By placing the bacteria in a matrix of leucine, high-yield, free-flowing, "vial-fillable" powders of bacteria (including M. smegmatis and M. bovis BCG) can be produced. These powders show relatively minor losses of activity after maintenance at 4 degrees C and 25 degrees C up to and beyond 4 months. Comparisons with lyophilized material prepared both with the same formulation and with a commercial formulation reveal that the spray-dried BCG has better overall viability on drying.

  20. Bovine Tuberculosis in Cattle: Vaccines, DIVA Tests, and Host Biomarker Discovery.

    PubMed

    Vordermeier, H Martin; Jones, Gareth J; Buddle, Bryce M; Hewinson, R Glyn; Villarreal-Ramos, Bernardo

    2016-01-01

    Bovine tuberculosis remains a major economic and animal welfare concern worldwide. Cattle vaccination is being considered as part of control strategies. This approach, used alongside conventional control policies, also requires the development of vaccine-compatible diagnostic assays to distinguish vaccinated from infected animals (DIVA). We discuss progress made on optimizing the only potentially available vaccine, bacille Calmette Guérin (BCG), and on strategies to improve BCG efficacy. We also describe recent advances in DIVA development based on the detection of host cellular immune responses by blood-testing or skin-testing approaches. Finally, to accelerate vaccine development, definition of host biomarkers that provide meaningful stage-gating criteria to select vaccine candidates for further testing is highly desirable. Some progress has also been made in this area of research, and we summarize studies that defined either markers predicting vaccine success or markers that correlate with disease stage or severity.

  1. EVOLUTION OF MYCOBACTERIUM TUBERCULOSIS AND IMPLICATIONS FOR VACCINE DEVELOPMENT.

    PubMed

    Gagneux, Sebastien

    2016-04-01

    Tuberculosis (TB) is a growing public health threat, particularly in the face of the global epidemics of multidrug resistance. Given the limited efficacy of the current TB vaccine and the recent clinical failure of the most advanced new TB vaccine candidate, novel concepts for vaccine design should be explored. Most T cell antigens in the human-adapted Mycobacterium tuberculosis complex (MTBC) are evolutionarily conserved and under strong purifying selection, indicating that host immune responses targeting these antigens might not be protective. By contrast, a few highly variable T cell epitopes have recently been discovered, which could serve as alternative vaccine antigens. Moreover, there is increasing evidence that the human-adapted MTBC has been co-evolving with the human host for a long time. Hence, studying the interaction between bacterial and human genetic diversity might help identify additional targets that could be exploited for TB vaccine development.

  2. Mycobacterium tuberculosis virulence: insights and impact on vaccine development.

    PubMed

    Delogu, Giovanni; Provvedi, Roberta; Sali, Michela; Manganelli, Riccardo

    2015-01-01

    The existing TB vaccine, the attenuated Mycobacterium bovis strain BCG, is effective in protecting infants from severe forms of the disease, while its efficacy in protecting adults from pulmonary TB is poor. In the last two decades, a renewed interest in TB resulted in the development of several candidate vaccines that are now entering clinical trials. However, most of these vaccines are based on a common rationale and aim to induce a strong T-cell response against Mycobacterium tuberculosis. Recent advancements in the understanding of M. tuberculosis virulence determinants and associated pathogenic strategies are opening a new and broader view of the complex interaction between this remarkable pathogen and the human host, providing insights at molecular level that could lead to a new rationale for the design of novel antitubercular vaccines. A vaccination strategy that simultaneously targets different steps in TB pathogenesis may result in improved protection and reduced TB transmission.

  3. Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines.

    PubMed

    Schito, Marco; Migliori, Giovanni Battista; Fletcher, Helen A; McNerney, Ruth; Centis, Rosella; D'Ambrosio, Lia; Bates, Matthew; Kibiki, Gibson; Kapata, Nathan; Corrah, Tumena; Bomanji, Jamshed; Vilaplana, Cris; Johnson, Daniel; Mwaba, Peter; Maeurer, Markus; Zumla, Alimuddin

    2015-10-15

    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.

  4. Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines

    PubMed Central

    Schito, Marco; Migliori, Giovanni Battista; Fletcher, Helen A.; McNerney, Ruth; Centis, Rosella; D'Ambrosio, Lia; Bates, Matthew; Kibiki, Gibson; Kapata, Nathan; Corrah, Tumena; Bomanji, Jamshed; Vilaplana, Cris; Johnson, Daniel; Mwaba, Peter; Maeurer, Markus; Zumla, Alimuddin

    2015-01-01

    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. PMID:26409271

  5. Lessons for tuberculosis vaccines from respiratory virus infection.

    PubMed

    Beverley, Peter Charles Leonard; Tchilian, Elma Zaven

    2008-10-01

    There is a worldwide epidemic of increasingly drug-resistant TB. Bacillus Calmette-Guérin vaccination provides partial protection against disseminated disease in infants but poor protection against later pulmonary TB. Cell-mediated protection against respiratory virus infections requires the presence of T cells in lung tissues, and the most effective prime-boost immunizations for Mycobacterium tuberculosis also induce lung-resident lymphocytes. These observations need to be taken into account when designing future vaccines against M. tuberculosis. PMID:18844591

  6. Recent advances towards tuberculosis control: vaccines and biomarkers

    PubMed Central

    Weiner, J; Kaufmann, S H E

    2014-01-01

    Weiner 3rd J, Kaufmann SHE (Max Planck Institute for Infection Biology, Berlin, Germany). Recent advances towards tuberculosis control: vaccines and biomarkers. (Review). J Intern Med 2014; 275: 467–480. Of all infectious diseases, tuberculosis (TB) remains one of the most important causes of morbidity and mortality. Recent advances in understanding the biology of Mycobacterium tuberculosis (Mtb) infection and the immune response of the infected host have led to the development of several new vaccines, a number of which are already undergoing clinical trials. These include pre-exposure prime vaccines, which could replace bacille Calmette–Guérin (BCG), and pre-exposure booster vaccines given in addition to BCG. Infants are the target population of these two types of vaccines. In addition, several postexposure vaccines given during adolescence or adult life, in addition to BCG as a priming vaccine during infancy, are undergoing clinical testing. Therapeutic vaccines are currently being assessed for their potential to cure active TB as an adjunct to chemotherapy. BCG replacement vaccines are viable recombinant BCG or double-deletion mutants of Mtb. All booster vaccines are composed of one or several antigens, either expressed by viral vectors or formulated with adjuvants. Therapeutic vaccines are killed mycobacterial preparations. Finally, multivariate biomarkers and biosignatures are being generated from high-throughput data with the aim of providing better diagnostic tools to specifically determine TB progression. Here, we provide a technical overview of these recent developments as well of the relevant computational approaches and highlight the obstacles that still need to be overcome. PMID:24635488

  7. Tuberculosis vaccines: beyond bacille Calmette–Guérin

    PubMed Central

    McShane, Helen

    2011-01-01

    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, Mycobacterium bovis bacille Calmette–Guérin (BCG) confers highly variable protection against pulmonary disease. An effective vaccination regimen would be the most efficient way to control the epidemic. However, BCG does confer consistent and reliable protection against disseminated disease in childhood, and most TB vaccine strategies being developed incorporate BCG to retain this protection. Cellular immunity is necessary for protection against TB and all the new vaccines in development are focused on inducing a strong and durable cellular immune response. There are two main strategies being pursued in TB vaccine development. The first is to replace BCG with an improved whole organism mycobacterial priming vaccine, which is either a recombinant BCG or an attenuated strain of M. tb. The second is to develop a subunit boosting vaccine, which is designed to be administered after BCG vaccination, and to enhance the protective efficacy of BCG. This article reviews the leading candidate vaccines in development and considers the current challenges in the field with regard to efficacy testing. PMID:21893541

  8. Use of vaccines as probes to define disease burden.

    PubMed

    Feikin, Daniel R; Scott, J Anthony G; Gessner, Bradford D

    2014-05-17

    Vaccine probe studies have emerged in the past 15 years as a useful way to characterise disease. By contrast, traditional studies of vaccines focus on defining the vaccine effectiveness or efficacy. The underlying basis for the vaccine probe approach is that the difference in disease burden between vaccinated and unvaccinated individuals can be ascribed to the vaccine-specific pathogen. Vaccine probe studies can increase understanding of a vaccine's public health value. For instance, even when a vaccine has a seemingly low efficacy, a high baseline disease incidence can lead to a large vaccine-preventable disease burden and thus that population-based vaccine introduction would be justified. So far, vaccines have been used as probes to characterise disease syndromes caused by Haemophilus influenzae type b, pneumococcus, rotavirus, and early infant influenza. However, vaccine probe studies have enormous potential and could be used more widely in epidemiology, for example, to define the vaccine-preventable burden of malaria, typhoid, paediatric influenza, and dengue, and to identify causal interactions between different pathogens.

  9. Complement component 3: a new paradigm in tuberculosis vaccine.

    PubMed

    De La Fuente, José; Gortázar, Christian; Juste, Ramón

    2016-01-01

    Vaccines are critical for the control of tuberculosis (TB) affecting humans and animals worldwide. First-generation vaccines protect from active TB but new vaccines are required to protect against pulmonary disease and infection. Recent advances in post-genomics technologies have allowed the characterization of host-pathogen interactions to discover new protective antigens and mechanisms to develop more effective vaccines against TB. Studies in the wild boar model resulted in the identification of complement component 3 (C3) as a natural correlate of protection against TB. Oral immunization with heat-inactivated mycobacteria protected wild boar against TB and showed that C3 plays a central role in protection. These results point at C3 as a target to develop novel vaccine formulations for more effective protection against TB in humans and animals. PMID:26605515

  10. Protective immunity following vaccination: how is it defined?

    PubMed

    Amanna, Ian J; Messaoudi, Ilhem; Slifka, Mark K

    2008-01-01

    Vaccination represents an important medical breakthrough pioneered by Edward Jenner over 200 years ago when he developed the world's first vaccine against smallpox. To this day, vaccination remains the most effective means available for combating infectious disease. There are currently over 20 vaccines licensed for use within the US with many more vaccines in the R&D pipeline. Although vaccines must demonstrate clinical efficacy in order to receive FDA approval, the correlates of immunity vary remarkably between different vaccines and may be based primarily on animal studies, clinical evidence, or a combination of these sources of information. Correlates of protection are critical for measuring vaccine efficacy but researchers should know the history and limitations of these values. As vaccine technologies advance, the way in which we measure and define protective correlates may need to evolve as well. Here, we describe the correlates of protective immunity for vaccines against smallpox, tetanus, yellow fever and measles and compare these to a more recently introduced vaccine against varicella zoster virus, wherein a strict correlate of immunity has yet to be fully defined. PMID:18398296

  11. Immunogenicity of candidate chimeric DNA vaccine against tuberculosis and leishmaniasis.

    PubMed

    Dey, Ayan; Kumar, Umesh; Sharma, Pawan; Singh, Sarman

    2009-08-13

    Mycobacterium tuberculosis and Leishmania donovani are important intracellular pathogens, especially in Indian context. In India and other South East Asian countries, both these infections are highly endemic and in about 20% cases co-infection of these pathogens is reported. For both these pathogens cell mediated immunity plays most important role. The available treatment of these infections is either prolonged or cumbersome or it is ineffective in controlling the outbreaks and spread. Therefore, potentiation of a common host defense mechanism can be used to prevent both the infections simultaneously. In this study we have developed a novel chimeric DNA vaccine candidate comprising the esat-6 gene of M. tuberculosis and kinesin motor domain gene of L. donovani. After developing this novel chimera, its immunogenicity was studied in mouse model. The immune response was compared with individual constructs of esat-6 and kinesin motor domain. The results showed that immunization with chimeric DNA vaccine construct resulted in stronger IFN-gamma and IL-2 response against kinesin (3012+/-102 and 367.5+/-8.92pg/ml) and ESAT-6 (1334+/-46.5 and 245.1+/-7.72pg/ml) in comparison to the individual vaccine constructs. The reciprocal immune response (IFN-gamma and IL-2) against individual construct was lower (kinesin motor domain: 1788+/-36.48 and 341.8+/-9.801pg/ml and ESAT-6: 867.0+/-47.23 and 170.8+/-4.578pg/ml, respectively). The results also suggest that using the chimeric construct both proteins yielded a reciprocal adjuvant affect over each other as the IFN-gamma production against chimera vaccination is statistically significant (p<0.0001) than individual construct vaccination. From this pilot study we could envisage that the chimeric DNA vaccine construct may offer an attractive strategy in controlling co-infection of leishmaniasis and tuberculosis and have important implication in future vaccine design. PMID:19559111

  12. Immunogenicity of candidate chimeric DNA vaccine against tuberculosis and leishmaniasis.

    PubMed

    Dey, Ayan; Kumar, Umesh; Sharma, Pawan; Singh, Sarman

    2009-08-13

    Mycobacterium tuberculosis and Leishmania donovani are important intracellular pathogens, especially in Indian context. In India and other South East Asian countries, both these infections are highly endemic and in about 20% cases co-infection of these pathogens is reported. For both these pathogens cell mediated immunity plays most important role. The available treatment of these infections is either prolonged or cumbersome or it is ineffective in controlling the outbreaks and spread. Therefore, potentiation of a common host defense mechanism can be used to prevent both the infections simultaneously. In this study we have developed a novel chimeric DNA vaccine candidate comprising the esat-6 gene of M. tuberculosis and kinesin motor domain gene of L. donovani. After developing this novel chimera, its immunogenicity was studied in mouse model. The immune response was compared with individual constructs of esat-6 and kinesin motor domain. The results showed that immunization with chimeric DNA vaccine construct resulted in stronger IFN-gamma and IL-2 response against kinesin (3012+/-102 and 367.5+/-8.92pg/ml) and ESAT-6 (1334+/-46.5 and 245.1+/-7.72pg/ml) in comparison to the individual vaccine constructs. The reciprocal immune response (IFN-gamma and IL-2) against individual construct was lower (kinesin motor domain: 1788+/-36.48 and 341.8+/-9.801pg/ml and ESAT-6: 867.0+/-47.23 and 170.8+/-4.578pg/ml, respectively). The results also suggest that using the chimeric construct both proteins yielded a reciprocal adjuvant affect over each other as the IFN-gamma production against chimera vaccination is statistically significant (p<0.0001) than individual construct vaccination. From this pilot study we could envisage that the chimeric DNA vaccine construct may offer an attractive strategy in controlling co-infection of leishmaniasis and tuberculosis and have important implication in future vaccine design.

  13. Immunopathogenesis of tuberculosis and novel mechanisms of vaccine activity.

    PubMed

    Schrager, Lewis K; Izzo, Angelo; Velmurugan, Kamalakannan

    2016-08-01

    The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Immunopathogenesis of Tuberculosis, and Immunopathogenesis and Novel Mechanisms of Vaccine Activity. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. PMID:27450395

  14. Modelling the impact of vaccination on tuberculosis in badgers.

    PubMed

    Hardstaff, J L; Bulling, M T; Marion, G; Hutchings, M R; White, P C L

    2013-07-01

    Tuberculosis (TB) in livestock, caused by Mycobacterium bovis, persists in many countries. In Britain, efforts to control TB through the culling of badgers (Meles meles), the principal wildlife host, have so far been unsuccessful, and there is significant interest in vaccination of badgers as an alternative or complementary strategy [corrected]. Using a simulation model, we show that where TB is self-contained within the badger population and there are no external sources of infection, limited-duration vaccination at a high level of efficacy can reduce or even eradicate TB from the badger population. However, where sources of external infection persist, benefits in TB reduction in badgers can only be achieved by ongoing, annual vaccination. Vaccination is likely to be most effective as part of an integrated disease management strategy incorporating a number of different approaches across the entire host community.

  15. Farmers' confidence in vaccinating badgers against bovine tuberculosis.

    PubMed

    Enticott, G; Maye, D; Ilbery, B; Fisher, R; Kirwan, J

    2012-02-25

    This paper examines UK farmers' levels of confidence in vaccinating badgers against bovine tuberculosis (bTB) and their trust in the Government's ability to deal with bTB. In 2010, a badger vaccine based on the BCG vaccine was licensed following field trials and used as part of the UK Government's Badger Vaccination Deployment Project. A stratified random sample of cattle farmers in five different locations of England was surveyed using a telephone survey to elicit their views of badger vaccination. The survey provided a total of 341 responses with a response rate of 80 per cent. Results suggest that the farmers are cautious about badger vaccination, appearing to be neither overly confident nor unconfident in it. However, the farmers did not reveal high levels of trust in the Government to manage bTB policy or badger vaccination. There were no differences in the levels of confidence or trust between farms that were under bTB restrictions at the time of the survey and those that were not or between farms with historically high levels of bTB. Analysis of principal components suggests that 33 per cent of the farmers accepted badger vaccination, but that acceptance is dependent on the wider social and political environment. PMID:22238199

  16. Farmers' confidence in vaccinating badgers against bovine tuberculosis.

    PubMed

    Enticott, G; Maye, D; Ilbery, B; Fisher, R; Kirwan, J

    2012-02-25

    This paper examines UK farmers' levels of confidence in vaccinating badgers against bovine tuberculosis (bTB) and their trust in the Government's ability to deal with bTB. In 2010, a badger vaccine based on the BCG vaccine was licensed following field trials and used as part of the UK Government's Badger Vaccination Deployment Project. A stratified random sample of cattle farmers in five different locations of England was surveyed using a telephone survey to elicit their views of badger vaccination. The survey provided a total of 341 responses with a response rate of 80 per cent. Results suggest that the farmers are cautious about badger vaccination, appearing to be neither overly confident nor unconfident in it. However, the farmers did not reveal high levels of trust in the Government to manage bTB policy or badger vaccination. There were no differences in the levels of confidence or trust between farms that were under bTB restrictions at the time of the survey and those that were not or between farms with historically high levels of bTB. Analysis of principal components suggests that 33 per cent of the farmers accepted badger vaccination, but that acceptance is dependent on the wider social and political environment.

  17. Tuberculosis vaccine development: Shifting focus amid increasing development challenges

    PubMed Central

    Graves, AJ; Hokey, DA

    2015-01-01

    A new tuberculosis vaccine is needed to replace or enhance BCG, which induces variable protection against Mycobacterium tuberculosis pulmonary infections in adults. Development of new TB vaccine candidates is severely hampered by the lack of a correlate of immunity, unproven animal models, and limited funding opportunities. One candidate, MVA85A, recently failed to meet its efficacy endpoint goals despite promising early-phase trial data. As a result, some in the field believe we should now shift our focus away from product development and toward a research-oriented approach. Here, we outline our suggestions for this research-oriented strategy including diversification of the candidate pipeline, expanding measurements of immunity, improving pre-clinical animal models, and investing in combination pre-clinical/experimental medicine studies. As with any evolution, this change in strategy comes at a cost but may also represent an opportunity for advancing the field. PMID:26125249

  18. Assessing vaccination as a control strategy in an ongoing epidemic: Bovine tuberculosis in African buffalo

    USGS Publications Warehouse

    Cross, Paul C.; Getz, W.M.

    2006-01-01

    Bovine tuberculosis (BTB) is an exotic disease invading the buffalo population (Syncerus caffer) of the Kruger National Park (KNP), South Africa. We used a sex and age-structured epidemiological model to assess the effectiveness of a vaccination program and define important research directions. The model allows for dispersal between a focal herd and background population and was parameterized with a combination of published data and analyses of over 130 radio-collared buffalo in the central region of the KNP. Radio-tracking data indicated that all sex and age categories move between mixed herds, and males over 8 years old had higher mortality and dispersal rates than any other sex or age category. In part due to the high dispersal rates of buffalo, sensitivity analyses indicate that disease prevalence in the background population accounts for the most variability in the BTB prevalence and quasi-eradication within the focal herd. Vaccination rate and the transmission coefficient were the second and third most important parameters of the sensitivity analyses. Further analyses of the model without dispersal suggest that the amount of vaccination necessary for quasi-eradication (i.e. prevalence < 5%) depends upon the duration that a vaccine grants protection. Vaccination programs are more efficient (i.e. fewer wasted doses) when they focus on younger individuals. However, even with a lifelong vaccine and a closed population, the model suggests that >70% of the calf population would have to be vaccinated every year to reduce the prevalence to less than 1%. If the half-life of the vaccine is less than 5 years, even vaccinating every calf for 50 years may not eradicate BTB. Thus, although vaccination provides a means of controlling BTB prevalence it should be combined with other control measures if eradication is the objective.

  19. Dual Neonate Vaccine Platform against HIV-1 and M. tuberculosis

    PubMed Central

    Hopkins, Richard; Bridgeman, Anne; Joseph, Joan; Gilbert, Sarah C.; McShane, Helen; Hanke, Tomáš

    2011-01-01

    Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the world's most devastating diseases. The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB. BCG protects against disseminated disease in the first 10 years of life, but provides a variable protection against pulmonary TB and enhancing boost delivered by recombinant modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of M. tuberculosis is currently in phase IIb evaluation in African neonates. If the newborn's mother is positive for human immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring HIV-1 through breastfeeding. We suggested that a vaccination consisting of recombinant BCG expressing HIV-1 immunogen administered at birth followed by a boost with rMVA sharing the same immunogen could serve as a strategy for prevention of mother-to-child transmission of HIV-1 and rMVA expressing an African HIV-1-derived immunogen HIVA is currently in phase I trials in African neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1 and TB consisting of BCG.HIVA administered at birth followed by a boost with MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed, in which the transgene transcription is driven by either modified H5 or short synthetic promoters, respectively, and tested for immunogenicity alone and in combination with BCG.HIVA222. mMVA.HIVA.85A was produced markerless and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice. A BCG.HIVA222–mMVA.HIVA.85A prime-boost regimen induced robust T cell responses to both HIV-1 and M. tuberculosis. Therefore, proof-of-principle for a dual anti-HIV-1/M. tuberculosis infant vaccine platform is established. Induction of immune responses against these pathogens soon after

  20. Development of new vaccines for tuberculosis. Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET).

    PubMed

    1998-08-21

    Tuberculosis (TB) remains a major, global public health problem, particularly in low-income countries. Better application of current diagnostic, treatment, and prevention strategies could lead to gradual decreases in the disease, but eliminating TB completely in the United States and internationally will require new tools. The greatest impact could come from a new vaccine, and recent technological advances have provided the basis for new vaccine development. However, sustained support is required to move the research from the laboratory to field trials of vaccines and to implement new vaccine programs. Recognizing the importance of TB vaccines, the Advisory Council for the Elimination of Tuberculosis (ACET) recommends that public agencies and vaccine manufacturers develop a comprehensive, consensual strategy to achieve these goals. This report outlines the elements that should be considered in devising a strategic plan for vaccine development.

  1. Efficacy of a Vaccine Formula against Tuberculosis in Cattle

    PubMed Central

    Canto Alarcon, Germinal J.; Rubio Venegas, Yezenia; Bojorquez Narvaez, Luis; Pizano Martínez, Oscar E.; García Casanova, Leticia; Sosa Gallegos, Susana; Nava Vargas, Alejandro; Olvera Ramírez, Andrea M.; Milian Suazo, Feliciano

    2013-01-01

    “Test-and-slaughter” has been successful in industrialized countries to control and eradicate tuberculosis from cattle; however, this strategy is too expensive for developing nations, where the prevalence is especially high. Vaccination with the Calmette-Guérin (BCG) strain has been shown to protect against the development of lesions in vaccinated animals: mouse, cattle and wildlife species. In this study, the immune response and the pathology of vaccinated (BCG-prime and BCG prime-CFP-boosted) and unvaccinated (controls) calves were evaluated under experimental settings. A 106 CFU dose of the BCG strain was inoculated subcutaneously on the neck to two groups of ten animas each. Thirty days after vaccination, one of the vaccinated groups was boosted with an M. bovis culture filtrate protein (CFP). Three months after vaccination, the three groups of animals were challenged with 5×105 CFU via intranasal by aerosol with a field strain of M. bovis. The immune response was monitored throughout the study. Protection was assessed based on immune response (IFN-g release) prechallenge, presence of visible lesions in lymph nodes and lungs at slaughter, and presence of bacilli in lymph nodes and lung samples in histological analysis. Vaccinated cattle, either with the BCG alone or with BCG and boosted with CFP showed higher IFN-g response, fewer lesions, and fewer bacilli per lesion than unvaccinated controls after challenge. Animals with low levels of IFN-g postvaccine-prechallenge showed more lesions than animals with high levels. Results from this study support the argument that vaccination could be incorporated into control programs to reduce the incidence of TB in cattle in countries with high prevalence. PMID:24204624

  2. Elimination of the cold-chain dependence of a nanoemulsion adjuvanted vaccine against tuberculosis by lyophilization

    PubMed Central

    Orr, Mark T.; Kramer, Ryan M.; Barnes, Lucien V; Dowling, Quinton M.; Desbien, Anthony L.; Beebe, Elyse A.; Laurance, John D.; Fox, Christopher B.; Reed, Steven G.; Coler, Rhea N.; Vedvick, Thomas S.

    2014-01-01

    Next-generation rationally-designed vaccine adjuvants represent a significant breakthrough to enable development of vaccines against challenging diseases including tuberculosis, HIV, and malaria. New vaccine candidates often require maintenance of a cold-chain process to ensure long-term stability and separate vials to enable bedside mixing of antigen and adjuvant. This presents a significant financial and technological barrier to worldwide implementation of such vaccines. Herein we describe the development and characterization of a tuberculosis vaccine comprised of both antigen and adjuvant components that are stable in a single vial at sustained elevated temperatures. Further this vaccine retains the ability to elicit both antibody and TH1 responses against the vaccine antigen and protect against experimental challenge with Mycobacterium tuberculosis. These results represent a significant breakthrough in the development of vaccine candidates that can be implemented throughout the world without being hampered by the necessity of a continuous cold chain or separate adjuvant and antigen vials. PMID:24382398

  3. Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis

    PubMed Central

    Kaushal, Deepak; Foreman, Taylor W.; Gautam, Uma S.; Alvarez, Xavier; Adekambi, Toidi; Rangel-Moreno, Javier; Golden, Nadia A.; Johnson, Ann-Marie F.; Phillips, Bonnie L.; Ahsan, Muhammad H.; Russell-Lodrigue, Kasi E.; Doyle, Lara A.; Roy, Chad J.; Didier, Peter J.; Blanchard, James L.; Rengarajan, Jyothi; Lackner, Andrew A.; Khader, Shabaana A.; Mehra, Smriti

    2015-01-01

    Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH (MtbΔsigH) results in significant recruitment of inducible bronchus-associated lymphoid tissue (iBALT) as well as CD4+ and CD8+ T cells expressing activation and proliferation markers to the lungs. Further, the findings indicate that pulmonary vaccination with MtbΔsigH elicited strong central memory CD4+ and CD8+ T-cell responses in the lung. Vaccination with MtbΔsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT. This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. These results suggest that future TB vaccine candidates can be developed on the basis of MtbΔsigH. PMID:26460802

  4. Oral vaccination with heat inactivated Mycobacterium bovis activates the complement system to protect against tuberculosis.

    PubMed

    Beltrán-Beck, Beatriz; de la Fuente, José; Garrido, Joseba M; Aranaz, Alicia; Sevilla, Iker; Villar, Margarita; Boadella, Mariana; Galindo, Ruth C; Pérez de la Lastra, José M; Moreno-Cid, Juan A; Fernández de Mera, Isabel G; Alberdi, Pilar; Santos, Gracia; Ballesteros, Cristina; Lyashchenko, Konstantin P; Minguijón, Esmeralda; Romero, Beatriz; de Juan, Lucía; Domínguez, Lucas; Juste, Ramón; Gortazar, Christian

    2014-01-01

    Tuberculosis (TB) remains a pandemic affecting billions of people worldwide, thus stressing the need for new vaccines. Defining the correlates of vaccine protection is essential to achieve this goal. In this study, we used the wild boar model for mycobacterial infection and TB to characterize the protective mechanisms elicited by a new heat inactivated Mycobacterium bovis vaccine (IV). Oral vaccination with the IV resulted in significantly lower culture and lesion scores, particularly in the thorax, suggesting that the IV might provide a novel vaccine for TB control with special impact on the prevention of pulmonary disease, which is one of the limitations of current vaccines. Oral vaccination with the IV induced an adaptive antibody response and activation of the innate immune response including the complement component C3 and inflammasome. Mycobacterial DNA/RNA was not involved in inflammasome activation but increased C3 production by a still unknown mechanism. The results also suggested a protective mechanism mediated by the activation of IFN-γ producing CD8+ T cells by MHC I antigen presenting dendritic cells (DCs) in response to vaccination with the IV, without a clear role for Th1 CD4+ T cells. These results support a role for DCs in triggering the immune response to the IV through a mechanism similar to the phagocyte response to PAMPs with a central role for C3 in protection against mycobacterial infection. Higher C3 levels may allow increased opsonophagocytosis and effective bacterial clearance, while interfering with CR3-mediated opsonic and nonopsonic phagocytosis of mycobacteria, a process that could be enhanced by specific antibodies against mycobacterial proteins induced by vaccination with the IV. These results suggest that the IV acts through novel mechanisms to protect against TB in wild boar.

  5. Oral Vaccination with Heat Inactivated Mycobacterium bovis Activates the Complement System to Protect against Tuberculosis

    PubMed Central

    Garrido, Joseba M.; Aranaz, Alicia; Sevilla, Iker; Villar, Margarita; Boadella, Mariana; Galindo, Ruth C.; Pérez de la Lastra, José M.; Moreno-Cid, Juan A.; Fernández de Mera, Isabel G.; Alberdi, Pilar; Santos, Gracia; Ballesteros, Cristina; Lyashchenko, Konstantin P.; Minguijón, Esmeralda; Romero, Beatriz; de Juan, Lucía; Domínguez, Lucas; Juste, Ramón; Gortazar, Christian

    2014-01-01

    Tuberculosis (TB) remains a pandemic affecting billions of people worldwide, thus stressing the need for new vaccines. Defining the correlates of vaccine protection is essential to achieve this goal. In this study, we used the wild boar model for mycobacterial infection and TB to characterize the protective mechanisms elicited by a new heat inactivated Mycobacterium bovis vaccine (IV). Oral vaccination with the IV resulted in significantly lower culture and lesion scores, particularly in the thorax, suggesting that the IV might provide a novel vaccine for TB control with special impact on the prevention of pulmonary disease, which is one of the limitations of current vaccines. Oral vaccination with the IV induced an adaptive antibody response and activation of the innate immune response including the complement component C3 and inflammasome. Mycobacterial DNA/RNA was not involved in inflammasome activation but increased C3 production by a still unknown mechanism. The results also suggested a protective mechanism mediated by the activation of IFN-γ producing CD8+ T cells by MHC I antigen presenting dendritic cells (DCs) in response to vaccination with the IV, without a clear role for Th1 CD4+ T cells. These results support a role for DCs in triggering the immune response to the IV through a mechanism similar to the phagocyte response to PAMPs with a central role for C3 in protection against mycobacterial infection. Higher C3 levels may allow increased opsonophagocytosis and effective bacterial clearance, while interfering with CR3-mediated opsonic and nonopsonic phagocytosis of mycobacteria, a process that could be enhanced by specific antibodies against mycobacterial proteins induced by vaccination with the IV. These results suggest that the IV acts through novel mechanisms to protect against TB in wild boar. PMID:24842853

  6. [Advances in the development of new vaccines against tuberculosis. 100 years after the introduction of BCG].

    PubMed

    Krysztopa-Grzybowska, Katarzyna; Lutyńska, Anna

    2014-01-01

    The BCG vaccine used in the world for nearly 100 years protects children against the most severe forms of tuberculosis, but its effectiveness in preventing the most commonly occurring tuberculosis and the one burdened with the highest risk of transmission in adults is very diverse. Contraindications for BCG vaccination include HIV infection and other conditions of immunosuppression. Tuberculosis is a global problem difficult to control because of three main reasons: poor diagnostics in developing countries, long-term therapy or discontinuation of treatment resulting in the emergence of drug-resistant mycobacteria, and the availability of a TB vaccine which only protects children from the most severe forms of tuberculosis. BCG has little to no efficacy in preventing the most common adult pulmonary TB. The development of a more effective vaccine against tuberculosis is undoubtedly still a public health priority in order to improve control of the disease throughout the world. Elimination of TB as a global public health goal by 2050 is particularly ambitious and its achievement depends on the development and application of new intervention measures and newly designed vaccines. Currently, 14 newly developed products are undergoing clinical trials. These include a prophylactic vaccine capable of replacing the current BCG, booster vaccines to increase the effects of BCG, and therapeutic vaccines. The aim of the study is to present the current state of knowledge on cutting-edge research into new vaccines against tuberculosis, their efficacy, immunogenicity and potential use in the future.

  7. The Progress of Therapeutic Vaccination with Regard to Tuberculosis

    PubMed Central

    Cardona, Pere-Joan

    2016-01-01

    A major problem with tuberculosis (TB) control is the long duration of drug therapy–both for latent and for active TB. Therapeutic vaccination has been postulated to improve this situation, and to this end there are several candidates already in clinical phases of development. These candidates follow two main designs, namely bacilli-directed therapy based on inactivated -whole or -fragmented bacillus (Mycobacterium w and RUTI) or fusion proteins that integrate non-replicating bacilli -related antigens (H56 vaccine), and host-directed therapy to reduce the tissue destruction. The administration of inactivated Mycobacterium vaccae prevents the “Koch phenomenon” response, and oral administration of heat-killed Mycobacterium manresensis prevents excessive neutrophilic infiltration of the lesions. This review also tries to explain the success of Mycobacterium tuberculosis by reviewing its evolution from infection to disease, and highlights the lack of a definitive understanding of the natural history of TB pathology and the need to improve our knowledge on TB immunology and pathogenesis. PMID:27733848

  8. Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

    PubMed Central

    Hoang, Truc; Agger, Else Marie; Cassidy, Joseph P.; Christensen, Jan P.

    2015-01-01

    Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse of Mycobacterium tuberculosis, as well as increased pathology, in both Mycobacterium bovis BCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ+ TNF-α+ and IFN-γ+ cells). PEM during M. tuberculosis infection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine against M. tuberculosis infection. PMID:25754202

  9. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations.

    PubMed

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-01-01

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed. PMID:26344627

  10. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

    PubMed Central

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-01-01

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed. PMID:26344627

  11. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations.

    PubMed

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-06-16

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

  12. Tuberculosis.

    PubMed

    Dheda, Keertan; Barry, Clifton E; Maartens, Gary

    2016-03-19

    Although the worldwide incidence of tuberculosis has been slowly decreasing, the global disease burden remains substantial (∼9 million cases and ∼1·5 million deaths in 2013), and tuberculosis incidence and drug resistance are rising in some parts of the world such as Africa. The modest gains achieved thus far are threatened by high prevalence of HIV, persisting global poverty, and emergence of highly drug-resistant forms of tuberculosis. Tuberculosis is also a major problem in health-care workers in both low-burden and high-burden settings. Although the ideal preventive agent, an effective vaccine, is still some time away, several new diagnostic technologies have emerged, and two new tuberculosis drugs have been licensed after almost 50 years of no tuberculosis drugs being registered. Efforts towards an effective vaccine have been thwarted by poor understanding of what constitutes protective immunity. Although new interventions and investment in control programmes will enable control, eradication will only be possible through substantial reductions in poverty and overcrowding, political will and stability, and containing co-drivers of tuberculosis, such as HIV, smoking, and diabetes.

  13. Tuberculosis.

    PubMed

    Dheda, Keertan; Barry, Clifton E; Maartens, Gary

    2016-03-19

    Although the worldwide incidence of tuberculosis has been slowly decreasing, the global disease burden remains substantial (∼9 million cases and ∼1·5 million deaths in 2013), and tuberculosis incidence and drug resistance are rising in some parts of the world such as Africa. The modest gains achieved thus far are threatened by high prevalence of HIV, persisting global poverty, and emergence of highly drug-resistant forms of tuberculosis. Tuberculosis is also a major problem in health-care workers in both low-burden and high-burden settings. Although the ideal preventive agent, an effective vaccine, is still some time away, several new diagnostic technologies have emerged, and two new tuberculosis drugs have been licensed after almost 50 years of no tuberculosis drugs being registered. Efforts towards an effective vaccine have been thwarted by poor understanding of what constitutes protective immunity. Although new interventions and investment in control programmes will enable control, eradication will only be possible through substantial reductions in poverty and overcrowding, political will and stability, and containing co-drivers of tuberculosis, such as HIV, smoking, and diabetes. PMID:26377143

  14. Defining the Needs for Next Generation Assays for Tuberculosis

    PubMed Central

    Denkinger, Claudia M.; Kik, Sandra V.; Cirillo, Daniela Maria; Casenghi, Martina; Shinnick, Thomas; Weyer, Karin; Gilpin, Chris; Boehme, Catharina C.; Schito, Marco; Kimerling, Michael; Pai, Madhukar

    2015-01-01

    To accelerate the fight against tuberculosis, major diagnostic challenges need to be addressed urgently. Post-2015 targets are unlikely to be met without the use of novel diagnostics that are more accurate and can be used closer to where patients first seek care in affordable diagnostic algorithms. This article describes the efforts by the stakeholder community that led to the identification of the high-priority diagnostic needs in tuberculosis. Subsequently target product profiles for the high-priority diagnostic needs were developed and reviewed in a World Health Organization (WHO)-led consensus meeting. The high-priority diagnostic needs included (1) a sputum-based replacement test for smear-microscopy; (2) a non-sputum-based biomarker test for all forms of tuberculosis, ideally suitable for use at levels below microscopy centers; (3) a simple, low cost triage test for use by first-contact care providers as a rule-out test, ideally suitable for use by community health workers; and (4) a rapid drug susceptibility test for use at the microscopy center level. The developed target product profiles, along with complimentary work presented in this supplement, will help to facilitate the interaction between the tuberculosis community and the diagnostics industry with the goal to lead the way toward the post-2015 global tuberculosis targets. PMID:25765104

  15. Evaluation of the immunogenicity and diagnostic interference caused by M. tuberculosis SO2 vaccination against tuberculosis in goats.

    PubMed

    Bezos, Javier; Casal, Carmen; Puentes, Eugenia; Díez-Guerrier, Alberto; Romero, Beatriz; Aguiló, Nacho; de Juan, Lucía; Martín, Carlos; Domínguez, Lucas

    2015-12-01

    The immunogenicity and diagnostic interference caused by M. tuberculosis SO2, a prototype vaccine first time tested in goats was evaluated. Tuberculosis-free goats were distributed in four groups: [1], non-vaccinated; [2], subcutaneously (SC) BCG vaccinated; [3], intranasally (IN) SO2 vaccinated and [4], SC SO2 vaccinated. Intradermal tuberculin and IFN-γ tests using PPDs and alternative antigenic cocktails containing mainly ESAT-6 and CFP-10 (E/C) were applied at different times post-vaccination. Results showed a significant (p<0.05) increase in the number of reactors detected using both PPD-based intradermal and IFN-γ tests at different times in all the vaccinated groups. No intradermal reactivity was detected in the vaccinated goats using a cocktail containing E/C, Rv3615c and Rv3020c. A higher overall reactivity was observed in the group [4] in comparison with the other vaccinated groups. Results showed that antigens used to differentiate BCG vaccinated animals could be potentially used to differentiate SO2 vaccinated ones.

  16. Evaluation of the immunogenicity and diagnostic interference caused by M. tuberculosis SO2 vaccination against tuberculosis in goats.

    PubMed

    Bezos, Javier; Casal, Carmen; Puentes, Eugenia; Díez-Guerrier, Alberto; Romero, Beatriz; Aguiló, Nacho; de Juan, Lucía; Martín, Carlos; Domínguez, Lucas

    2015-12-01

    The immunogenicity and diagnostic interference caused by M. tuberculosis SO2, a prototype vaccine first time tested in goats was evaluated. Tuberculosis-free goats were distributed in four groups: [1], non-vaccinated; [2], subcutaneously (SC) BCG vaccinated; [3], intranasally (IN) SO2 vaccinated and [4], SC SO2 vaccinated. Intradermal tuberculin and IFN-γ tests using PPDs and alternative antigenic cocktails containing mainly ESAT-6 and CFP-10 (E/C) were applied at different times post-vaccination. Results showed a significant (p<0.05) increase in the number of reactors detected using both PPD-based intradermal and IFN-γ tests at different times in all the vaccinated groups. No intradermal reactivity was detected in the vaccinated goats using a cocktail containing E/C, Rv3615c and Rv3020c. A higher overall reactivity was observed in the group [4] in comparison with the other vaccinated groups. Results showed that antigens used to differentiate BCG vaccinated animals could be potentially used to differentiate SO2 vaccinated ones. PMID:26679799

  17. Progress in the development of tuberculosis vaccines for cattle and wildlife.

    PubMed

    Buddle, B M; Wedlock, D N; Denis, M

    2006-02-25

    Vaccination against bovine tuberculosis is likely to become an important disease control strategy in developing countries, which cannot afford a test and slaughter control programme, or in countries which have a wildlife reservoir of Mycobacterium bovis infection. In the past decade, considerable progress has been made in the development and evaluation of tuberculosis vaccines for cattle and for a range of wildlife maintenance hosts including possums, badgers, deer and African buffaloes. Experimental challenge systems have been established for the different target species and the resulting disease process has mimicked that seen in the field. In cattle, neonatal vaccination with BCG appeared to be more effective than vaccination of 6-month-old calves and in most situations no other vaccine has been shown to be better than BCG. However, prime-boost strategies involving combinations of BCG with a protein or DNA vaccine, to improve on BCG vaccination alone, have produced very encouraging results. Differential diagnostic tests have been developed using mycobacterial antigens that are only present in virulent M. bovis to differentiate between BCG-vaccinated and M. bovis-infected cattle. BCG vaccine has been shown to reduce the spread of tuberculous lesions in a range of wildlife species and a prototype oral bait delivery system has been developed. Prospects for the development of improved vaccines against bovine tuberculosis are promising and vaccination approaches could become very valuable in the control and eradication of bovine tuberculosis. PMID:16326043

  18. Multi-Stage Tuberculosis Subunit Vaccine Candidate LT69 Provides High Protection against Mycobacterium tuberculosis Infection in Mice

    PubMed Central

    Niu, Hongxia; Peng, Jinxiu; Bai, Chunxiang; Liu, Xun; Hu, Lina; Luo, Yanping; Wang, Bingxiang; Zhang, Ying; Chen, Jianzhu; Yu, Hongjuan; Xian, Qiaoyang; Zhu, Bingdong

    2015-01-01

    Effective tuberculosis (TB) vaccine should target tubercle bacilli with various metabolic states and confer long-term protective immunity. In this study, we constructed a novel multi-stage TB subunit vaccine based on fusion protein ESAT6-Ag85B-MPT64(190-198)-Mtb8.4-HspX (LT69 for short) which combined early expressed antigens and latency-associated antigen. The fusion protein was mixed with an adjuvant being composed of N, N’-dimethyl-N, N’-dioctadecylammonium bromide (DDA) and polyriboinosinic polyribocytidylic acid (PolyI:C) to construct subunit vaccine, whose immunogenicity and protective ability were evaluated in C57BL/6 mice. The results showed that LT69 had strong immunogenicity and high protective effect against Mycobacterium tuberculosis (M. tuberculosis) H37Rv aerosol challenge. Low-dose (2 μg) of LT69 generated long-term immune memory responses and provided effective protection, which was even higher than traditional vaccine BCG did at 30 weeks post the last vaccination. In conclusion, multistage subunit vaccine LT69 showed high and long-term protection against M. tuberculosis infection in mice, whose effect could be enhanced by using a relative low dosage of antigen. PMID:26098302

  19. Mathematical model for transmission of tuberculosis in badger population with vaccination

    NASA Astrophysics Data System (ADS)

    Tasmi, Aldila, D.; Soewono, E.; Nuraini, N.

    2016-04-01

    Badger was first time identified as a carrier of Bovine tuberculosis disease in England since 30 years ago. Bovine tuberculosis can be transmitted to another species through the faces, saliva, and breath. The control of tuberculosis in the badger is necessary to reduce the spread of the disease to other species. Many actions have been taken by the government to tackle the disease such as culling badgers with cyanide gas, but this way destroys the natural balance and disrupts the badger population. An alternative way to eliminate tuberculosis within badger population is by vaccination. Here in this paper a model for transmission of badger tuberculosis with vaccination is discussed. The existence of the endemic equilibrium, the stability and the basic reproduction ratio are shown analytically. Numerical simulations show that with proper vaccination level, the basic reproduction ratio could be reduced significantly. Sensitivity analysis for variation of parameters are shown numerically.

  20. Assessing vaccination as a control strategy in an ongoing epidemic: Bovine tuberculosis in African buffalo

    USGS Publications Warehouse

    Cross, P.C.; Getz, W.M.

    2006-01-01

    Bovine tuberculosis (BTB) is an exotic disease invading the buffalo population (Syncerus caffer) of the Kruger National Park (KNP), South Africa. We used a sex and age-structured epidemiological model to assess the effectiveness of a vaccination program and define important research directions. The model allows for dispersal between a focal herd and background population and was parameterized with a combination of published data and analyses of over 130 radio-collared buffalo in the central region of the KNP. Radio-tracking data indicated that all sex and age categories move between mixed herds, and males over 8 years old had higher mortality and dispersal rates than any other sex or age category. In part due to the high dispersal rates of buffalo, sensitivity analyses indicate that disease prevalence in the background population accounts for the most variability in the BTB prevalence and quasi-eradication within the focal herd. Vaccination rate and the transmission coefficient were the second and third most important parameters of the sensitivity analyses. Further analyses of the model without dispersal suggest that the amount of vaccination necessary for quasi-eradication (i.e. prevalence 70% of the calf population would have to be vaccinated every year to reduce the prevalence to less than 1%. If the half-life of the vaccine is less than 5 years, even vaccinating every calf for 50 years may not eradicate BTB. Thus, although vaccination provides a means of controlling BTB prevalence it should be combined with other control measures if eradication is the objective.

  1. Trained immunity: a new avenue for tuberculosis vaccine development.

    PubMed

    Lerm, M; Netea, M G

    2016-04-01

    Adaptive immunity towards tuberculosis (TB) has been extensively studied for many years. In addition, in recent years the profound contribution of innate immunity to host defence against this disease has become evident. The discovery of pattern recognition receptors, which allow innate immunity to tailor its response to different infectious agents, has challenged the view that this arm of immunity is nonspecific. Evidence is now accumulating that innate immunity can remember a previous exposure to a microorganism and respond differently during a second exposure. Although the specificity and memory of innate immunity cannot compete with the highly sophisticated adaptive immune response, its contribution to host defence against infection and to vaccine-induced immunity should not be underestimated and needs to be explored. Here, we present the concept of trained immunity and discuss how this may contribute to new avenues for control of TB.

  2. Protection by novel vaccine candidates, Mycobacterium tuberculosis ΔmosR and ΔechA7, against challenge with a Mycobacterium tuberculosis Beijing strain

    PubMed Central

    Marcus, Sarah A.; Steinberg, Howard; Talaat, Adel M.

    2015-01-01

    Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), infects over two billion people, claiming around 1.5 million lives annually. The only vaccine approved for clinical use against this disease is the Bacillus Calmette-Guérin (BCG) vaccine. Unfortunately, BCG has limited efficacy against the adult, pulmonary form of tuberculosis. This vaccine was developed from M. bovis with antigen expression and host specificity that differ from M. tuberculosis. To address these problems, we have designed two novel, live attenuated vaccine (LAV) candidates on an M. tuberculosis background: ΔmosR and ΔechA7. These targeted genes are important to M. tuberculosis pathogenicity during infection. To examine the efficacy of these strains, C57BL/6 mice were vaccinated subcutaneously with either LAV, BCG, or PBS. Both LAV strains persisted up to 16 weeks in the spleens or lungs of vaccinated mice, while eliciting minimal pathology prior to challenge. Following challenge with a selected, high virulence M. tuberculosis Beijing strain, protection was notably greater for both groups of LAV vaccinated animals as compared to BCG at both 30 and 60 days post-challenge. Additionally, vaccination with either ΔmosR or ΔechA7 elicited an immune response similar to BCG. Although these strains require further development to meet safety standards, this first evidence of protection by these two new, live attenuated vaccine candidates shows promise. PMID:26363381

  3. Monitoring vaccination coverage: Defining the role of surveys.

    PubMed

    Cutts, Felicity T; Claquin, Pierre; Danovaro-Holliday, M Carolina; Rhoda, Dale A

    2016-07-29

    Vaccination coverage is a widely used indicator of programme performance, measured by registries, routine administrative reports or household surveys. Because the population denominator and the reported number of vaccinations used in administrative estimates are often inaccurate, survey data are often considered to be more reliable. Many countries obtain survey data on vaccination coverage every 3-5years from large-scale multi-purpose survey programs. Additional surveys may be needed to evaluate coverage in Supplemental Immunization Activities such as measles or polio campaigns, or after major changes have occurred in the vaccination programme or its context. When a coverage survey is undertaken, rigorous statistical principles and field protocols should be followed to avoid selection bias and information bias. This requires substantial time, expertise and resources hence the role of vaccination coverage surveys in programme monitoring needs to be carefully defined. At times, programmatic monitoring may be more appropriate and provides data to guide program improvement. Practical field methods such as health facility-based assessments can evaluate multiple aspects of service provision, costs, coverage (among clinic attendees) and data quality. Similarly, purposeful sampling or censuses of specific populations can help local health workers evaluate their own performance and understand community attitudes, without trying to claim that the results are representative of the entire population. Administrative reports enable programme managers to do real-time monitoring, investigate potential problems and take timely remedial action, thus improvement of administrative estimates is of high priority. Most importantly, investment in collecting data needs to be complemented by investment in acting on results to improve performance. PMID:27349841

  4. Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool

    PubMed Central

    Karp, Christopher L; Wilson, Christopher B; Stuart, Lynda M

    2015-01-01

    The road to a more efficacious vaccine that could be a truly transformative tool for decreasing tuberculosis morbidity and mortality, along with Mycobacterium tuberculosis transmission, is quite daunting. Despite this, there are reasons for optimism. Abetted by better conceptual clarity, clear acknowledgment of the degree of our current immunobiological ignorance, the availability of powerful new tools for dissecting the immunopathogenesis of human tuberculosis, the generation of more creative diversity in tuberculosis vaccine concepts, the development of better fit-for-purpose animal models, and the potential of more pragmatic approaches to the clinical testing of vaccine candidates, the field has promise for delivering novel tools for dealing with this worldwide scourge of poverty. PMID:25703572

  5. Efficacy of parainfluenza virus 5 (PIV5)-based tuberculosis vaccines in mice.

    PubMed

    Chen, Zhenhai; Gupta, Tuhina; Xu, Pei; Phan, Shannon; Pickar, Adrian; Yau, Wilson; Karls, Russell K; Quinn, Frederick D; Sakamoto, Kaori; He, Biao

    2015-12-16

    Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is an important human pathogen. Bacillus Calmette-Guérin (BCG), a live, attenuated variant of Mycobacterium bovis, is currently the only available TB vaccine despite its low efficacy against the infectious pulmonary form of the disease in adults. Thus, a more-effective TB vaccine is needed. Parainfluenza virus 5 (PIV5), a paramyxovirus, has several characteristics that make it an attractive vaccine vector. It is safe, inexpensive to produce, and has been previously shown to be efficacious as the backbone of vaccines for influenza, rabies, and respiratory syncytial virus. In this work, recombinant PIV5 expressing M. tuberculosis antigens 85A (PIV5-85A) and 85B (PIV5-85B) have been generated and their immunogenicity and protective efficacy evaluated in a mouse aerosol infection model. In a long-term protection study, a single dose of PIV5-85A was found to be most effective in reducing M. tuberculosis colony forming units (CFU) in lungs when compared to unvaccinated, whereas the BCG vaccinated animals had similar numbers of CFUs to unvaccinated animals. BCG-prime followed by a PIV5-85A or PIV5-85B boost produced better outcomes highlighted by close to three-log units lower lung CFUs compared to PBS. The results indicate that PIV5-based M. tuberculosis vaccines are promising candidates for further development.

  6. Efficacy of parainfluenza virus 5 (PIV5)-based tuberculosis vaccines in mice.

    PubMed

    Chen, Zhenhai; Gupta, Tuhina; Xu, Pei; Phan, Shannon; Pickar, Adrian; Yau, Wilson; Karls, Russell K; Quinn, Frederick D; Sakamoto, Kaori; He, Biao

    2015-12-16

    Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is an important human pathogen. Bacillus Calmette-Guérin (BCG), a live, attenuated variant of Mycobacterium bovis, is currently the only available TB vaccine despite its low efficacy against the infectious pulmonary form of the disease in adults. Thus, a more-effective TB vaccine is needed. Parainfluenza virus 5 (PIV5), a paramyxovirus, has several characteristics that make it an attractive vaccine vector. It is safe, inexpensive to produce, and has been previously shown to be efficacious as the backbone of vaccines for influenza, rabies, and respiratory syncytial virus. In this work, recombinant PIV5 expressing M. tuberculosis antigens 85A (PIV5-85A) and 85B (PIV5-85B) have been generated and their immunogenicity and protective efficacy evaluated in a mouse aerosol infection model. In a long-term protection study, a single dose of PIV5-85A was found to be most effective in reducing M. tuberculosis colony forming units (CFU) in lungs when compared to unvaccinated, whereas the BCG vaccinated animals had similar numbers of CFUs to unvaccinated animals. BCG-prime followed by a PIV5-85A or PIV5-85B boost produced better outcomes highlighted by close to three-log units lower lung CFUs compared to PBS. The results indicate that PIV5-based M. tuberculosis vaccines are promising candidates for further development. PMID:26552000

  7. BCG vaccination reduces risk of tuberculosis infection in vaccinated badgers and unvaccinated badger cubs.

    PubMed

    Carter, Stephen P; Chambers, Mark A; Rushton, Stephen P; Shirley, Mark D F; Schuchert, Pia; Pietravalle, Stéphane; Murray, Alistair; Rogers, Fiona; Gettinby, George; Smith, Graham C; Delahay, Richard J; Hewinson, R Glyn; McDonald, Robbie A

    2012-01-01

    Wildlife is a global source of endemic and emerging infectious diseases. The control of tuberculosis (TB) in cattle in Britain and Ireland is hindered by persistent infection in wild badgers (Meles meles). Vaccination with Bacillus Calmette-Guérin (BCG) has been shown to reduce the severity and progression of experimentally induced TB in captive badgers. Analysis of data from a four-year clinical field study, conducted at the social group level, suggested a similar, direct protective effect of BCG in a wild badger population. Here we present new evidence from the same study identifying both a direct beneficial effect of vaccination in individual badgers and an indirect protective effect in unvaccinated cubs. We show that intramuscular injection of BCG reduced by 76% (Odds ratio = 0.24, 95% confidence interval (CI) 0.11-0.52) the risk of free-living vaccinated individuals testing positive to a diagnostic test combination to detect progressive infection. A more sensitive panel of tests for the detection of infection per se identified a reduction of 54% (Odds ratio = 0.46, 95% CI 0.26-0.88) in the risk of a positive result following vaccination. In addition, we show the risk of unvaccinated badger cubs, but not adults, testing positive to an even more sensitive panel of diagnostic tests decreased significantly as the proportion of vaccinated individuals in their social group increased (Odds ratio = 0.08, 95% CI 0.01-0.76; P = 0.03). When more than a third of their social group had been vaccinated, the risk to unvaccinated cubs was reduced by 79% (Odds ratio = 0.21, 95% CI 0.05-0.81; P = 0.02).

  8. Impact of proteomics on anti-Mycobacterium tuberculosis (MTB) vaccine development.

    PubMed

    Jagusztyn-Krynicka, Elzbieta K; Roszczenko, Paula; Grabowska, Anna

    2009-01-01

    Tuberculosis is a serious infection disease which causes more than two million deaths annually. The TB pandemic has continued despite widespread use of the only available licensed TB vaccine--Bacillus Calmette-Guerin (BCG). Additionally, the increasing incidences of multidrug resistant strains and coinfection with HIV mean that tuberculosis constitutes a growing global threat. Thus, improvement of the vaccination strategy against TB is an urgent need, requiring international cooperation of the research community. The completion of many mycobacterial genome sequences has greatly facilitated the global analysis at the transcriptome and proteome level. This in consequence has accelerated progress in the vaccinology field resulting in identification of a large numbers of antigens with potential in TB vaccines. This review concentrates on the proteomic contribution to TB vaccinology. At the end of the article some recent achievements of structural proteomics and developing an epitope-driven tuberculosis vaccine are presented.

  9. The Neonatal calf Tuberculosis Vaccine Model: Immune Responses to Protective and Non-protective Vaccines after Aerosol Challenge with Virulent Mycobacterium bovis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An attenuated Mycobacterium tuberculosis delta RD1 knockout and pantothenate auxotroph (mc**2 6030) vaccine failed to protect neonatal calves from a low dose, aerosol M. bovis challenge. In contrast, M. bovis bacille Calmette Guerin (BCG)-vaccinates had reduced tuberculosis-associated pathology as c...

  10. SATVI - after 10 years closing in on a new and better vaccine to prevent tuberculosis.

    PubMed

    Hanekom, Willem A; Hawkridge, Anthony; Mahomed, Hassan; Scriba, Thomas J; Tameris, Michele; Hughes, Jane; Hatherill, Mark; Day, Cheryl L; Hussey, Gregory D

    2012-03-02

    The vision of the South African Tuberculosis Vaccine Initiative (SATVI) (www.satvi.uct.ac.za) is 'A World Without TB' and our mission is 'Innovative and high-quality TB vaccine research in Africa, to impact the global epidemic'. Over the last 10 years, our focus has been twofold: first, clinical trials of BCG and of new candidate vaccines, and second, complementary research that addresses critical questions in TB vaccine development. SATVI is now widely regarded as the leading TB vaccine clinical research site in the world.

  11. Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

    PubMed Central

    Ottenhoff, Tom H. M.; Kaufmann, Stefan H. E.

    2012-01-01

    In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB. PMID:22589713

  12. Tuberculosis in domestic livestock: pathogenesis, transmission, and vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Mycobacterium tuberculosis complex includes agents such as M. tuberculosis and M. bovis, the cause of tuberculosis in most animals and a zoonotic pathogen. Mycobacterium bovis has one of the broadest host ranges of any pathogen, infecting most mammals, including humans. Models are used to study ...

  13. Identification of Novel Potential Vaccine Candidates against Tuberculosis Based on Reverse Vaccinology.

    PubMed

    Monterrubio-López, Gloria P; González-Y-Merchand, Jorge A; Ribas-Aparicio, Rosa María

    2015-01-01

    Tuberculosis (TB) is a chronic infectious disease, considered as the second leading cause of death worldwide, caused by Mycobacterium tuberculosis. The limited efficacy of the bacillus Calmette-Guérin (BCG) vaccine against pulmonary TB and the emergence of multidrug-resistant TB warrants the need for more efficacious vaccines. Reverse vaccinology uses the entire proteome of a pathogen to select the best vaccine antigens by in silico approaches. M. tuberculosis H37Rv proteome was analyzed with NERVE (New Enhanced Reverse Vaccinology Environment) prediction software to identify potential vaccine targets; these 331 proteins were further analyzed with VaxiJen for the determination of their antigenicity value. Only candidates with values ≥0.5 of antigenicity and 50% of adhesin probability and without homology with human proteins or transmembrane regions were selected, resulting in 73 antigens. These proteins were grouped by families in seven groups and analyzed by amino acid sequence alignments, selecting 16 representative proteins. For each candidate, a search of the literature and protein analysis with different bioinformatics tools, as well as a simulation of the immune response, was conducted. Finally, we selected six novel vaccine candidates, EsxL, PE26, PPE65, PE_PGRS49, PBP1, and Erp, from M. tuberculosis that can be used to improve or design new TB vaccines.

  14. Identification of Novel Potential Vaccine Candidates against Tuberculosis Based on Reverse Vaccinology

    PubMed Central

    Monterrubio-López, Gloria P.; González-Y-Merchand, Jorge A.; Ribas-Aparicio, Rosa María

    2015-01-01

    Tuberculosis (TB) is a chronic infectious disease, considered as the second leading cause of death worldwide, caused by Mycobacterium tuberculosis. The limited efficacy of the bacillus Calmette-Guérin (BCG) vaccine against pulmonary TB and the emergence of multidrug-resistant TB warrants the need for more efficacious vaccines. Reverse vaccinology uses the entire proteome of a pathogen to select the best vaccine antigens by in silico approaches. M. tuberculosis H37Rv proteome was analyzed with NERVE (New Enhanced Reverse Vaccinology Environment) prediction software to identify potential vaccine targets; these 331 proteins were further analyzed with VaxiJen for the determination of their antigenicity value. Only candidates with values ≥0.5 of antigenicity and 50% of adhesin probability and without homology with human proteins or transmembrane regions were selected, resulting in 73 antigens. These proteins were grouped by families in seven groups and analyzed by amino acid sequence alignments, selecting 16 representative proteins. For each candidate, a search of the literature and protein analysis with different bioinformatics tools, as well as a simulation of the immune response, was conducted. Finally, we selected six novel vaccine candidates, EsxL, PE26, PPE65, PE_PGRS49, PBP1, and Erp, from M. tuberculosis that can be used to improve or design new TB vaccines. PMID:25961021

  15. Assessment of vaccine testing at three laboratories using the guinea pig model of tuberculosis.

    PubMed

    Grover, Ajay; Troudt, Jolynn; Arnett, Kimberly; Izzo, Linda; Lucas, Megan; Strain, Katie; McFarland, Christine; Hall, Yper; McMurray, David; Williams, Ann; Dobos, Karen; Izzo, Angelo

    2012-01-01

    The guinea pig model of tuberculosis is used extensively in different locations to assess the efficacy of novel tuberculosis vaccines during pre-clinical development. Two key assays are used to measure protection against virulent challenge: a 30 day post-infection assessment of mycobacterial burden and long-term post-infection survival and pathology analysis. To determine the consistency and robustness of the guinea pig model for testing vaccines, a comparative assessment between three sites that are currently involved in testing tuberculosis vaccines from external providers was performed. Each site was asked to test two "subunit" type vaccines in their routine animal model as if testing vaccines from a provider. All sites performed a 30 day study, and one site also performed a long-term survival/pathology study. Despite some differences in experimental approach between the sites, such as the origin of the Mycobacterium tuberculosis strain and the type of aerosol exposure device used to infect the animals and the source of the guinea pigs, the data obtained between sites were consistent in regard to the ability of each "vaccine" tested to reduce the mycobacterial burden. The observations also showed that there was good concurrence between the results of short-term and long-term studies. This validation exercise means that efficacy data can be compared between sites.

  16. MTBVAC vaccine is safe, immunogenic and confers protective efficacy against Mycobacterium tuberculosis in newborn mice.

    PubMed

    Aguilo, Nacho; Uranga, Santiago; Marinova, Dessislava; Monzon, Marta; Badiola, Juan; Martin, Carlos

    2016-01-01

    Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG.

  17. MTBVAC vaccine is safe, immunogenic and confers protective efficacy against Mycobacterium tuberculosis in newborn mice

    PubMed Central

    Aguilo, Nacho; Uranga, Santiago; Marinova, Dessislava; Monzon, Marta; Badiola, Juan; Martin, Carlos

    2016-01-01

    Summary Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG. PMID:26786657

  18. Attenuated Mycobacterium tuberculosis SO2 vaccine candidate is unable to induce cell death.

    PubMed

    Aporta, Adriana; Arbues, Ainhoa; Aguilo, Juan I; Monzon, Marta; Badiola, Juan J; de Martino, Alba; Ferrer, Nadia; Marinova, Dessislava; Anel, Alberto; Martin, Carlos; Pardo, Julian

    2012-01-01

    It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death. The parental M. tuberculosis MT103 strain and the current vaccine against tuberculosis Bacillus Calmette-Guérin (BCG) were used as comparators in mouse models in vitro and in vivo. Our data reveal that attenuated SO2 was unable to induce apoptotic events neither in mouse macrophages in vitro nor during lung infection in vivo. In contrast, virulent MT103 triggers typical apoptotic events with phosphatidylserine exposure, caspase-3 activation and nuclear condensation and fragmentation. BCG strain behaved like SO2 and did not induce apoptosis. A clonogenic survival assay confirmed that viability of BCG- or SO2-infected macrophages was unaffected. Our results discard apoptosis as the protective mechanism induced by SO2 vaccine and provide evidence for positive correlation between classical apoptosis induction and virulent strains, suggesting apoptosis as a possible virulence determinant during M. tuberculosis infection. PMID:23028853

  19. Attenuated Mycobacterium tuberculosis SO2 Vaccine Candidate Is Unable to Induce Cell Death

    PubMed Central

    Monzon, Marta; Badiola, Juan J.; de Martino, Alba; Ferrer, Nadia; Marinova, Dessislava; Anel, Alberto; Martin, Carlos; Pardo, Julian

    2012-01-01

    It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death. The parental M. tuberculosis MT103 strain and the current vaccine against tuberculosis Bacillus Calmette-Guérin (BCG) were used as comparators in mouse models in vitro and in vivo. Our data reveal that attenuated SO2 was unable to induce apoptotic events neither in mouse macrophages in vitro nor during lung infection in vivo. In contrast, virulent MT103 triggers typical apoptotic events with phosphatidylserine exposure, caspase-3 activation and nuclear condensation and fragmentation. BCG strain behaved like SO2 and did not induce apoptosis. A clonogenic survival assay confirmed that viability of BCG- or SO2-infected macrophages was unaffected. Our results discard apoptosis as the protective mechanism induced by SO2 vaccine and provide evidence for positive correlation between classical apoptosis induction and virulent strains, suggesting apoptosis as a possible virulence determinant during M. tuberculosis infection. PMID:23028853

  20. Vaccination with an Attenuated Ferritin Mutant Protects Mice against Virulent Mycobacterium tuberculosis

    PubMed Central

    Subbian, Selvakumar; Pandey, Ruchi; Soteropoulos, Patricia; Rodriguez, G. Marcela

    2015-01-01

    Mycobacterium tuberculosis the causative agent of tuberculosis affects millions of people worldwide. New tools for treatment and prevention of tuberculosis are urgently needed. We previously showed that a ferritin (bfrB) mutant of M. tuberculosis has altered iron homeostasis and increased sensitivity to antibiotics and to microbicidal effectors produced by activated macrophages. Most importantly, M. tuberculosis lacking BfrB is strongly attenuated in mice, especially, during the chronic phase of infection. In this study, we examined whether immunization with a bfrB mutant could confer protection against subsequent infection with virulent M. tuberculosis in a mouse model. The results show that the protection elicited by immunization with the bfrB mutant is comparable to BCG vaccination with respect to reduction of bacterial burden. However, significant distinctions in the disease pathology and host genome-wide lung transcriptome suggest improved containment of Mtb infection in animals vaccinated with the bfrB mutant, compared to BCG. We found that downmodulation of inflammatory response and enhanced fibrosis, compared to BCG vaccination, is associated with the protective response elicited by the bfrB mutant. PMID:26339659

  1. A PE_PGRS33 protein of Mycobacterium tuberculosis: an ideal target for future tuberculosis vaccine design.

    PubMed

    Gastelum-Aviña, Paola; Velazquez, Carlos; Espitia, Clara; Lares-Villa, Fernando; Garibay-Escobar, Adriana

    2015-05-01

    It is known that cellular immune response is relevant to fight against tuberculosis (TB); hence, identification of mycobacterial antigens that induce a protective immune cellular response is of great interest, especially for the development of effective TB vaccines. Genomic data have an impact on the identification of potential antigens as new vaccine targets. In this review, we summarize the current knowledge about the advances in new TB vaccine designs as well as the features reported for the pro-glu_polymorphic GC-rich sequence (PE_PGRS33) protein, considering this molecule as a prototype of the PE_PGRS family to better understand the biological function of this protein family that could be considered an ideal target for future vaccine design.

  2. Mathematical model of tuberculosis transmission in a two-strain with vaccination

    NASA Astrophysics Data System (ADS)

    Nainggolan, J.; Supian, S.; Supriatna, A. K.; Anggriani, N.

    2014-02-01

    This paper deals with the mathematical analysis of the spread of tuberculosis with vaccination in a two-strain model. The vaccination reproduction ratio (Rrs) and equilibria quantities for the models are determined and stability of the solution is analyzed. We prove that if the vaccination reproduction ratio Rrs < 1 the disease free equilibrium is locally and asymptotically stable on the nonnegative orthant and if Rrs > 1 of the other equilibria is locally and asymptotically stable. At the end of this study, the numerical computation presented and it shows that vaccination and treatment capable to reduce the number of exposed and infected compartments.

  3. Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine.

    PubMed

    Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

    2015-01-01

    Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8(+) epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6'-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4(+) Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ(+) CD8(+) T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8(+) T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine.

  4. Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

    PubMed Central

    Kurtz, Sherry L.

    2015-01-01

    A critical hindrance to the development of a novel vaccine against Mycobacterium tuberculosis is a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-based in vitro model system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strain Mycobacterium bovis BCG or virulent M. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulent M. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our understanding of antimycobacterial immune responses. PMID:26269537

  5. Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

    PubMed Central

    Laddy, Dominick; Mishra, Bibhuti B.; Moss, Caitlin; Gutierrez, Nuria Martinez; Barreira-Silva, Palmira; Phuah, Jia Yao; Baker, Richard E.; Behar, Samuel M.; Evans, Thomas G.; Beamer, Gillian

    2016-01-01

    ABSTRACT The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines. PMID:27651361

  6. Vaccines displaying mycobacterial proteins on biopolyester beads stimulate cellular immunity and induce protection against tuberculosis.

    PubMed

    Parlane, Natalie A; Grage, Katrin; Mifune, Jun; Basaraba, Randall J; Wedlock, D Neil; Rehm, Bernd H A; Buddle, Bryce M

    2012-01-01

    New improved vaccines are needed for control of both bovine and human tuberculosis. Tuberculosis protein vaccines have advantages with regard to safety and ease of manufacture, but efficacy against tuberculosis has been difficult to achieve. Protective cellular immune responses can be preferentially induced when antigens are displayed on small particles. In this study, Escherichia coli and Lactococcus lactis were engineered to produce spherical polyhydroxybutyrate (PHB) inclusions which displayed a fusion protein of Mycobacterium tuberculosis, antigen 85A (Ag85A)-early secreted antigenic target 6-kDa protein (ESAT-6). L. lactis was chosen as a possible production host due its extensive use in the food industry and reduced risk of lipopolysaccharide contamination. Mice were vaccinated with PHB bead vaccines with or without displaying Ag85A-ESAT-6, recombinant Ag85A-ESAT-6, or M. bovis BCG. Separate groups of mice were used to measure immune responses and assess protection against an aerosol M. bovis challenge. Increased amounts of antigen-specific gamma interferon, interleukin-17A (IL-17A), IL-6, and tumor necrosis factor alpha were produced from splenocytes postvaccination, but no or minimal IL-4, IL-5, or IL-10 was produced, indicating Th1- and Th17-biased T cell responses. Decreased lung bacterial counts and less extensive foci of inflammation were observed in lungs of mice receiving BCG or PHB bead vaccines displaying Ag85A-ESAT-6 produced in either E. coli or L. lactis compared to those observed in the lungs of phosphate-buffered saline-treated control mice. No differences between those receiving wild-type PHB beads and those receiving recombinant Ag85A-ESAT-6 were observed. This versatile particulate vaccine delivery system incorporates a relatively simple production process using safe bacteria, and the results show that it is an effective delivery system for a tuberculosis protein vaccine. PMID:22072720

  7. TLR2-targeted secreted proteins from Mycobacterium tuberculosis are protective as powdered pulmonary vaccines.

    PubMed

    Tyne, Anneliese S; Chan, John Gar Yan; Shanahan, Erin R; Atmosukarto, Ines; Chan, Hak-Kim; Britton, Warwick J; West, Nicholas P

    2013-09-13

    Despite considerable research efforts towards effective treatments, tuberculosis (TB) remains a staggering burden on global health. Suitably formulated sub-unit vaccines offer potential as safe and effective generators of protective immunity. The Mycobacterium tuberculosis antigens, cutinase-like proteins (Culp) 1 and 6 and MPT83, were conjugated directly to the novel adjuvant Lipokel (Lipotek Pty Ltd), a TLR2 ligand that delivers antigen to immune cells in a self-adjuvanting context. Protein-Lipokel complexes were formulated as dry powders for pulmonary delivery directly to the lungs of mice by intra-tracheal insufflation, leading to recruitment of neutrophils and antigen presenting cell populations to the lungs at 72 h, that persisted at 7 days post immunisation. Significant increases in the frequency of activated dendritic cells were observed in the mediastinal lymph node (MLN) at 1 and 4 weeks after homologous boosting with protein-Lipokel vaccine. This was associated with the increased recruitment of effector CD4(+) and CD8(+) T-lymphocytes to the MLN and systemic antigen-specific, IFN-γ producing T-lymphocyte and IgG responses. Notably, pulmonary immunisation with either Culp1-6-Lipokel or MPT83-Lipokel powder vaccines generated protective responses in the lungs against aerosol M. tuberculosis challenge. The successful combination of TLR2-targeting and dry powder vaccine formulation, together with important practical benefits, offers potential for pulmonary vaccination against M. tuberculosis. PMID:23880366

  8. Motivations and concerns about adolescent tuberculosis vaccine trial participation in rural Uganda: a qualitative study

    PubMed Central

    Buregyeya, Esther; Kulane, Asli; Kiguli, Juliet; Musoke, Phillipa; Mayanja, Harriet; Mitchell, Ellen Maeve Hanlon

    2015-01-01

    Introduction Research is being carried out to develop and test new potentially more effective tuberculosis vaccines. Among the vaccines being developed are those that target adolescents. This study explored the stakeholders’ perceptions about adolescent participation in a hypothetical tuberculosis vaccine trial in Ugandan adolescents. Methods Focus group discussions with adolescents, parents of infants and adolescents, and key informant interviews with community leaders and traditional healers were conducted. Results The majority of the respondents expressed potential willingness to allow their children participate in a tuberculosis vaccine trial. Main motivations for potential participation would be being able to learn about health-related issues. Hesitations included the notion that trial participation would distract the youths from their studies, fear of possible side effects of an investigational product, and potential for being sexually exploited by researchers. In addition, bad experiences from participation in previous research and doubts about the importance of research were mentioned. Suggested ways to motivate participation included: improved clarity on study purpose, risks, benefits and better scheduling of study procedures to minimize disruption to participants’ academic schedules. Conclusion Findings from this study suggest that the community is open to potential participation of adolescents in a tuberculosis vaccine trial. However, there is a need to communicate more effectively with the community about the purpose of the trial and its effects, including safety data, in a low-literacy, readily understood format. This raises a challenge to researchers, who cannot know all the potential effects of a trial product before it is tested. PMID:26834929

  9. The Role of Neutrophils in the Induction of Specific Th1 and Th17 during Vaccination against Tuberculosis.

    PubMed

    Trentini, Monalisa M; de Oliveira, Fábio M; Kipnis, André; Junqueira-Kipnis, Ana P

    2016-01-01

    Mycobacterium tuberculosis causes tuberculosis (TB), a disease that killed more than 1.5 million people worldwide in 2014, and the Bacillus Calmette Guérin (BCG) vaccine is the only currently available vaccine against TB. However, it does not protect adults. Th1 and Th17 cells are crucial for TB control, as well as the neutrophils that are directly involved in DC trafficking to the draining lymph nodes and the activation of T lymphocytes during infection. Although several studies have shown the importance of neutrophils during M. tuberculosis infection, none have shown its role in the development of a specific response to a vaccine. The vaccine mc(2)-CMX was shown to protect mice against M. tuberculosis challenge, mainly due to specific Th1 and Th17 cells. This study evaluated the importance of neutrophils in the generation of the Th1- and Th17-specific responses elicited by this vaccine. The vaccine injection induced a neutrophil rich lesion with a necrotic central area. The IL-17 KO mice did not generate vaccine-specific Th1 cells. The vaccinated IL-22 KO mice exhibited Th1- and Th17-specific responses. Neutrophil depletion during vaccination abrogated the induction of Th1-specific responses and prohibited the bacterial load reduction observed in the vaccinated animals. The results show, for the first time, the role of neutrophils in the generation of specific Th1 and Th17 cells in response to a tuberculosis vaccine. PMID:27375607

  10. The Role of Neutrophils in the Induction of Specific Th1 and Th17 during Vaccination against Tuberculosis

    PubMed Central

    Trentini, Monalisa M.; de Oliveira, Fábio M.; Kipnis, André; Junqueira-Kipnis, Ana P.

    2016-01-01

    Mycobacterium tuberculosis causes tuberculosis (TB), a disease that killed more than 1.5 million people worldwide in 2014, and the Bacillus Calmette Guérin (BCG) vaccine is the only currently available vaccine against TB. However, it does not protect adults. Th1 and Th17 cells are crucial for TB control, as well as the neutrophils that are directly involved in DC trafficking to the draining lymph nodes and the activation of T lymphocytes during infection. Although several studies have shown the importance of neutrophils during M. tuberculosis infection, none have shown its role in the development of a specific response to a vaccine. The vaccine mc2-CMX was shown to protect mice against M. tuberculosis challenge, mainly due to specific Th1 and Th17 cells. This study evaluated the importance of neutrophils in the generation of the Th1- and Th17-specific responses elicited by this vaccine. The vaccine injection induced a neutrophil rich lesion with a necrotic central area. The IL-17 KO mice did not generate vaccine-specific Th1 cells. The vaccinated IL-22 KO mice exhibited Th1- and Th17-specific responses. Neutrophil depletion during vaccination abrogated the induction of Th1-specific responses and prohibited the bacterial load reduction observed in the vaccinated animals. The results show, for the first time, the role of neutrophils in the generation of specific Th1 and Th17 cells in response to a tuberculosis vaccine. PMID:27375607

  11. Tuberculosis in Elephants: Antibody Responses to Defined Antigens of Mycobacterium tuberculosis, Potential for Early Diagnosis, and Monitoring of Treatment

    PubMed Central

    Lyashchenko, Konstantin P.; Greenwald, Rena; Esfandiari, Javan; Olsen, John H.; Ball, Ray; Dumonceaux, Genevieve; Dunker, Freeland; Buckley, Carol; Richard, Michael; Murray, Suzan; Payeur, Janet B.; Andersen, Peter; Pollock, John M.; Mikota, Susan; Miller, Michele; Sofranko, Denise; Waters, W. Ray

    2006-01-01

    Tuberculosis (TB) in elephants is a re-emerging zoonotic disease caused primarily by Mycobacterium tuberculosis. Current diagnosis relies on trunk wash culture, the only officially recognized test, which has serious limitations. Innovative and efficient diagnostic methods are urgently needed. Rapid identification of infected animals is a crucial prerequisite for more effective control of TB, as early diagnosis allows timely initiation of chemotherapy. Serology has diagnostic potential, although key antigens have not been identified and optimal immunoassay formats are not established. To characterize the humoral responses in elephant TB, we tested 143 serum samples collected from 15 elephants over time. These included 48 samples from five culture-confirmed TB cases, of which four were in Asian elephants infected with M. tuberculosis and one was in an African elephant with Mycobacterium bovis. Multiantigen print immunoassay (MAPIA) employing a panel of 12 defined antigens was used to identify serologic correlates of active disease. ESAT-6 was the immunodominant antigen recognized in elephant TB. Serum immunoglobulin G antibodies to ESAT-6 and other proteins were detected up to 3.5 years prior to culture of M. tuberculosis from trunk washes. Antibody levels to certain antigens gradually decreased in response to antitubercular therapy, suggesting the possibility of treatment monitoring. In addition to MAPIA, serum samples were evaluated with a recently developed rapid test (RT) based on lateral flow technology (ElephantTB STAT-PAK). Similarly to MAPIA, infected elephants were identified using the RT up to 4 years prior to positive culture. These findings demonstrate the potential for TB surveillance and treatment monitoring using the RT and MAPIA, respectively. PMID:16829608

  12. Protection against tuberculosis in Eurasian wild boar vaccinated with heat-inactivated Mycobacterium bovis.

    PubMed

    Garrido, Joseba M; Sevilla, Iker A; Beltrán-Beck, Beatriz; Minguijón, Esmeralda; Ballesteros, Cristina; Galindo, Ruth C; Boadella, Mariana; Lyashchenko, Konstantin P; Romero, Beatriz; Geijo, Maria Victoria; Ruiz-Fons, Francisco; Aranaz, Alicia; Juste, Ramón A; Vicente, Joaquín; de la Fuente, José; Gortázar, Christian

    2011-01-01

    Tuberculosis (TB) caused by Mycobacterium bovis and closely related members of the Mycobacterium tuberculosis complex continues to affect humans and animals worldwide and its control requires vaccination of wildlife reservoir species such as Eurasian wild boar (Sus scrofa). Vaccination efforts for TB control in wildlife have been based primarily on oral live BCG formulations. However, this is the first report of the use of oral inactivated vaccines for controlling TB in wildlife. In this study, four groups of 5 wild boar each were vaccinated with inactivated M. bovis by the oral and intramuscular routes, vaccinated with oral BCG or left unvaccinated as controls. All groups were later challenged with a field strain of M. bovis. The results of the IFN-gamma response, serum antibody levels, M. bovis culture, TB lesion scores, and the expression of C3 and MUT genes were compared between these four groups. The results suggested that vaccination with heat-inactivated M. bovis or BCG protect wild boar from TB. These results also encouraged testing combinations of BCG and inactivated M. bovis to vaccinate wild boar against TB. Vaccine formulations using heat-inactivated M. bovis for TB control in wildlife would have the advantage of being environmentally safe and more stable under field conditions when compared to live BCG vaccines. The antibody response and MUT expression levels can help differentiating between vaccinated and infected wild boar and as correlates of protective response in vaccinated animals. These results suggest that vaccine studies in free-living wild boar are now possible to reveal the full potential of protecting against TB using oral M. bovis inactivated and BCG vaccines.

  13. Genetically susceptible mice remain proportionally more susceptible to tuberculosis after vaccination

    PubMed Central

    Medina, E; North, R J

    1999-01-01

    DBA/2 mice are much more susceptible to infection with Mycobacterium tuberculosis than major histocompatibility complex-compatible BALB/c mice. It is shown here that, although vaccination provided mice of both strains with a capacity to reduce the level of infection in their lungs, vaccinated DBA/2 mice remained much more susceptible in this organ than vaccinated BALB/c mice. Consequently, the former mice developed more lung pathology and died much earlier than the latter. On the other hand, colony-forming unit counts and histology suggest that vaccination provided mice of both strains with an increased and equal ability to express immunity in the liver and spleen, thereby indicating that they possessed equal systemic levels of vaccine-induced immunity at the time of M. tuberculosis challenge. The results indicate that inefficient expression of immunity in the lungs is likely to prove an obstacle to successful vaccination against tuberculosis in resistant and susceptible mouse strains, but more so in the latter strains. PMID:10233673

  14. BCG vaccination against tuberculosis in European badgers (Meles meles): a review.

    PubMed

    Robinson, Philip A; Corner, Leigh A L; Courcier, Emily A; McNair, Jim; Artois, Marc; Menzies, Fraser D; Abernethy, Darrell A

    2012-07-01

    Tuberculosis (TB) is a significant animal health problem in many parts of the world, and reservoirs of infection in wild animals complicate disease control efforts in farmed livestock, particularly cattle. Badgers (Meles meles) are a significant wildlife reservoir of Mycobacterium bovis infection for cattle in the United Kingdom (UK) and Republic of Ireland (ROI). Vaccination of badgers using an M. bovis strain bacille Calmette-Guérin (BCG) vaccine could potentially be an option in the national TB eradication strategy. Wildlife vaccination has been used successfully for other diseases in wildlife species, and may have a role to play in reducing M. bovis transmission at the wildlife-livestock interface. Research to date has provided evidence that BCG is protective in badgers, and a parenteral badger BCG vaccine has been licensed in the UK. Further research is required to develop effective strategies for vaccine deployment and to determine the effect of badger vaccination on cattle TB incidence.

  15. Comparative genomics of the Mycobacterium signaling architecture and implications for a novel live attenuated Tuberculosis vaccine.

    PubMed

    Zhou, Peifu; Xie, Jianping

    2014-01-01

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a major threat to global public health. A new TB vaccine affording superior immune protection to M. bovis Bacillus Calmette-Guérin (BCG) is imperative. The advantage of a live attenuated vaccine is that it can mimic the bona fide pathogen, elicit immune responses similar to natural infection, and potentially provide more protection than other vaccines. BCG, the only vaccine and a live attenuated vaccine that is the result of cumulative mutations by serial passage of M. bovis, has provided clues for the construction of novel improved vaccines. A strategy is put forward for identifying a new live attenuated TB vaccine generated by cumulative mutation based on M.tb. Given the important role of the M.tb signaling network consisting of a two-component system, eukaryotic-like Ser/Thr protein kinase system and sigma factor system based on comparisons among M.tb H37Rv, M. bovis, and BCG, we have put a premium on this signaling circuit as the starting point for the generation of an attenuated TB vaccine.

  16. A coordinated strategy for evaluating new vaccines for human and animal tuberculosis.

    PubMed

    McMurray, D N

    2001-01-01

    There is a remarkable convergence in the current efforts to develop and evaluate new tuberculosis (TB) vaccine candidates for use in humans, domestic animals, and wild animal reservoirs. It is quite likely that similar vaccination strategies will prove useful in these diverse host species. Many TB vaccine candidates are being screened for protective efficacy in conventional laboratory animals (e.g. mouse, guinea pig), in captive wild species under laboratory conditions (e.g. brushtail possum), and in the target hosts (e.g. cattle, deer). These systems share some important features, e.g. direct challenge infection of the lung by intratracheal or aerosol exposure, and the use of bacterial enumeration, and gross and microscopic histopathology, as the readouts. Some TB vaccine candidates have been tested in many models, yielding important insights into common mechanisms of resistance to Mycobacterium tuberculosis and M. bovis, and providing evidence of the vaccine's ability to induce protection under widely different circumstances. Coordination of this global search for better TB vaccines, irrespective of target species, would facilitate the rapid application of new technologies and maximize the sharing of materials and experiences between human and veterinary TB researchers. The creation of liaisons between TB vaccine research efforts of government-sponsored medical and agricultural research programs, international bodies such as the World Health Organization (WHO) and the European Community (EC), private foundations and the vaccine industry, will yield a high return.

  17. Tuberculosis in European badgers (Meles meles) and the control of infection with bacille Calmette-Guérin vaccination.

    PubMed

    Corner, L A L; Murphy, D; Costello, E; Gormley, E

    2009-10-01

    The eradication of tuberculosis (Mycobacterium bovis infection) from cattle herds may be compromised if infected wildlife species, such as European badgers (Meles meles), share the same environment and contribute to transfer of infection. Options for dealing with tuberculosis in this wild reservoir host are limited by conservation and social concerns, despite a clear implication that infected badgers are involved with the initiation of tuberculosis in cattle herds. Vaccination of badgers against M. bovis, if successfully employed, would directly facilitate the completion of bovine tuberculosis eradication in affected areas. Vaccine trials in captive badgers have established that the M. bovis bacille Calmette-Guérin (BCG) vaccine can induce a protective response that limits the distribution and severity of tuberculosis disease following experimental challenge. The protective effect of the vaccine has been demonstrated when the vaccine was delivered by subcutaneous injection, deposited on mucous membranes, and given orally in a lipid formulation. A large-scale field trial of oral BCG vaccine has been designed to measure the protection generated in wild badgers subjected to natural transmission of infection and to estimate vaccine efficacy. These parameters will be estimated by comparing the prevalence of M. bovis infection in vaccinated and nonvaccinated badgers. The results will provide a framework for the development and implementation of a national strategy to eliminate the disease in badger populations and if successful will remove this major impediment to bovine tuberculosis eradication.

  18. Potential Benefits of Cattle Vaccination as a Supplementary Control for Bovine Tuberculosis

    PubMed Central

    Conlan, Andrew J. K.; Brooks Pollock, Ellen; McKinley, Trevelyan J.; Mitchell, Andrew P.; Jones, Gareth J.; Vordermeier, Martin; Wood, James L. N.

    2015-01-01

    Vaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette-Guérin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers’ willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post

  19. Potential benefits of cattle vaccination as a supplementary control for bovine tuberculosis.

    PubMed

    Conlan, Andrew J K; Brooks Pollock, Ellen; McKinley, Trevelyan J; Mitchell, Andrew P; Jones, Gareth J; Vordermeier, Martin; Wood, James L N

    2015-02-01

    Vaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette-Guérin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers' willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post-mortem detection.

  20. Viral Booster Vaccines Improve Mycobacterium bovis BCG-Induced Protection Against Bovine Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous work in small animal laboratory models of tuberculosis have shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacille Calmette-Guerin (BCG) to prime and Modified Vaccinia Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad8...

  1. US College and University Student Health Screening Requirements for Tuberculosis and Vaccine-Preventable Diseases, 2012

    ERIC Educational Resources Information Center

    Jewett, Amy; Bell, Teal; Cohen, Nicole J.; Buckley, Kirsten; Leino, E. Victor; Even, Susan; Beavers, Suzanne; Brown, Clive; Marano, Nina

    2016-01-01

    Objective: Colleges are at risk for communicable disease outbreaks because of the high degree of person-to-person interactions and relatively crowded dormitory settings. This report describes the US college student health screening requirements among US resident and international students for tuberculosis (TB) and vaccine-preventable diseases…

  2. The Calf Model of Immunity for Development of a Vaccine Against Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Abstract: Tuberculosis (TB) remains a major public health threat and can be considered a reemerging disease due to many factors and is especially problematic in developing countries where co-infection with HIV significantly increases morbidity and mortality. Vaccination is a low cost and effective ...

  3. Bo-lysin: A Potential Candidate as a biomarker of Protection after Vaccination against Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis (TB) is still a major health problem worldwide. A Th1 type response with release of IFN {gamma}vaccination include IFN {...

  4. Trial design to estimate the effect of vaccination on tuberculosis incidence in badgers.

    PubMed

    Aznar, Inma; McGrath, Guy; Murphy, Denise; Corner, Leigh A L; Gormley, Eamonn; Frankena, Klaas; More, Simon J; Martin, Wayne; O'Keeffe, James; De Jong, Mart C M

    2011-07-01

    The principal wildlife reservoir of Mycobacterium bovis in Ireland is the European badger. Studies in the Republic of Ireland (RoI) have shown that badgers culled in association with cattle herd tuberculosis breakdowns (focal culling) have a higher prevalence of infection than the badger population at large. This observation is one rationale for the medium term national strategy of focal badger culling. A vaccination strategy for the control of bovine tuberculosis (bTB) in badgers is a preferred long-term option. The Bacillus Calmette-Guérin (BCG) vaccine has been shown to decrease disease severity in captive badgers under controlled conditions. As the vaccine has been tested in a controlled environment with precise information on infection pressure, it cannot be assumed a priori that the effects of vaccination are similar in the wild, where other environmental and/or ecological factors prevail. For this reason we have designed a vaccine field trial to assess the impact of vaccination on the incidence of TB infection in a wild badger population. The selected study area for the vaccine trial (approximately 755 square kilometers) is divided into three zones each of which has similar characteristics in terms of size, number of main badger setts, cattle herds, cattle and land classification type. Three vaccination levels (100%, 50% and 0%) will be allocated to the three zones in a way that a gradient of vaccination coverage North to South is achieved. The middle zone (zone B) will be vaccinated at a 50% coverage but zone A and C will be randomly allocated with 100% or 0% vaccination coverage. Vaccination within zone B will be done randomly at individual badger level. The objective of this paper is to describe the design of a field tuberculosis vaccination trial for badgers, the epidemiological methods that were used to design the trial and the subsequent data analysis. The analysis will enable us to quantify the magnitude of the observed vaccination effect on M. bovis

  5. Effects of vaccination against paratuberculosis on tuberculosis in goats: diagnostic interferences and cross-protection

    PubMed Central

    2012-01-01

    Background Most countries carrying out campaigns of bovine tuberculosis (TB) eradication impose a ban on the use of mycobacterial vaccines in cattle. However, vaccination against paratuberculosis (PTB) in goats is often allowed even when its effect on TB diagnosis has not been fully evaluated. To address this issue, goat kids previously vaccinated against PTB were experimentally infected with TB. Results Evaluation of interferon-γ (IFN-γ) secretion induced by avian and bovine tuberculins (PPD) showed a predominant avian PPD-biased response in the vaccinated group from week 4 post-vaccination onward. Although 60% of the animals were bovine reactors at week 14, avian PPD-biased responses returned at week 16. After challenge with M. caprae, the IFN-γ responses radically changed to show predominant bovine PPD-biased responses from week 18 onward. In addition, cross-reactions with bovine PPD that had been observed in the vaccinated group at week 14 were reduced when using the M. tuberculosis complex-specific antigens ESAT-6/CFP-10 and Rv3615c as new DIVA (differentiation of infected and vaccinated animals) reagents, which further maintained sensitivity post-challenge. Ninety percent of the animals reacted positively to the tuberculin cervical comparative intradermal test performed at 12 weeks post-infection. Furthermore, post-mortem analysis showed reductions in tuberculous lesions and bacterial burden in some vaccinated animals, particularly expressed in terms of the degree of extrapulmonary dissemination of TB infection. Conclusions Our results suggest a degree of interference of PTB vaccination with current TB diagnostics that can be fully mitigated when using new DIVA reagents. A partial protective effect associated with vaccination was also observed in some vaccinated animals. PMID:23072619

  6. Cholera toxin enhances vaccine-induced protection against Mycobacterium tuberculosis challenge in mice.

    PubMed

    Griffiths, Kristin L; Stylianou, Elena; Poyntz, Hazel C; Betts, Gareth J; Fletcher, Helen A; McShane, Helen

    2013-01-01

    Interleukin (IL)-17 is emerging as an important cytokine in vaccine-induced protection against tuberculosis disease in animal models. Here we show that compared to parenteral delivery, BCG delivered mucosally enhances cytokine production, including interferon gamma and IL-17, in the lungs. Furthermore, we find that cholera toxin, delivered mucosally along with BCG, further enhances IL-17 production by CD4(+) T cells over mucosal BCG alone both in the lungs and systemically. This boosting effect of CT is also observed using a vaccine regimen of BCG followed by the candidate vaccine MVA85A. Using a murine Mycobacterium tuberculosis (M.tb) aerosol challenge model, we demonstrate the ability of cholera toxin delivered at the time of a priming BCG vaccination to improve protection against tuberculosis disease in a manner at least partially dependent on the observed increase in IL-17. This observed increase in IL-17 in the lungs has no adverse effect on lung pathology following M.tb challenge, indicating that IL-17 can safely be boosted in murine lungs in a vaccine/M.tb challenge setting. PMID:24194918

  7. Drug Treatment Combined with BCG Vaccination Reduces Disease Reactivation in Guinea Pigs Infected with Mycobacterium tuberculosis

    PubMed Central

    Shang, Shaobin; Shanley, Crystal A.; Caraway, Megan L.; Orme, Eileen A.; Henao-Tamayo, Marcela; Hascall-Dove, Laurel; Ackart, David; Orme, Ian M.; Ordway, Diane J.; Basaraba, Randall J.

    2012-01-01

    Bacillus-Calmette-Guerin (BCG), the only human tuberculosis vaccine, primes a partially protective immune response against M. tuberculosis infection in humans and animals. In guinea pigs, BCG vaccination slows the progression of disease and reduces the severity of necrotic granulomas, which harbor a population of drug-tolerant bacilli. The objective of this study was to determine if reducing disease severity by BCG vaccination of guinea pigs prior to M. tuberculosis challenge enhanced the efficacy of combination drug therapy. At 20 days of infection, treatment of vaccinated and non-vaccinated animals with rifampin, isoniazid, and pyrizinamide (RHZ) was initiated for 4 or 8 weeks. On days 50, 80 and 190 of infection (10 weeks after drug were withdrawn), treatment efficacy was evaluated by quantifying clinical condition, bacterial loads, lesion severity, and dynamic changes in peripheral blood and lung leukocyte numbers by flow cytometry. In a separate, long-term survival study, treatment efficacy was evaluated by determining disease reactivation frequency post-mortem. BCG vaccination alone delayed pulmonary and extra-pulmonary disease progression, but failed to prevent dissemination of bacilli and the formation of necrotic granulomas. Drug therapy either alone or in combination with BCG, was more effective at lessening clinical disease and lesion severity compared to control animals or those receiving BCG alone. Fewer residual lesions in BCG vaccinated and drug treated animals, equated to a reduced frequency of reactivation disease and improvement in survival even out to 500 days of infection. The combining of BCG vaccination and drug therapy was more effective at resolving granulomas such that fewer animals had evidence of residual infection and thus less reactivation disease. PMID:22244979

  8. Development of a BCG challenge model for the testing of vaccine candidates against tuberculosis in cattle.

    PubMed

    Villarreal-Ramos, Bernardo; Berg, Stefan; Chamberlain, Laura; McShane, Helen; Hewinson, R Glyn; Clifford, Derek; Vordermeier, Martin

    2014-09-29

    Vaccination is being considered as part of a sustainable strategy for the control of bovine tuberculosis (BTB) in the UK. The live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used experimentally to vaccinate cattle against BTB. However, BCG confers partial protection against BTB and therefore, there is a need to develop improved vaccines. BTB vaccine efficacy experiments require the use of biosafety level 3 facilities which are expensive to maintain, generally oversubscribed and represent a bottle neck for the testing of vaccine candidates. One indicator of the induction of protective responses would be the ability of the host's immune response to control/kill mycobacteria. In this work we have evaluated an intranodal BCG challenge for the selection of vaccine candidates at biosafety level 2 which are capable of inducing mycobactericidal responses. To our knowledge, this is the first such report. Whilst BCG only confers partial protection, it is still the standard against which other vaccines are judged. Therefore we tested the BCG intranodal challenge in BCG (Danish strain) vaccinated cattle and showed that vaccinated cattle had lower BCG cfu counts than naïve cattle at 14 and 21 days after intranodal challenge with BCG (Tokyo strain). This model could help prioritize competing TB vaccine candidates and exploration of primary and secondary immune responses to mycobacteria. PMID:25138291

  9. Vaccination of cattle with Mycobacterium bovis culture filtrate proteins and CpG oligodeoxynucleotides induces protection against bovine tuberculosis.

    PubMed

    Wedlock, D N; Skinner, M A; de Lisle, G W; Vordermeier, H M; Hewinson, R G; Hecker, R; van Drunen Littel-van den Hurk, S; Babiuk, L A; Buddle, B M

    2005-06-15

    Culture filtrate protein (CFP) vaccines have been shown to be effective in small animal models for protecting against tuberculosis while immunisation with these types of vaccines in cattle has been less successful. A study was conducted in cattle to evaluate the ability of selected adjuvants and immunomodulators to stimulate protective immune responses to tuberculosis in animals vaccinated with Mycobacterium bovis CFP. Seven groups of cattle (n=5) were vaccinated with M. bovis CFP formulated with either Emulsigen or Polygen adjuvant alone or in combination with a specific oligodeoxynucleotides (ODN), polyinosinic acid: polycytidylic acid (poly I:C) or poly I:C and recombinant granulocyte-macrophage colony stimulating factor. Two additional groups were vaccinated subcutaneously with BCG or non-vaccinated. In contrast to the strong interferon-gamma (IFN-gamma) responses induced by BCG, the CFP vaccines induced strong antibody responses but weak IFN-gamma responses. The addition of CpG ODN to CFP significantly enhanced cell-mediated responses and elevated antibody responses to mycobacterial antigens. Of the CFP vaccinated groups, the strongest IFN-gamma responses to CFP vaccines were measured in animals vaccinated with CFP/Emulsigen+CpG or CFP/Polygen+CpG. The animals in these two groups, together with those in the BCG and non-vaccinated groups were challenged intratracheally with virulent M. bovis at 13 weeks after the first vaccination and protection was assessed, by examination for presence of tuberculous lesions in the lungs and lymph nodes, 13 weeks later at postmortem. While BCG gave the best overall protection against tuberculosis, significant protection was also seen in animals vaccinated with CFP/Emulsigen+CpG. These results establish an important role for CpG ODN in stimulating protective Th1 responses to tuberculosis in cattle and indicate that a sub-unit protein vaccine can protect these animals against tuberculosis. PMID:15910992

  10. Vaccine approaches for bovine tuberculosis: Correlates of protection and relevance to human tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is a classic model of the One Health Concept. M. bovis Bacillus Calmette Guerin (BCG) was first proven effective in cattle prior to use in humans. Recent experimental trials with cattle have d...

  11. The Case for Live Attenuated Vaccines against the Neglected Zoonotic Diseases Brucellosis and Bovine Tuberculosis

    PubMed Central

    Pandey, Aseem; Cabello, Ana; Akoolo, Lavoisier; Rice-Ficht, Allison; Arenas-Gamboa, Angela; McMurray, David; Ficht, Thomas A.; de Figueiredo, Paul

    2016-01-01

    Vaccination of humans and animals with live attenuated organisms has proven to be an effective means of combatting some important infectious diseases. In fact, the 20th century witnessed tremendous improvements in human and animal health worldwide as a consequence of large-scale vaccination programs with live attenuated vaccines (LAVs). Here, we use the neglected zoonotic diseases brucellosis and bovine tuberculosis (BTb) caused by Brucella spp. and Mycobacterium bovis (M. bovis), respectively, as comparative models to outline the merits of LAV platforms with emphasis on molecular strategies that have been pursued to generate LAVs with enhanced vaccine safety and efficacy profiles. Finally, we discuss the prospects of LAV platforms in the fight against brucellosis and BTb and outline new avenues for future research towards developing effective vaccines using LAV platforms. PMID:27537413

  12. The Case for Live Attenuated Vaccines against the Neglected Zoonotic Diseases Brucellosis and Bovine Tuberculosis.

    PubMed

    Pandey, Aseem; Cabello, Ana; Akoolo, Lavoisier; Rice-Ficht, Allison; Arenas-Gamboa, Angela; McMurray, David; Ficht, Thomas A; de Figueiredo, Paul

    2016-08-01

    Vaccination of humans and animals with live attenuated organisms has proven to be an effective means of combatting some important infectious diseases. In fact, the 20th century witnessed tremendous improvements in human and animal health worldwide as a consequence of large-scale vaccination programs with live attenuated vaccines (LAVs). Here, we use the neglected zoonotic diseases brucellosis and bovine tuberculosis (BTb) caused by Brucella spp. and Mycobacterium bovis (M. bovis), respectively, as comparative models to outline the merits of LAV platforms with emphasis on molecular strategies that have been pursued to generate LAVs with enhanced vaccine safety and efficacy profiles. Finally, we discuss the prospects of LAV platforms in the fight against brucellosis and BTb and outline new avenues for future research towards developing effective vaccines using LAV platforms. PMID:27537413

  13. Vaccination against ovine cysticercosis using a defined recombinant antigen.

    PubMed

    Johnson, K S; Harrison, G B; Lightowlers, M W; O'Hoy, K L; Cougle, W G; Dempster, R P; Lawrence, S B; Vinton, J G; Heath, D D; Rickard, M D

    1989-04-13

    Cysticercosis caused by larval tapeworms is a major public health problem and a cause of substantial economic losses in the farm-animal industries. Taenia ovis in sheep is a particularly important example. Immunity to reinfection with the larvae has a central role in regulating natural transmission of the parasites, and vaccination with antigens from the early larval oncosphere stage can induce complete protection against infection. As it is impractical to obtain enough oncospheres for a commercial vaccine against these tapeworms, an alternative approach is to use recombinant DNA methods to generate a cheap and plentiful supply of antigens. We report here the expression in Escherichia coli of complementary DNA encoding T. ovis antigens as fusion proteins with the Schistosoma japonicum glutathione S-transferase. Vaccination of sheep with these fusion proteins gave significant, although not complete, immunity against challenge infection with T. ovis eggs. Commercial development of a vaccine is being pursued.

  14. Phenotypic variability in childhood TB: implications for diagnostic endpoints in tuberculosis vaccine trials.

    PubMed

    Mulenga, Humphrey; Moyo, Sizulu; Workman, Lesley; Hawkridge, Tony; Verver, Suzanne; Tameris, Michele; Geldenhuys, Hennie; Hanekom, Willem; Mahomed, Hassan; Hussey, Gregory; Hatherill, Mark

    2011-06-10

    The endpoint definition for infant tuberculosis (TB) vaccine trials should match the TB disease phenotype expected in the control arm of the study population. Our aim was to analyse selected combinations of the clinical, radiological, and microbiological features of pulmonary TB among children investigated under vaccine trial conditions, in order to estimate case frequency for a range of expected TB phenotypes. Two thousand one hundred and eighty five South African children were investigated over a nine-year period (2001-2009). Evidence of TB exposure and classical symptoms were several times more common than chest radiography (CXR) compatible with TB, or positive Mycobacterium tuberculosis culture. Discordance between clinical, radiological, and microbiological features was common in individual children. Up to one third of children with compatible CXR, and up to half the children who were M. tuberculosis culture positive, were asymptomatic. The culture positive rate fell over time, although rates of TB exposure and compatible chest radiography increased. Consequently, the annual incidence of diagnostic combinations that included M. tuberculosis culture fell to <0.2%. However, in this study population (children <2 years of age), annual incidence of the TB disease phenotype that included the triad of TB exposure, symptoms, and compatible CXR, approached 1% (n=848 per 100,000). These findings allow modelling of expected TB case frequency in multi-centre infant TB vaccine trials, based upon benchmarking of diagnostic data against the key indicator variables that constitute the building blocks of a trial endpoint. PMID:21527304

  15. A Mycobacterium tuberculosis Dormancy Antigen Differentiates Latently Infected Bacillus Calmette–Guérin-vaccinated Individuals

    PubMed Central

    Peña, Delfina; Rovetta, Ana I.; Hernández Del Pino, Rodrigo E.; Amiano, Nicolás O.; Pasquinelli, Virginia; Pellegrini, Joaquín M.; Tateosian, Nancy L.; Rolandelli, Agustín; Gutierrez, Marisa; Musella, Rosa M.; Palmero, Domingo J.; Gherardi, María M.; Iovanna, Juan; Chuluyan, H. Eduardo; García, Verónica E.

    2015-01-01

    IFN-γ release assays (IGRAs) are better indicators of Mycobacterium tuberculosis infection than the tuberculin skin test (TST) in Bacillus Calmette–Guérin (BCG)-vaccinated populations. However, IGRAs do not discriminate active and latent infections (LTBI) and no gold standard for LTBI diagnosis is available. Thus, since improved tests to diagnose M. tuberculosis infection are required, we assessed the efficacy of several M. tuberculosis latency antigens. BCG-vaccinated healthy donors (HD) and tuberculosis (TB) patients were recruited. QuantiFERON-TB Gold In-Tube, TST and clinical data were used to differentiate LTBI. IFN-γ production against CFP-10, ESAT-6, Rv2624c, Rv2626c and Rv2628 antigens was tested in peripheral blood mononuclear cells. LTBI subjects secreted significantly higher IFN-γ levels against Rv2626c than HD. Additionally, Rv2626c peptide pools to which only LTBI responded were identified, and their cumulative IFN-γ response improved LTBI discrimination. Interestingly, whole blood stimulation with Rv2626c allowed the discrimination between active and latent infections, since TB patients did not secrete IFN-γ against Rv2626c, in contrast to CFP-10 + ESAT-6 stimulation that induced IFN-γ response from both LTBI and TB patients. ROC analysis confirmed that Rv2626c discriminated LTBI from HD and TB patients. Therefore, since only LTBI recognizes specific epitopes from Rv2626c, this antigen could improve LTBI diagnosis, even in BCG-vaccinated people. PMID:26425695

  16. [Multifocal tuberculosis in immunocompetent patients].

    PubMed

    Rezgui, Amel; Fredj, Fatma Ben; Mzabi, Anis; Karmani, Monia; Laouani, Chadia

    2016-01-01

    Multifocal tuberculosis is defined as the presence of lesions affecting at least two extrapulmonary sites, with or without pulmonary involvement. This retrospective study of 10 cases aims to investigate the clinical and evolutionary characteristics of multifocal tuberculosis. It included 41 cases with tuberculosis collected between 1999 and 2013. Ten patients had multifocal tuberculosis (24%): 9 women and 1 man, the average age was 50 years (30-68 years). Our patients were correctly BCG vaccinated. The evaluation of immunodepression was negative in all patients. 7 cases had lymph node tuberculosis, 3 cases digestive tuberculosis, 2 cases pericardial tuberculosis, 2 cases osteoarticular tuberculosis, 1 case brain tuberculosis, 2 cases urinary tuberculosis, 4 cases urogenital tuberculosis, 1 case adrenal tuberculosis, 1 case cutaneous and 1 case muscle tuberculosis. All patients received anti-tuberculosis treatment for a mean duration of 10 months, with good evolution. Multifocal tuberculosis is difficult to diagnose. It can affect immunocompetent patients but often has good prognosis. Anti-tuberculosis therapy must be initiated as soon as possible to avoid sequelae. PMID:27583077

  17. Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine

    PubMed Central

    Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

    2015-01-01

    Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8+ epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6′-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4+ Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ+ CD8+ T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8+ T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine. PMID:25905680

  18. Oral vaccination reduces the incidence of tuberculosis in free-living brushtail possums

    PubMed Central

    Tompkins, D. M.; Ramsey, D. S. L.; Cross, M. L.; Aldwell, F. E.; de Lisle, G. W.; Buddle, B. M.

    2009-01-01

    Bovine tuberculosis (Tb) caused by Mycobacterium bovis has proved refractory to eradication from domestic livestock in countries with wildlife disease reservoirs. Vaccination of wild hosts offers a way of controlling Tb in livestock without wildlife culling. This study was conducted in a Tb-endemic region of New Zealand, where the introduced Australian brushtail possum (Trichosurus vulpecula) is the main wildlife reservoir of Tb. Possums were trapped and vaccinated using a prototype oral-delivery system to deliver the Tb vaccine bacille Calmette–Guerin. Vaccinated and control possums were matched according to age, sex and location, re-trapped bimonthly and assessed for Tb status by palpation and lesion aspiration; the site was depopulated after 2 years and post-mortem examinations were conducted to further identify clinical Tb cases and subclinical infection. Significantly fewer culture-confirmed Tb cases were recorded in vaccinated possums (1/51) compared with control animals (12/71); the transition probability from susceptible to infected was significantly reduced in both males and females by vaccination. Vaccine efficacy was estimated at 95 per cent (87–100%) for females and 96 per cent (82–99%) for males. Hence, this trial demonstrates that orally delivered live bacterial vaccines can significantly protect wildlife against natural disease exposure, indicating that wildlife vaccination, along with existing control methods, could be used to eradicate Tb from domestic animals. PMID:19493904

  19. MPT-51/CpG DNA vaccine protects mice against Mycobacterium tuberculosis.

    PubMed

    Silva, Bruna Daniella de Souza; da Silva, Ediane Batista; do Nascimento, Ivan Pereira; Dos Reis, Michelle Cristina Guerreiro; Kipnis, André; Junqueira-Kipnis, Ana Paula

    2009-07-16

    Tuberculosis (TB) is a severe infectious disease that kills approximately two million people worldwide every year. Because BCG protection is variable and does not protects adults, there is a great need for a new vaccine against TB that does not represent a risk for immunocompromised patients and that is also capable of protecting adult individuals. MPT-51 is a protein found in the genome of mycobacteria and binds to the fibronectin of the extracellular matrix, which may have a role in host tissue attachment and virulence. In order to test the usefulness of MPT-51 as a subunit vaccine, BALB/c were vaccinated and challenged with Mycobacterium tuberculosis. The infection of BALB/c with M. tuberculosis increased the number of IFN-gamma(+) T lymphocytes specific to MPT-51 in the spleen and lungs. Inoculation with rMPT-51/FIA and with rMPT-51/CpG DNA in non-infected BALB/c increased the amounts of IFN-gamma(+) T lymphocytes. Inoculation with rMPT-51/FIA also induced a humoral response specific to MPT-51. CFU counts of lung tissues done 60 days after infection showed a reduction of about 2 log in the bacteria load in the group of animals inoculated with rMPT-51/CpG DNA. These results make MPT-51 a valuable component to be further evaluated in the development of other subunit vaccines.

  20. The Ag85B protein of the BCG vaccine facilitates macrophage uptake but is dispensable for protection against aerosol Mycobacterium tuberculosis infection.

    PubMed

    Prendergast, Kelly A; Counoupas, Claudio; Leotta, Lisa; Eto, Carolina; Bitter, Wilbert; Winter, Nathalie; Triccas, James A

    2016-05-17

    Defining the function and protective capacity of mycobacterial antigens is crucial for progression of tuberculosis (TB) vaccine candidates to clinical trials. The Ag85B protein is expressed by all pathogenic mycobacteria and is a component of multiple TB vaccines under evaluation in humans. In this report we examined the role of the BCG Ag85B protein in host cell interaction and vaccine-induced protection against virulent Mycobacterium tuberculosis infection. Ag85B was required for macrophage infection in vitro, as BCG deficient in Ag85B expression (BCG:(Δ85B)) was less able to infect RAW 264.7 macrophages compared to parental BCG, while an Ag85B-overexpressing BCG strain (BCG:(oex85B)) demonstrated improved uptake. A similar pattern was observed in vivo after intradermal delivery to mice, with significantly less BCG:(Δ85B) present in CD64(hi)CD11b(hi) macrophages compared to BCG or BCG:(oex85B). After vaccination of mice with BCG:(Δ85B) or parental BCG and subsequent aerosol M. tuberculosis challenge, similar numbers of activated CD4(+) and CD8(+) T cells were detected in the lungs of infected mice for both groups, suggesting the reduced macrophage uptake observed by BCG:(Δ85B) did not alter host immunity. Further, vaccination with both BCG:(Δ85B) and parental BCG resulted in a comparable reduction in pulmonary M. tuberculosis load. These data reveal an unappreciated role for Ag85B in the interaction of mycobacteria with host cells and indicates that single protective antigens are dispensable for protective immunity induced by BCG. PMID:27060378

  1. The Ag85B protein of the BCG vaccine facilitates macrophage uptake but is dispensable for protection against aerosol Mycobacterium tuberculosis infection.

    PubMed

    Prendergast, Kelly A; Counoupas, Claudio; Leotta, Lisa; Eto, Carolina; Bitter, Wilbert; Winter, Nathalie; Triccas, James A

    2016-05-17

    Defining the function and protective capacity of mycobacterial antigens is crucial for progression of tuberculosis (TB) vaccine candidates to clinical trials. The Ag85B protein is expressed by all pathogenic mycobacteria and is a component of multiple TB vaccines under evaluation in humans. In this report we examined the role of the BCG Ag85B protein in host cell interaction and vaccine-induced protection against virulent Mycobacterium tuberculosis infection. Ag85B was required for macrophage infection in vitro, as BCG deficient in Ag85B expression (BCG:(Δ85B)) was less able to infect RAW 264.7 macrophages compared to parental BCG, while an Ag85B-overexpressing BCG strain (BCG:(oex85B)) demonstrated improved uptake. A similar pattern was observed in vivo after intradermal delivery to mice, with significantly less BCG:(Δ85B) present in CD64(hi)CD11b(hi) macrophages compared to BCG or BCG:(oex85B). After vaccination of mice with BCG:(Δ85B) or parental BCG and subsequent aerosol M. tuberculosis challenge, similar numbers of activated CD4(+) and CD8(+) T cells were detected in the lungs of infected mice for both groups, suggesting the reduced macrophage uptake observed by BCG:(Δ85B) did not alter host immunity. Further, vaccination with both BCG:(Δ85B) and parental BCG resulted in a comparable reduction in pulmonary M. tuberculosis load. These data reveal an unappreciated role for Ag85B in the interaction of mycobacteria with host cells and indicates that single protective antigens are dispensable for protective immunity induced by BCG.

  2. Monosodium Urate Crystals Promote Innate Anti-Mycobacterial Immunity and Improve BCG Efficacy as a Vaccine against Tuberculosis

    PubMed Central

    Taus, Francesco; Santucci, Marilina B.; Greco, Emanuela; Morandi, Matteo; Palucci, Ivana; Mariotti, Sabrina; Poerio, Noemi; Nisini, Roberto; Delogu, Giovanni; Fraziano, Maurizio

    2015-01-01

    A safer and more effective anti-Tuberculosis vaccine is still an urgent need. We probed the effects of monosodium urate crystals (MSU) on innate immunity to improve the Bacille Calmette-Guerin (BCG) vaccination. Results showed that in vitro MSU cause an enduring macrophage stimulation of the anti-mycobacterial response, measured as intracellular killing, ROS production and phagolysosome maturation. The contribution of MSU to anti-mycobacterial activity was also shown in vivo. Mice vaccinated in the presence of MSU showed a lower number of BCG in lymph nodes draining the vaccine inoculation site, in comparison to mice vaccinated without MSU. Lastly, we showed that MSU improved the efficacy of BCG vaccination in mice infected with Mycobacterium tuberculosis (MTB), measured in terms of lung and spleen MTB burden. These results demonstrate that the use of MSU as adjuvant may represent a novel strategy to enhance the efficacy of BCG vaccination. PMID:26023779

  3. Vaccination of guinea pigs using mce operon mutants of Mycobacterium tuberculosis

    PubMed Central

    Obregón-Henao, Andrés; Shanley, Crystal; Bianco, María Verónica; Cataldi, Angel A; Basaraba, Randall J; Orme, Ian M; Bigi, Fabiana

    2011-01-01

    The limited efficacy of the BCG vaccine for tuberculosis, coupled with emerging information suggesting that it is poorly protective against newly emerging strains of Mycobacterium tuberculosis such as the W-Beijing isolates, makes it paramount to search for more potent alternatives. One such class of candidates is attenuated mutants derived from M. tuberculosis itself. We demonstrate here, in an initial short term assay, that mutants derived from disruption of the mce genes of the bacillus were highly protective in guinea pigs exposed by low dose aerosol infection with the virulent W-Beijing isolate SA161. This protection was demonstrated by a significant reduction in the numbers of bacilli harvested from the lungs, and dramatic improvements in lung histopathology. PMID:21515327

  4. Immunogenicity of orally-delivered lipid-formulated BCG vaccines and protection against Mycobacterium tuberculosis infection.

    PubMed

    Vipond, Julia; Cross, Martin L; Lambeth, Matthew R; Clark, Simon; Aldwell, Frank E; Williams, Ann

    2008-01-01

    Lipid formulations containing BCG strains Danish 1331 or Moreau (Rio de Janeiro) were trialled as oral vaccines in rodent models. In mice, oral-delivery of either strain resulted in BCG colonisation of the alimentary tract lymphatics and induction of gamma-interferon responses. In guinea pigs, both strains provided pulmonary protection against Mycobacterium tuberculosis aerosol challenge, as shown by significantly reduced bacterial loads and lung:body weight ratios. Lipid-formulated BCG provided superior protection against M. tuberculosis over unformulated orally-delivered BCG (Moreau), and equivalent protection to sub-cutaneous BCG (Danish) immunisation. Oral-delivery of lipid-formulated BCG may offer a practical alternative to parenteral-route BCG vaccination.

  5. Why don’t we have an effective tuberculosis vaccine yet?

    PubMed Central

    Davenne, Tamara; McShane, Helen

    2016-01-01

    ABSTRACT Mycobacterium tuberculosis (M.tb) has co-evolved with humans for thousands of years, to cause tuberculosis (TB). The success of M.tb as a pathogen is in part because of the ways in which M.tb evades and exploits different cell subsets, to persist and cause disease. M.tb expresses numerous molecules to prevent its recognition and destruction by immune cells. The only licensed vaccine against TB, Bacillle Calmette-Guerin (BCG), is effective at preventing disseminated disease in infants but confers highly variable efficacy against pulmonary TB in adults, particularly in the developing world. A greater understanding of the reasons for this variability, together with a better understanding of the early, innate, and non-antigen specific mechanisms of protection would facilitate the design and development of more effective vaccines. PMID:27010255

  6. Of postulates and peccadilloes: Robert Koch and vaccine (tuberculin) therapy for tuberculosis.

    PubMed

    Burke, D S

    1993-01-01

    In August 1890, Robert Koch dramatically announced that he had discovered a cure for tuberculosis, and the world rejoiced. The miracle substance was subsequently revealed to be tuberculin, inoculated as a 'vaccine therapy'. However, within a matter of months his claims were disputed and debunked, and his reputation was grievously damaged. The nationalistic pressures, professional jealousies and pecuniary interests that drove Koch's premature announcement are reviewed here and discussed in a context relevant to the development of therapeutic vaccines for human immunodeficiency virus infections.

  7. Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines

    PubMed Central

    Olsen, Aaron; Chen, Yong; Ji, Qingzhou; Zhu, Guofeng; De Silva, Aruna Dharshan; Vilchèze, Catherine; Weisbrod, Torin; Li, Weimin; Xu, Jiayong; Larsen, Michelle; Zhang, Jinghang; Porcelli, Steven A.; Jacobs, William R.

    2016-01-01

    ABSTRACT Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4+ T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8+ T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis. The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4+ and CD8+ T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. PMID:27247233

  8. Multiantigenic subunitary vaccines against tuberculosis in clinical trials: Where do we stand and where do we need to go?

    PubMed

    Guapillo, Carolina; Hernández-Pando, Rogelio; Flores-Valdez, Mario Alberto

    2016-05-01

    The idea of presenting this commentary is to bring attention to the current status of clinical tests from several multiantigen vaccine candidates based on proteins produced by means of genetic engineering and molecular biology approaches and to suggest how new emerging technologies (OMICs) and bioinformatics might benefit vaccine development for better control of tuberculosis.

  9. Global Gene Transcriptome Analysis in Vaccinated Cattle Revealed a Dominant Role of IL-22 for Protection against Bovine Tuberculosis

    PubMed Central

    Villarreal-Ramos, Bernardo; Xing, Zhou; Singh, Mahavir; Vordermeier, H. Martin

    2012-01-01

    Bovine tuberculosis (bTB) is a chronic disease of cattle caused by Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex group of bacteria. Vaccination of cattle might offer a long-term solution for controlling the disease and priority has been given to the development of a cattle vaccine against bTB. Identification of biomarkers in tuberculosis research remains elusive and the goal is to identify host correlates of protection. We hypothesized that by studying global gene expression we could identify in vitro predictors of protection that could help to facilitate vaccine development. Calves were vaccinated with BCG or with a heterologous BCG prime adenovirally vectored subunit boosting protocol. Protective efficacy was determined after M. bovis challenge. RNA was prepared from PPD-stimulated PBMC prepared from vaccinated-protected, vaccinated-unprotected and unvaccinated control cattle prior to M. bovis challenge and global gene expression determined by RNA-seq. 668 genes were differentially expressed in vaccinated-protected cattle compared with vaccinated-unprotected and unvaccinated control cattle. Cytokine-cytokine receptor interaction was the most significant pathway related to this dataset with IL-22 expression identified as the dominant surrogate of protection besides INF-γ. Finally, the expression of these candidate genes identified by RNA-seq was evaluated by RT-qPCR in an independent set of PBMC samples from BCG vaccinated and unvaccinated calves. This experiment confirmed the importance of IL-22 as predictor of vaccine efficacy. PMID:23300440

  10. Global gene transcriptome analysis in vaccinated cattle revealed a dominant role of IL-22 for protection against bovine tuberculosis.

    PubMed

    Bhuju, Sabin; Aranday-Cortes, Elihu; Villarreal-Ramos, Bernardo; Xing, Zhou; Singh, Mahavir; Vordermeier, H Martin

    2012-12-01

    Bovine tuberculosis (bTB) is a chronic disease of cattle caused by Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex group of bacteria. Vaccination of cattle might offer a long-term solution for controlling the disease and priority has been given to the development of a cattle vaccine against bTB. Identification of biomarkers in tuberculosis research remains elusive and the goal is to identify host correlates of protection. We hypothesized that by studying global gene expression we could identify in vitro predictors of protection that could help to facilitate vaccine development. Calves were vaccinated with BCG or with a heterologous BCG prime adenovirally vectored subunit boosting protocol. Protective efficacy was determined after M. bovis challenge. RNA was prepared from PPD-stimulated PBMC prepared from vaccinated-protected, vaccinated-unprotected and unvaccinated control cattle prior to M. bovis challenge and global gene expression determined by RNA-seq. 668 genes were differentially expressed in vaccinated-protected cattle compared with vaccinated-unprotected and unvaccinated control cattle. Cytokine-cytokine receptor interaction was the most significant pathway related to this dataset with IL-22 expression identified as the dominant surrogate of protection besides INF-γ. Finally, the expression of these candidate genes identified by RNA-seq was evaluated by RT-qPCR in an independent set of PBMC samples from BCG vaccinated and unvaccinated calves. This experiment confirmed the importance of IL-22 as predictor of vaccine efficacy.

  11. Construction of two Listeria ivanovii attenuated strains expressing Mycobacterium tuberculosis antigens for TB vaccine purposes.

    PubMed

    Lin, Qingqing; Zhou, Mengying; Xu, Zongkai; Khanniche, Asma; Shen, Hao; Wang, Chuan

    2015-02-20

    Bacillus Calmette-Guerin (BCG) has failed in complete control of tuberculosis (TB), thus, novel tuberculosis vaccines are urgently needed. We have constructed several TB vaccine candidates, which are characterized by the use of Listeria ivanovii (LI) strain as an antigen delivery vector. Two L. ivanovii attenuated recombinant strains L. ivanovii△actAplcB-Rv0129c and L. ivanovii△actAplcB-Rv3875 were successfully screened. Results from genome PCR and sequencing showed that the Mycobacterium tuberculosis antigen gene cassette coding for Ag85C or ESAT-6 protein respectively had been integrated into LI genome downstream of mpl gene. Western blot confirmed the secretion of Ag85C or ESAT-6 protein from the recombinant LI strains. These two recombinant strains showed similar growth curves as wide type strain in vitro. In vivo, they transiently propagated in mice spleen and liver, and induced specific CD8(+) IFN-γ secretion. Therefore, in this paper, two novel LI attenuated strains expressing specific TB antigens were successfully constructed. The promising growth characteristics in mice immune system and the capability of induction of IFN-γ secretion make them of potential interest for development of TB vaccines.

  12. The reinfection threshold promotes variability in tuberculosis epidemiology and vaccine efficacy.

    PubMed Central

    Gomes, M. Gabriela M.; Franco, Ana O.; Gomes, Manuel C.; Medley, Graham F.

    2004-01-01

    Population patterns of infection are determined largely by susceptibility to infection. Infection and vaccination induce an immune response that, typically, reduces susceptibility to subsequent infections. With a general epidemic model, we detect a 'reinfection threshold', above which reinfection is the principal type of transmission and, consequently, infection levels are much higher and vaccination fails. The model is further developed to address human tuberculosis (TB) and the impact of vaccination. The bacille Calmette-Guérin (BCG) is the only vaccine in current use against TB, and there is no consensus about its usefulness. Estimates of protection range from 0 to 80%, and this variability is aggravated by an association between low vaccine efficacy and high prevalence of the disease. We propose an explanation based on three postulates: (i) the potential for transmission varies between populations, owing to differences in socio-economic and environmental factors; (ii) exposure to mycobacteria induces an immune response that is partially protective against reinfection; and (iii) this protection is not significantly improved by BCG vaccination. These postulates combine to reproduce the observed trends, and this is attributed to a reinfection threshold intrinsic to the transmission dynamics. Finally, we demonstrate how reinfection thresholds can be manipulated by vaccination programmes, suggesting that they have a potentially powerful role in global control. PMID:15156920

  13. The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection

    PubMed Central

    Lin, Philana Ling; Dietrich, Jes; Tan, Esterlina; Abalos, Rodolfo M.; Burgos, Jasmin; Bigbee, Carolyn; Bigbee, Matthew; Milk, Leslie; Gideon, Hannah P.; Rodgers, Mark; Cochran, Catherine; Guinn, Kristi M.; Sherman, David R.; Klein, Edwin; Janssen, Christopher; Flynn, JoAnne L.; Andersen, Peter

    2011-01-01

    It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress–induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56. PMID:22133873

  14. Adjuvant formulation structure and composition are critical for the development of an effective vaccine against tuberculosis

    PubMed Central

    Orr, Mark T.; Fox, Christopher B.; Baldwin, Susan L.; Sivananthan, Sandra J.; Lucas, Elyse; Lin, Susan; Phan, Tony; Moon, James J.; Vedvick, Thomas S.; Reed, Steven G.; Coler, Rhea N.

    2013-01-01

    One third of the world is infected with Mycobacterium tuberculosis (Mtb) with eight million new cases of active tuberculosis (TB) each year. Development of a new vaccine to augment or replace the only approved TB vaccine, BCG, is needed to control this disease. Mtb infection is primarily controlled by TH1 cells through the production of IFN-γ and TNF which activate infected macrophages to kill the bacterium. Here we examine an array of adjuvant formulations containing the TLR4 agonist GLA to identify candidate adjuvants to pair with ID93, a lead TB vaccine antigen, to elicit protective TH1 responses. We evaluate a variety of adjuvant formulations including alum, liposomes, and oil-in-water emulsions to determine how changes in formulation composition alter adjuvant activity. We find that alum and an aqueous nanosuspension of GLA synergize to enhance generation of ID93-specific TH1 responses, whereas neither on their own are effective adjuvants for generation of ID93-specific TH1 responses. For GLA containing oil-in-water emulsions, the selection of the oil component is critical for adjuvant activity, whereas a variety of lipid components may be used in liposomal formulations of GLA. The composition of the liposome formulation of ID93/GLA does alter the magnitude of the TH1 response. These results demonstrate that there are multiple solutions for an effective formulation of a novel TB vaccine candidate that enhances both TH1 generation and protective efficacy. PMID:23933525

  15. HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells.

    PubMed

    Riou, Catherine; Strickland, Natalie; Soares, Andreia P; Corleis, Björn; Kwon, Douglas S; Wherry, E John; Wilkinson, Robert J; Burgers, Wendy A

    2016-04-01

    HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-α (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets.

  16. Bacillus Calmette-Guérin vaccination reduces the severity and progression of tuberculosis in badgers.

    PubMed

    Chambers, Mark A; Rogers, Fiona; Delahay, Richard J; Lesellier, Sandrine; Ashford, Roland; Dalley, Deanna; Gowtage, Sonya; Davé, Dipesh; Palmer, Si; Brewer, Jacky; Crawshaw, Timothy; Clifton-Hadley, Richard; Carter, Steve; Cheeseman, Chris; Hanks, Chris; Murray, Alistair; Palphramand, Kate; Pietravalle, Stéphane; Smith, Graham C; Tomlinson, Alexandra; Walker, Neil J; Wilson, Gavin J; Corner, Leigh A L; Rushton, Stephen P; Shirley, Mark D F; Gettinby, George; McDonald, Robbie A; Hewinson, R Glyn

    2011-06-22

    Control of bovine tuberculosis (TB) in cattle has proven particularly challenging where reservoirs of infection exist in wildlife populations. In Britain and Ireland, control is hampered by a reservoir of infection in Eurasian badgers (Meles meles). Badger culling has positive and negative effects on bovine TB in cattle and is difficult, costly and controversial. Here we show that Bacillus Calmette-Guérin (BCG) vaccination of captive badgers reduced the progression, severity and excretion of Mycobacterium bovis infection after experimental challenge. In a clinical field study, BCG vaccination of free-living badgers reduced the incidence of positive serological test results by 73.8 per cent. In common with other species, BCG did not appear to prevent infection of badgers subjected to experimental challenge, but did significantly reduce the overall disease burden. BCG vaccination of badgers could comprise an important component of a comprehensive programme of measures to control bovine TB in cattle.

  17. Pulmonary but Not Subcutaneous Delivery of BCG Vaccine Confers Protection to Tuberculosis-Susceptible Mice by an Interleukin 17-Dependent Mechanism.

    PubMed

    Aguilo, Nacho; Alvarez-Arguedas, Samuel; Uranga, Santiago; Marinova, Dessislava; Monzón, Marta; Badiola, Juan; Martin, Carlos

    2016-03-01

    Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis-specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis-specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis.

  18. Pulmonary but Not Subcutaneous Delivery of BCG Vaccine Confers Protection to Tuberculosis-Susceptible Mice by an Interleukin 17-Dependent Mechanism.

    PubMed

    Aguilo, Nacho; Alvarez-Arguedas, Samuel; Uranga, Santiago; Marinova, Dessislava; Monzón, Marta; Badiola, Juan; Martin, Carlos

    2016-03-01

    Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis-specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis-specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis. PMID:26494773

  19. ESAT-6 (EsxA) and TB10.4 (EsxH) based vaccines for pre- and post-exposure tuberculosis vaccination.

    PubMed

    Hoang, Truc; Aagaard, Claus; Dietrich, Jes; Cassidy, Joseph P; Dolganov, Gregory; Schoolnik, Gary K; Lundberg, Carina Vingsbo; Agger, Else Marie; Andersen, Peter

    2013-01-01

    The ESX systems from Mycobacterium tuberculosis are responsible for the secretion of highly immunogenic proteins of key importance for bacterial survival and growth. The two prototypic proteins, ESAT-6 (EsxA from ESX-1) and TB10.4 (EsxH from ESX-3) share a lot of characteristics regarding genome organization, size, antigenic properties, and vaccine potential but the two molecules clearly have very different roles in bacterial physiology. To further investigate the role of ESAT-6 and TB10.4 as preventive and post-exposure tuberculosis vaccines, we evaluated four different fusion-protein vaccines; H1, H4, H56 and H28, that differ only in these two components. We found that all of these vaccines give rise to protection in a conventional prophylactic vaccination model. In contrast, only the ESAT-6-containing vaccines resulted in significant protection against reactivation, when administered post-exposure. This difference in post-exposure activity did not correlate with a difference in gene expression during infection or a differential magnitude or quality of the vaccine-specific CD4 T cells induced by ESAT-6 versus TB10.4-containing vaccines. The post-exposure effect of the ESAT-6 based vaccines was found to be influenced by the infectious load at the time-point of vaccination and was abolished in chronically infected animals with high bacterial loads at the onset of vaccination. Our data demonstrate that there are specific requirements for the immune system to target an already established tuberculosis infection and that ESAT-6 has a unique potential in post-exposure vaccination strategies.

  20. Field evaluation of the protective efficacy of Mycobacterium bovis BCG vaccine against bovine tuberculosis.

    PubMed

    Lopez-Valencia, G; Renteria-Evangelista, T; Williams, J de Jesús; Licea-Navarro, A; Mora-Valle, A De la; Medina-Basulto, G

    2010-02-01

    The protective efficacy of Mycobacterium bovis BCG (1 x 10(6) single dose) was evaluated under field conditions. A total of 140 male Holstein Friesian calves, one to two week-old were selected. Two groups of 70 each were formed, one group was vaccinated and the other was injected with a placebo during their second week of age and followed until 12 months of age. The study considered a positive case of tuberculosis to be an animal that had a positive reaction to the three following tests in a row: tuberculin, IFNgamma PPD-B and IFNgamma ESAT6-CFP10 during the 12 months of exposure. The results showed a 59.4% efficacy (IC95%: 47.64-71.16). The non-vaccinated calves were 2.4 times more at risk of becoming infected (IC95%: 1.07-5.68) compared to vaccinated animals. As a complementary test a PCR test was performed using nasal exudates in some animals from both groups using a Mycobacterium complex detection kit. All the positive PCR reactions (5/44) were found in the non-vaccinated animals. These findings suggest that the use of the BCG vaccine, even though it is not capable of protecting 100%, does prevent TB vaccinated animals from excreting bacilli in their nasal secretions at their first year of age.

  1. The Efficacy of the BCG Vaccine against Newly Emerging Clinical Strains of Mycobacterium tuberculosis

    PubMed Central

    Henao-Tamayo, Marcela; Shanley, Crystal A.; Verma, Deepshikha; Zilavy, Andrew; Stapleton, Margaret C.; Furney, Synthia K.; Podell, Brendan; Orme, Ian M.

    2015-01-01

    To date, most new vaccines against Mycobacterium tuberculosis, including new recombinant versions of the current BCG vaccine, have usually been screened against the laboratory strains H37Rv or Erdman. In this study we took advantage of our recent work in characterizing an increasingly large panel of newly emerging clinical isolates [from the United States or from the Western Cape region of South Africa], to determine to what extent vaccines would protect against these [mostly high virulence] strains. We show here that both BCG Pasteur and recombinant BCG Aeras-422 [used here as a good example of the new generation BCG vaccines] protected well in both mouse and guinea pig low dose aerosol infection models against the majority of clinical isolates tested. However, Aeras-422 was not effective in a long term survival assay compared to BCG Pasteur. Protection was very strongly expressed against all of the Western Cape strains tested, reinforcing our viewpoint that any attempt at boosting BCG would be very difficult to achieve statistically. This observation is discussed in the context of the growing argument made by others that the failure of a recent vaccine trial disqualifies the further use of animal models to predict vaccine efficacy. This viewpoint is in our opinion completely erroneous, and that it is the fitness of prevalent strains in the trial site area that is the centrally important factor, an issue that is not being addressed by the field. PMID:26368806

  2. The Efficacy of the BCG Vaccine against Newly Emerging Clinical Strains of Mycobacterium tuberculosis.

    PubMed

    Henao-Tamayo, Marcela; Shanley, Crystal A; Verma, Deepshikha; Zilavy, Andrew; Stapleton, Margaret C; Furney, Synthia K; Podell, Brendan; Orme, Ian M

    2015-01-01

    To date, most new vaccines against Mycobacterium tuberculosis, including new recombinant versions of the current BCG vaccine, have usually been screened against the laboratory strains H37Rv or Erdman. In this study we took advantage of our recent work in characterizing an increasingly large panel of newly emerging clinical isolates [from the United States or from the Western Cape region of South Africa], to determine to what extent vaccines would protect against these [mostly high virulence] strains. We show here that both BCG Pasteur and recombinant BCG Aeras-422 [used here as a good example of the new generation BCG vaccines] protected well in both mouse and guinea pig low dose aerosol infection models against the majority of clinical isolates tested. However, Aeras-422 was not effective in a long term survival assay compared to BCG Pasteur. Protection was very strongly expressed against all of the Western Cape strains tested, reinforcing our viewpoint that any attempt at boosting BCG would be very difficult to achieve statistically. This observation is discussed in the context of the growing argument made by others that the failure of a recent vaccine trial disqualifies the further use of animal models to predict vaccine efficacy. This viewpoint is in our opinion completely erroneous, and that it is the fitness of prevalent strains in the trial site area that is the centrally important factor, an issue that is not being addressed by the field.

  3. Tuberculosis

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Tuberculosis KidsHealth > For Teens > Tuberculosis Print A A A Text Size What's in ... Duration When to Call the Doctor en español Tuberculosis TB Basics Tuberculosis (also known as "TB") is ...

  4. Live attenuated Salmonella vaccines against Mycobacterium tuberculosis with antigen delivery via the type III secretion system.

    PubMed

    Juárez-Rodríguez, María Dolores; Arteaga-Cortés, Lourdes T; Kader, Rebin; Curtiss, Roy; Clark-Curtiss, Josephine E

    2012-02-01

    Tuberculosis remains a global health threat, and there is dire need to develop a vaccine that is safe and efficacious and confers long-lasting protection. In this study, we constructed recombinant attenuated Salmonella vaccine (RASV) strains with plasmids expressing fusion proteins consisting of the 80 amino-terminal amino acids of the type 3 secretion system effector SopE of Salmonella and the Mycobacterium tuberculosis antigens early secreted antigenic target 6-kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10). We demonstrated that the SopE-mycobacterial antigen fusion proteins were translocated into the cytoplasm of INT-407 cells in cell culture assays. Oral immunization of mice with RASV strains synthesizing SopE-ESAT-6-CFP-10 fusion proteins resulted in significant protection of the mice against aerosol challenge with M. tuberculosis H37Rv that was similar to the protection afforded by immunization with Mycobacterium bovis bacillus Calmette-Guérin (BCG) administered subcutaneously. In addition, oral immunization with the RASV strains specifying these mycobacterial antigens elicited production of significant antibody titers to ESAT-6 and production of ESAT-6- or CFP-10-specific gamma interferon (IFN-γ)-secreting and tumor necrosis factor alpha (TNF-α)-secreting splenocytes. PMID:22144486

  5. Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries.

    PubMed

    Knight, Gwenan M; Griffiths, Ulla K; Sumner, Tom; Laurence, Yoko V; Gheorghe, Adrian; Vassall, Anna; Glaziou, Philippe; White, Richard G

    2014-10-28

    To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middle-income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies.

  6. Ipr1 modified BCG as a novel vaccine induces stronger immunity than BCG against tuberculosis infection in mice.

    PubMed

    Wang, Yuwei; Yang, Chun; He, Yonglin; Zhan, Xingxing; Xu, Lei

    2016-08-01

    Tuberculosis is a major challenge to global public health. However, the Bacille Calmette‑Guérin (BCG), the only vaccine available against tuberculosis, has been questioned for the low protective effect. The present study used the mouse gene intracellular pathogen resistance I (Ipr1) gene to alter the current BCG vaccine and evaluated its immunity effect against tuberculosis. This study also investigated the intrinsic relationships of Ipr1 and innate immunity. The reformed BCG (BCGi) carrying the Ipr1 gene was constructed. The mice were intranasally challenged with the M. tuberculosis H37Rv strain after vaccination with BCGi. Protection efficacy of the vaccine was assessed by the organ coefficient, bacterial load and pathological changes in the lung. The differential expression of 113 immune‑related genes between BCGi and BCG groups were detected by an oligo microarray. According to the results of organ coefficient, bacterial load and pathological changes in the organization, BCGi had been shown to have stronger protective effects against M. tuberculosis than BCG. The oligo microarray and reverse transcription‑quantitative polymerase chain reaction further revealed that the Ipr1 gene could upregulate the expression of 13 genes, including a >3‑fold increase in Toll‑like receptor (TLR)4 and 10‑fold increase in surfactant protein D (sftpd). The two genes not only participate in innate immunity against pathogens, but also are closely interrelated. Ipr1 could activate the TLR4 and sftpd signaling pathway and improve the innate immunity against tuberculosis, therefore Ipr1 modified BCG may be a candidate vaccine against M. tuberculosis.

  7. Paratuberculosis vaccination causes only limited cross-reactivity in the skin test for diagnosis of bovine tuberculosis.

    PubMed

    Garrido, Joseba M; Vazquez, Patricia; Molina, Elena; Plazaola, Jose M; Sevilla, Iker A; Geijo, Maria V; Alonso-Hearn, Marta; Juste, Ramon A

    2013-01-01

    Although there is a wide consensus on the efficacy of paratuberculosis vaccination to limit economic losses, its use has been restricted because of its interference in the diagnosis of tuberculosis. Data from a vaccine clinical trial in the Basque Country (Spain) has been evaluated in relationship with bovine tuberculosis intradermal test results. The trial included two herds applying a Test and Culling strategy and five applying an inactivated vaccine. The vaccine was applied to animals of all ages present in each vaccinated herd when joining the trial, and then to all the replacers within their first three months of life. Yearly testing done with the comparative intradermal test (CIT) was applied to all animals older than 6 weeks. Between 2005 and 2011, the study generated 2,033 records from Vaccinated Herds (VH) and 2,252 from Test and Cull herds (TC). Pre-vaccination positive results rate was 2.40% among the 7 herds in the single bovine intradermal tuberculin test (BSIT). Two years later it rose to 20.42% in the VH and remained below at 0.75% in the TC. Applying the CIT reduced these rates to only 0.58% in the VH and to 0.25% in the TC ons. Regarding time since each animal joined the program, the proportion of positives to BSIT was variable and, in some cases, significantly different between time points. With regard to the age of vaccination, no significant differences were found between vaccination within the first year of life and afterwards. Vaccinated animals showed seventeen times more reactions than the non-vaccinated in the BSIT, but only four times more in the CIT. In conclusion, comparative intradermal test can be a useful tool to differentiate paratuberculosis vaccine cross-reactions from specific bovine tuberculosis reactions according to the European and Spanish legislation.

  8. Intracellular Cytokine Staining and Flow Cytometry: Considerations for Application in Clinical Trials of Novel Tuberculosis Vaccines.

    PubMed

    Smith, Steven G; Smits, Kaatje; Joosten, Simone A; van Meijgaarden, Krista E; Satti, Iman; Fletcher, Helen A; Caccamo, Nadia; Dieli, Francesco; Mascart, Francoise; McShane, Helen; Dockrell, Hazel M; Ottenhoff, Tom H M

    2015-01-01

    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.

  9. Subunit Protein Vaccine Delivery System for Tuberculosis Based on Hepatitis B Virus Core VLP (HBc-VLP) Particles.

    PubMed

    Dhanasooraj, Dhananjayan; Kumar, R Ajay; Mundayoor, Sathish

    2016-01-01

    Despite the development of modern medicine, tuberculosis (TB), caused by the pathogenic bacterium, Mycobacterium tuberculosis (Mtb), remains one of the deadliest diseases. This bacterium can lay dormant in individuals and get activated when immunity goes down and has also shown considerable prowess in mutating into drug resistant forms. The global emergence of such drug resistant Mtb and the lack of efficacy of Bacille Calmette Guérin (BCG), the only vaccine available so far, have resulted in a situation which cries out for a safe and effective tuberculosis vaccine.Number of different strategies has been used for developing new anti-TB vaccines and several protective antigens have been identified so far. One strategy, the use of protein subunits, has the potential to develop into a powerful tuberculosis vaccine, not only because of its efficacy and safety, but also because they are economical. The proper delivery of protein subunit vaccines with adjuvants or novel delivery systems is necessary for inducing protective immune responses. The available adjuvants or delivery systems are inadequate for generating such a response. In the present method, we have constructed a vaccine delivery system for tuberculosis based on Virus-Like Particles (VLPs). Hepatitis B Virus core antigen gene was recombinantly modified using Overlap Extension PCR (OEPCR). The final construct was designed to express HBc-VLP carrying external antigen (fusion VLP). Mycobacterium tuberculosis antigen CFP-10 was used for the construction of fusion VLP. The recombinant gene for the construct was cloned into a pET expression system and transformed into E. coli BL21(DE3) and induced with IPTG to express the protein. The fusion protein was purified using the Histidine tag and allowed to form VLPs. The preformed VLPs were purified by sucrose density gradient centrifugation. The VLPs were characterized using Transmission Electron Microscopy (TEM). PMID:27076312

  10. Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses

    PubMed Central

    Zvi, Anat; Ariel, Naomi; Fulkerson, John; Sadoff, Jerald C; Shafferman, Avigdor

    2008-01-01

    Background Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%–80%), and directed essentially against early phase infection. Methods A genome-scale dataset was constructed by analyzing published data of: (1) global gene expression studies under conditions which simulate intra-macrophage stress, dormancy, persistence and/or reactivation; (2) cellular and humoral immunity, and vaccine potential. This information was compiled along with revised annotation/bioinformatic characterization of selected gene products and in silico mapping of T-cell epitopes. Protocols for scoring, ranking and prioritization of the antigens were developed and applied. Results Cross-matching of literature and in silico-derived data, in conjunction with the prioritization scheme and biological rationale, allowed for selection of 189 putative vaccine candidates from the entire genome. Within the 189 set, the relative distribution of antigens in 3 functional categories differs significantly from their distribution in the whole genome, with reduction in the Conserved hypothetical category (due to improved annotation) and enrichment in Lipid and in Virulence categories. Other prominent representatives in the 189 set are the PE/PPE proteins; iron sequestration, nitroreductases and proteases, all within the Intermediary metabolism and respiration category; ESX secretion systems, resuscitation promoting factors and lipoproteins, all within the Cell wall category. Application of a ranking scheme based on qualitative and quantitative scores, resulted in a list of 45 best-scoring antigens, of which: 74% belong to the dormancy/reactivation/resuscitation classes; 30% belong

  11. Farmer attitudes to vaccination and culling of badgers in controlling bovine tuberculosis.

    PubMed

    Warren, M; Lobley, M; Winter, M

    2013-07-13

    Controversy persists in England, Wales and Northern Ireland concerning methods of controlling the transmission of bovine tuberculosis (bTB) between badgers and cattle. The National Trust, a major land-owning heritage organisation, in 2011, began a programme of vaccinating badgers against bTB on its Killerton Estate in Devon. Most of the estate is farmed by 18 tenant farmers, who thus have a strong interest in the Trust's approach, particularly as all have felt the effects of the disease. This article reports on a study of the attitudes to vaccination of badgers and to the alternative of a culling programme, using face-to-face interviews with 14 of the tenants. The results indicated first that the views of the respondents were more nuanced than the contemporary public debate about badger control would suggest. Secondly, the attitude of the interviewees to vaccination of badgers against bTB was generally one of resigned acceptance. Thirdly, most respondents would prefer a combination of an effective vaccination programme with an effective culling programme, the latter reducing population of density sufficiently (and preferably targeting the badgers most likely to be diseased) for vaccination to have a reasonable chance of success. While based on a small sample, these results will contribute to the vigorous debate concerning contrasting policy approaches to bTB control in England, Wales and Northern Ireland.

  12. On the impact of masking and blocking hypotheses for measuring the efficacy of new tuberculosis vaccines

    PubMed Central

    Sanz, Joaquín; Marinova, Dessislava; Martín, Carlos; Moreno, Yamir

    2016-01-01

    Over the past 60 years, the Mycobacterium bovis bacille Calmette–Guérin (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. PMID:26893956

  13. Safety and immunogenicity of a defined vaccine for the prevention of cutaneous leishmaniasis.

    PubMed

    Vélez, Iván D; Gilchrist, Katherine; Martínez, Sofía; Ramírez-Pineda, José R; Ashman, Jill A; Alves, Fabiana P; Coler, Rhea N; Bogatzki, Lisa Y; Kahn, Stuart J; Beckmann, Anna Marie; Cowgill, Karen D; Reed, Steven G; Piazza, Franco M

    2009-12-11

    Healthy Colombian adult volunteers with no history of leishmaniasis were evaluated for evidence of previous subclinical infection with Leishmania based on the Montenegro skin test (MST). Twelve MST-positive subjects were enrolled in an open-label, uncontrolled clinical trial (the "MST-positive trial") and received three injections of the LEISH-F1+MPL-SE vaccine (consisting of 10 microg recombinant Leishmania polyprotein LEISH-F1 antigen [TSA+LmSTI1+LeIF]+25 microg MPL-SE adjuvant). Sixty-eight MST-negative subjects were enrolled in a randomized, double-blind, controlled trial (the "MST-negative trial") and were randomly assigned to receive three injections of either the vaccine (n=34), 10 microg LEISH-F1 protein alone (n=17), or saline placebo (n=17). In both trials, the study injections were given subcutaneously on Days 0, 28, and 56, and subjects were followed for safety and immunological endpoints. The LEISH-F1+MPL-SE vaccine was safe and well tolerated in MST-positive and MST-negative subjects. In both trials, an IFN-gamma response to the LEISH-F1 antigen at Day 84 was observed in more than half of the vaccine recipients. In the MST-negative trial, the IFN-gamma response was significantly more frequent and of greater magnitude in vaccine recipients than in protein-alone or placebo recipients. An IgG antibody response to LEISH-F1 was observed in all vaccine recipients. In both trials, delayed-type hypersensitivity (DTH) to LEISH-F1 was observed in most of the vaccine recipients. In the MST-negative trial, DTH was significantly higher in vaccine than placebo recipients. These clinical trials of the first defined vaccine for leishmaniasis show that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in healthy subjects with and without evidence of previous subclinical infection with Leishmania.

  14. Progress in Oral Vaccination against Tuberculosis in Its Main Wildlife Reservoir in Iberia, the Eurasian Wild Boar

    PubMed Central

    Beltrán-Beck, Beatriz; Ballesteros, Cristina; Vicente, Joaquín; de la Fuente, José; Gortázar, Christian

    2012-01-01

    Eurasian wild boar (Sus scrofa) is the main wildlife reservoir for tuberculosis (TB) in Iberia. This review summarizes the current knowledge on wild boar vaccination including aspects of bait design, delivery and field deployment success; wild boar response to vaccination with Bacillus Calmette-Guérin (BCG) and inactivated Mycobacterium bovis; and wild boar vaccination biosafety issues as well as prospects on future research. Oral vaccination with BCG in captive wild boar has shown to be safe with significant levels of protection against challenge with virulent M. bovis. An oral vaccination with a new heat-killed M. bovis vaccine conferred a protection similar to BCG. The study of host-pathogen interactions identified biomarkers of resistance/susceptibility to tuberculosis in wild boar such as complement component 3 (C3) and methylmalonyl coenzyme A mutase (MUT) that were used for vaccine development. Finally, specific delivery systems were developed for bait-containing vaccines to target different age groups. Ongoing research includes laboratory experiments combining live and heat-killed vaccines and the first field trial for TB control in wild boar. PMID:22848869

  15. Tuberculosis

    MedlinePlus

    Tuberculosis (TB) is a disease caused by bacteria called Mycobacterium tuberculosis. The bacteria usually attack the lungs, but they can also damage other parts of the body. TB spreads through the air when a person with ...

  16. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials.

    PubMed

    Arbues, Ainhoa; Aguilo, Juan I; Gonzalo-Asensio, Jesus; Marinova, Dessislava; Uranga, Santiago; Puentes, Eugenia; Fernandez, Conchita; Parra, Alberto; Cardona, Pere Joan; Vilaplana, Cristina; Ausina, Vicente; Williams, Ann; Clark, Simon; Malaga, Wladimir; Guilhot, Christophe; Gicquel, Brigitte; Martin, Carlos

    2013-10-01

    The development of a new tuberculosis vaccine is an urgent need due to the failure of the current vaccine, BCG, to protect against the respiratory form of the disease. MTBVAC is an attenuated Mycobacterium tuberculosis vaccine candidate genetically engineered to fulfil the Geneva consensus requirements to enter human clinical trials. We selected a M. tuberculosis clinical isolate to generate two independent deletions without antibiotic-resistance markers in the genes phoP, coding for a transcription factor key for the regulation of M. tuberculosis virulence, and fadD26, essential for the synthesis of the complex lipids phthiocerol dimycocerosates (DIM), one of the major mycobacterial virulence factors. The resultant strain MTBVAC exhibits safety and biodistribution profiles similar to BCG and confers superior protection in preclinical studies. These features have enabled MTBVAC to be the first live attenuated M. tuberculosis vaccine to enter clinical evaluation.

  17. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials.

    PubMed

    Arbues, Ainhoa; Aguilo, Juan I; Gonzalo-Asensio, Jesus; Marinova, Dessislava; Uranga, Santiago; Puentes, Eugenia; Fernandez, Conchita; Parra, Alberto; Cardona, Pere Joan; Vilaplana, Cristina; Ausina, Vicente; Williams, Ann; Clark, Simon; Malaga, Wladimir; Guilhot, Christophe; Gicquel, Brigitte; Martin, Carlos

    2013-10-01

    The development of a new tuberculosis vaccine is an urgent need due to the failure of the current vaccine, BCG, to protect against the respiratory form of the disease. MTBVAC is an attenuated Mycobacterium tuberculosis vaccine candidate genetically engineered to fulfil the Geneva consensus requirements to enter human clinical trials. We selected a M. tuberculosis clinical isolate to generate two independent deletions without antibiotic-resistance markers in the genes phoP, coding for a transcription factor key for the regulation of M. tuberculosis virulence, and fadD26, essential for the synthesis of the complex lipids phthiocerol dimycocerosates (DIM), one of the major mycobacterial virulence factors. The resultant strain MTBVAC exhibits safety and biodistribution profiles similar to BCG and confers superior protection in preclinical studies. These features have enabled MTBVAC to be the first live attenuated M. tuberculosis vaccine to enter clinical evaluation. PMID:23965219

  18. Ag85A/ESAT-6 chimeric DNA vaccine induces an adverse response in tuberculosis-infected mice

    PubMed Central

    Liang, Yan; Bai, Xuejuang; Zhang, Junxian; Song, Jingying; Yang, Yourong; Yu, Qi; Li, Ning; Wu, Xueqiong

    2016-01-01

    The Mycobacterium tuberculosis (M. tb) antigens encoded by the 6 kDa early secretory antigenic target (esat-6) and antigen 85A (ag85a) genes are known to exert protective effects against tuberculosis in animal models. In addition, these antigens represent vaccine components that were tested in early human clinical trials. In the present study, a chimeric DNA vaccine was constructed that contained two copies of the esat-6 gene inserted into the ag85a gene from M. tb. BALB/c mice were treated with this chimeric vaccine following infection with either M. tb H37Rv or a clinical multi drug resistant tuberculosis isolate. Treatment of both groups of mice with the chimeric vaccine resulted in accelerated mortality. These findings are in contrast with previous results, which indicated that DNA vaccines expressing the individual antigens were either beneficial or at least not harmful. The results of the present study suggested that the ESAT-6 antigen is not suitable for inclusion in therapeutic vaccines. PMID:27279275

  19. Mycobacterium bovis DNA detection in colostrum as a potential indicator of vaccination effectiveness against bovine tuberculosis.

    PubMed

    Herrera-Rodríguez, Sara E; Gordiano-Hidalgo, María Alejandra; López-Rincón, Gonzálo; Bojorquez-Narváez, Luis; Padilla-Ramírez, Francisco Javier; Pereira-Suárez, Ana Laura; Flores-Valdez, Mario Alberto; Estrada-Chávez, Ciro

    2013-04-01

    Bovine tuberculosis (bTB) remains a problem on many dairy farms in Mexico, as well as a public health risk. We previously found a high frequency of Mycobacterium bovis DNA in colostrum from dairy cows using a nested PCR to detect mpb70. Since there are no reliable in vivo tests to determine the effectiveness of booster Mycobacterium bovis BCG vaccination against bTB, in this work we monitored M. bovis DNA in colostrum by using this nested PCR. In order to decrease the risk of adverse reactions in animals likely containing viable M. bovis, a single application of BCG and a subunit vaccine (EEP-1) formulated with M. bovis culture filtrate proteins (CFP) and a copolymer as the adjuvant was performed in tuberculin skin test-negative cattle (TST(-)), while TST reactor animals (TST(+)) received EEP-1 only. Booster immunization using EEP-1 was applied to both groups, 2 months after primary vaccination to whole herds and 12 months later to lactating cows. Colostrum samples were collected from 6 farms where the cows were vaccinated over a 12-month period postvaccination and, for comparison, from one control farm where the cows were not vaccinated with comparable bTB prevalence. We observed an inverse relationship between the frequency of M. bovis DNA detection and time postvaccination at the first (P < 0.001) and second (P < 0.0001) 6-month periods. Additionally, the concentration of gamma interferon (IFN-γ) was higher in mpb70 PCR-positive colostrum samples (P = 0.0003). These results suggest that M. bovis DNA frequency in colostrum could be a potentially useful biomarker for bTB vaccine efficacy on commercial dairy farms. PMID:23425597

  20. Mycobacterium bovis DNA detection in colostrum as a potential indicator of vaccination effectiveness against bovine tuberculosis.

    PubMed

    Herrera-Rodríguez, Sara E; Gordiano-Hidalgo, María Alejandra; López-Rincón, Gonzálo; Bojorquez-Narváez, Luis; Padilla-Ramírez, Francisco Javier; Pereira-Suárez, Ana Laura; Flores-Valdez, Mario Alberto; Estrada-Chávez, Ciro

    2013-04-01

    Bovine tuberculosis (bTB) remains a problem on many dairy farms in Mexico, as well as a public health risk. We previously found a high frequency of Mycobacterium bovis DNA in colostrum from dairy cows using a nested PCR to detect mpb70. Since there are no reliable in vivo tests to determine the effectiveness of booster Mycobacterium bovis BCG vaccination against bTB, in this work we monitored M. bovis DNA in colostrum by using this nested PCR. In order to decrease the risk of adverse reactions in animals likely containing viable M. bovis, a single application of BCG and a subunit vaccine (EEP-1) formulated with M. bovis culture filtrate proteins (CFP) and a copolymer as the adjuvant was performed in tuberculin skin test-negative cattle (TST(-)), while TST reactor animals (TST(+)) received EEP-1 only. Booster immunization using EEP-1 was applied to both groups, 2 months after primary vaccination to whole herds and 12 months later to lactating cows. Colostrum samples were collected from 6 farms where the cows were vaccinated over a 12-month period postvaccination and, for comparison, from one control farm where the cows were not vaccinated with comparable bTB prevalence. We observed an inverse relationship between the frequency of M. bovis DNA detection and time postvaccination at the first (P < 0.001) and second (P < 0.0001) 6-month periods. Additionally, the concentration of gamma interferon (IFN-γ) was higher in mpb70 PCR-positive colostrum samples (P = 0.0003). These results suggest that M. bovis DNA frequency in colostrum could be a potentially useful biomarker for bTB vaccine efficacy on commercial dairy farms.

  1. Mycobacterium bovis DNA Detection in Colostrum as a Potential Indicator of Vaccination Effectiveness against Bovine Tuberculosis

    PubMed Central

    Herrera-Rodríguez, Sara E.; Gordiano-Hidalgo, María Alejandra; López-Rincón, Gonzálo; Bojorquez-Narváez, Luis; Padilla-Ramírez, Francisco Javier; Pereira-Suárez, Ana Laura; Flores-Valdez, Mario Alberto

    2013-01-01

    Bovine tuberculosis (bTB) remains a problem on many dairy farms in Mexico, as well as a public health risk. We previously found a high frequency of Mycobacterium bovis DNA in colostrum from dairy cows using a nested PCR to detect mpb70. Since there are no reliable in vivo tests to determine the effectiveness of booster Mycobacterium bovis BCG vaccination against bTB, in this work we monitored M. bovis DNA in colostrum by using this nested PCR. In order to decrease the risk of adverse reactions in animals likely containing viable M. bovis, a single application of BCG and a subunit vaccine (EEP-1) formulated with M. bovis culture filtrate proteins (CFP) and a copolymer as the adjuvant was performed in tuberculin skin test-negative cattle (TST−), while TST reactor animals (TST+) received EEP-1 only. Booster immunization using EEP-1 was applied to both groups, 2 months after primary vaccination to whole herds and 12 months later to lactating cows. Colostrum samples were collected from 6 farms where the cows were vaccinated over a 12-month period postvaccination and, for comparison, from one control farm where the cows were not vaccinated with comparable bTB prevalence. We observed an inverse relationship between the frequency of M. bovis DNA detection and time postvaccination at the first (P < 0.001) and second (P < 0.0001) 6-month periods. Additionally, the concentration of gamma interferon (IFN-γ) was higher in mpb70 PCR-positive colostrum samples (P = 0.0003). These results suggest that M. bovis DNA frequency in colostrum could be a potentially useful biomarker for bTB vaccine efficacy on commercial dairy farms. PMID:23425597

  2. Identification of Mycobacterium tuberculosis vaccine candidates using human CD4+ T-cells expression cloning

    PubMed Central

    Coler, Rhea N.; Dillon, Davin C.; Skeiky, Yasir A. W.; Kahn, Maria; Orme, Ian M.; Lobet, Yves; Reed, Steven G.; Alderson, Mark R.

    2009-01-01

    To identify Mycobacterium tuberculosis (Mtb) antigens as candidates for a subunit vaccine against tuberculosis (TB), we have employed a CD4+ T-cell expression screening method. Mtb-specific CD4+ T-cell lines from nine healthy PPD positive donors were stimulated with different antigenic substrates including autologous dendritic cells (DC) infected with Mtb, culture filtrate proteins (CFP), and purified protein derivative of Mtb (PPD). These lines were used to screen a genomic Mtb library expressed in Escherichia coli and processed and presented by autologous DC. This screening led to the recovery of numerous T-cell antigens, including both novel and previously described antigens. One of these novel antigens, referred to as Mtb9.8 (Rv0287), was recognized by multiple T-cell lines, stimulated with either Mtb-infected DC or CFP. Using the mouse and guinea pig models of TB, high levels of IFN-γ were produced, and solid protection from Mtb challenge was observed following immunization with Mtb9.8 formulated in either AS02A or AS01B Adjuvant Systems. These results demonstrate that T-cell screening of the Mtb genome can be used to identify CD4+ T-cell antigens that are candidates for vaccine development. PMID:19000730

  3. Developing whole mycobacteria cell vaccines for tuberculosis: Workshop proceedings, Max Planck Institute for Infection Biology, Berlin, Germany, July 9, 2014.

    PubMed

    2015-06-12

    On July 9, 2014, Aeras and the Max Planck Institute for Infection Biology convened a workshop entitled "Whole Mycobacteria Cell Vaccines for Tuberculosis" at the Max Planck Institute for Infection Biology on the grounds of the Charité Hospital in Berlin, Germany, close to the laboratory where, in 1882, Robert Koch first identified Mycobacterium tuberculosis (Mtb) as the pathogen responsible for tuberculosis (TB). The purpose of the meeting was to discuss progress in the development of TB vaccines based on whole mycobacteria cells. Live whole cell TB vaccines discussed at this meeting were derived from Mtb itself, from Bacille Calmette-Guérin (BCG), the only licensed vaccine against TB, which was genetically modified to reduce pathogenicity and increase immunogenicity, or from commensal non-tuberculous mycobacteria. Inactivated whole cell TB and non-tuberculous mycobacterial vaccines, intended as immunotherapy or as safer immunization alternatives for HIV+ individuals, also were discussed. Workshop participants agreed that TB vaccine development is significantly hampered by imperfect animal models, unknown immune correlates of protection and the absence of a human challenge model. Although a more effective TB vaccine is needed to replace or enhance the limited effectiveness of BCG in all age groups, members of the workshop concurred that an effective vaccine would have the greatest impact on TB control when administered to adolescents and adults, and that use of whole mycobacteria cells as TB vaccine candidates merits greater support, particularly given the limited understanding of the specific Mtb antigens necessary to generate an immune response capable of preventing Mtb infection and/or disease.

  4. Construction and immunogenicity of a new Fc-based subunit vaccine candidate against Mycobacterium tuberculosis.

    PubMed

    Kebriaei, Abdollah; Derakhshan, Mohammad; Meshkat, Zahra; Eidgahi, Mohammad Reza Akbari; Rezaee, Seyed Abdolrahim; Farsiani, Hadi; Mosavat, Arman; Soleimanpour, Saman; Ghazvini, Kiarash

    2016-09-01

    As an ancient disease, tuberculosis (TB) is a major global health threat. Therefore, there is an urgent need for an effective and safe anti-TB vaccine. In the current study, a delivery system of Fc domain of mouse IgG2a and early secreted antigenic target protein 6 (ESAT-6) was evaluated for the selective uptake of antigens by antigen-presenting cells (APCs). Thus, it was based on the immunogenicity of a fusion protein. The study was initiated by the transfer of recombinant expression vectors of pPICZαA-ESAT-6:Fcγ2a and pPICZαA-ESAT-6: His into Pichia pastoris (P. pastoris). Recombinant proteins were assessed for immunogenicity following the immunoblotting analysis. High levels of IFN-γ and IL-12 were produced to induce Th1-type cellular responses through vaccination with both recombinant proteins [ESAT-6:Fcγ2a (EF) and ESAT-6:His (EH)]. The Fc-tagged recombinant protein induced more effective Th1-type cellular responses with a low increment in IL-4 compared to PBS, BCG, and EH groups. Although in all the immunized groups, the ratio of IFN-γ/IL-4 was in favor of Th1 responses, the highest Th1/Th2 balance was observed in EF immunized group. Fc fragment of mouse IgG2a may induce a selective uptake of APCs towards the cross-presentation and formation of Th1 responses in favor of an appropriate protective anti-tuberculosis reaction. Thus, further research on Fc-fusion proteins is required to develop Fc-based TB vaccines. PMID:27251218

  5. A New Recombinant BCG Vaccine Induces Specific Th17 and Th1 Effector Cells with Higher Protective Efficacy against Tuberculosis

    PubMed Central

    da Costa, Adeliane Castro; Costa-Júnior, Abadio de Oliveira; de Oliveira, Fábio Muniz; Nogueira, Sarah Veloso; Rosa, Joseane Damaceno; Resende, Danilo Pires; Kipnis, André; Junqueira-Kipnis, Ana Paula

    2014-01-01

    Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that is a major public health problem. The vaccine used for TB prevention is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which provides variable efficacy in protecting against pulmonary TB among adults. Consequently, several groups have pursued the development of a new vaccine with a superior protective capacity to that of BCG. Here we constructed a new recombinant BCG (rBCG) vaccine expressing a fusion protein (CMX) composed of immune dominant epitopes from Ag85C, MPT51, and HspX and evaluated its immunogenicity and protection in a murine model of infection. The stability of the vaccine in vivo was maintained for up to 20 days post-vaccination. rBCG-CMX was efficiently phagocytized by peritoneal macrophages and induced nitric oxide (NO) production. Following mouse immunization, this vaccine induced a specific immune response in cells from lungs and spleen to the fusion protein and to each of the component recombinant proteins by themselves. Vaccinated mice presented higher amounts of Th1, Th17, and polyfunctional specific T cells. rBCG-CMX vaccination reduced the extension of lung lesions caused by challenge with Mtb as well as the lung bacterial load. In addition, when this vaccine was used in a prime-boost strategy together with rCMX, the lung bacterial load was lower than the result observed by BCG vaccination. This study describes the creation of a new promising vaccine for TB that we hope will be used in further studies to address its safety before proceeding to clinical trials. PMID:25398087

  6. [Tuberculosis].

    PubMed

    Iinuma, Y

    2000-11-01

    The incidence of tuberculosis in Japan is the highest among developed countries, with approximately 42,000 new cases reported in 1997, marking the first increase in 38 years. The growing incidence among the elderly and group infections among young adults may be responsible for this increase. Infection with tubercle bacilli(TB) occurs via airborne transmission, which involves dissemination of either airborne droplet nuclei on evaporated droplets that may remain suspended in the air for long periods of time. Microorganisms carried in this manner can be dispersed widely by air currents, therefore, special air handling and ventilation are required to prevent airborne transmission. Patients with infectious TB must be placed in a single room with negative pressure and a ventilation rate of 6 or more air changes per hour. Health care workers must wear an N95 mask when entering the room, and if an incident involving possible TB infection occurs in the hospital, the concerned people should be examined for Tuberculin reaction. Two to 12 weeks after the TB infection has occurred, the tuberculin reaction converts to positive. However, most Japanese people have been vaccinated with BCG, so assessment of the results is difficult. A comparison of the diameter of erythema before and after the potential infection may be the most confirmatory. If latent TB infection is suspected, preventive therapy with isoniazid must be considered. Special biohazard systems in the clinical laboratory and autopsy room have also been proposed to prevent TB dispersal. DOTS(Directly Observed Treatment, Short-course) is useful to prevent the emergence of multi-drug-resistant TB. In some areas of Japan that have low levels of compliance with TB therapy, trials of DOTS have been started. PMID:11132556

  7. Effect of an inactivated paratuberculosis vaccine on the intradermal testing of goats for tuberculosis.

    PubMed

    Chartier, Christophe; Mercier, Pascale; Pellet, Marie-Pierre; Vialard, Jaquemine

    2012-03-01

    The effect of an inactivated paratuberculosis vaccine on the diagnosis of tuberculosis (TB) in goats was investigated in a herd with a history of clinical paratuberculosis but which was free of TB. Cohorts of animals in 2006, 2008 and 2009, were vaccinated once at 1 month of age, and 50% of the 2006 cohort served as unvaccinated controls. The goats were aged 8 months, 20 months and 3.5 years old at the time of the survey. All animals were assessed using a single intradermal injection of bovine tuberculin purified protein derivative (PPD) (SID test), or using both bovine and avian PPD (CID test). An interferon (IFN)-γ assay using both bovine and avian PPD was carried out on the 2006 cohort and was interpreted according to three different 'cut-off' points. No unvaccinated (control) animals tested positive to any of the assays, confirming that the herd was TB-free. The SID test had a low specificity in vaccinated animals at 8 and 20 months of age, whereas the CID test demonstrated 100% specificity in animals ≥20 months-old. The specificity of IFN-γ assay was less than maximal for vaccinated animals 3.5 years old as small numbers of false positives were detected, although this depended on the chosen cut-off point. The study findings demonstrate that the use of an inactivated paratuberculosis vaccine in goats <1 month-old in a TB-free herd does not result in false positives to a CID test for TB when performed in animals ≥20 months-old.

  8. Host cell-induced components of the sulfate assimilation pathway are major protective antigens of Mycobacterium tuberculosis.

    PubMed

    Pinto, Rachel; Leotta, Lisa; Shanahan, Erin R; West, Nicholas P; Leyh, Thomas S; Britton, Warwick; Triccas, James A

    2013-03-01

    New therapies to control tuberculosis are urgently required because of the inability of the only available vaccine, BCG, to adequately protect against tuberculosis. Here we demonstrate that proteins of the Mycobacterium tuberculosis sulfate-assimilation pathway (SAP) represent major immunogenic targets of the bacillus, as defined by strong T-cell recognition by both mice and humans infected with M. tuberculosis. SAP proteins displayed increased expression when M. tuberculosis was resident within host cells, which may account in part for their ability to stimulate anti-M. tuberculosis host immunity. Vaccination with the first enzyme in this pathway, adenosine-5'-triphosphate sulfurylase, conferred significant protection against murine tuberculosis and boosted BCG-induced protective immunity in the lung. Therefore, we have identified SAP components as a new family of M. tuberculosis antigens, and we have demonstrated that these components are promising candidate for inclusion in new vaccines to control tuberculosis in humans. PMID:23225904

  9. Host Cell–Induced Components of the Sulfate Assimilation Pathway Are Major Protective Antigens of Mycobacterium tuberculosis

    PubMed Central

    Pinto, Rachel; Leotta, Lisa; Shanahan, Erin R.; West, Nicholas P.; Leyh, Thomas S.; Britton, Warwick; Triccas, James A.

    2013-01-01

    New therapies to control tuberculosis are urgently required because of the inability of the only available vaccine, BCG, to adequately protect against tuberculosis. Here we demonstrate that proteins of the Mycobacterium tuberculosis sulfate-assimilation pathway (SAP) represent major immunogenic targets of the bacillus, as defined by strong T-cell recognition by both mice and humans infected with M. tuberculosis. SAP proteins displayed increased expression when M. tuberculosis was resident within host cells, which may account in part for their ability to stimulate anti-M. tuberculosis host immunity. Vaccination with the first enzyme in this pathway, adenosine-5′-triphosphate sulfurylase, conferred significant protection against murine tuberculosis and boosted BCG-induced protective immunity in the lung. Therefore, we have identified SAP components as a new family of M. tuberculosis antigens, and we have demonstrated that these components are promising candidate for inclusion in new vaccines to control tuberculosis in humans. PMID:23225904

  10. [Efficacy and safety of vaccines against tuberculosis in the relation to genetic variability of Mycobacterium bovis BCG strains].

    PubMed

    Prygiel, Marta; Janaszek-Seydlitz, Wiesława; Bucholc, Bozena

    2011-01-01

    All vaccines against tuberculosis used actually over the world contain Mycobacterium bovis BCG strains (Bacillus Calmette-Guerin) as active substance. Strain BCG, that was obtained in 1921 by Calmette and Guerin after 13 years ofpassaging on the potato-glicerol medium with addition of bile, was distributed to many laboratories for vaccine production. The repeated passages of M. bovis BCG strain in different culture conditions caused the numerous mutations and formation of many BCG substrains that differed according to efficacy and safety. The review of many publications related to genetic differences between BCG substrains was performed for identify the genes responsible for their virulence and protective characteristics. Possibility of development of new generation vaccines against tuberculosis is discussed. PMID:22390050

  11. Protection against bovine tuberculosis induced by oral vaccination of cattle with Mycobacterium bovis BCG is not enhanced by co-administration of mycobacterial protein vaccines.

    PubMed

    Wedlock, D Neil; Aldwell, Frank E; Vordermeier, H Martin; Hewinson, R Glyn; Buddle, Bryce M

    2011-12-15

    Mycobacterium bovis bacille Calmette-Guérin (BCG) delivered to calves by the oral route in a formulated lipid matrix has been previously shown to induce protection against bovine tuberculosis. A study was conducted in cattle to determine if a combination of a low dose of oral BCG and a protein vaccine could induce protective immunity to tuberculosis while not sensitising animals to tuberculin. Groups of calves (10 per group) were vaccinated by administering 2 × 10(7)colony forming units (CFU) of BCG orally or a combination of 2 × 10(7)CFU oral BCG and a protein vaccine comprised of M. bovis culture filtrate proteins (CFP) formulated with the adjuvants Chitin and Gel 01 and delivered by the intranasal route, or CFP formulated with Emulsigen and the TLR2 agonist Pam(3)CSK(4) and administered by the subcutaneous (s.c.) route. Two further groups were vaccinated with the CFP/Chitin/Gel 01 or CFP/Emulsigen/Pam(3)CSK(4) vaccines alone. Positive control groups were given 10(8)CFU oral BCG or 10(6)CFU s.c. BCG while a negative control group was non-vaccinated. All animals were challenged with M. bovis 15 weeks after vaccination and euthanized and necropsied at 16 weeks following challenge. Groups of cattle vaccinated with s.c. BCG, 10(8)CFU or 2 × 10(7)CFU oral BCG showed significant reductions in seven, three and four pathological or microbiological disease parameters, respectively, compared to the results for the non-vaccinated group. There was no evidence of protection in calves vaccinated with the combination of oral BCG and CFP/Emulsigen/Pam(3)CSK(4) or oral BCG and CFP/Chitin/Gel 01 or vaccinated with the protein vaccines alone. Positive responses in the comparative cervical skin test at 12 weeks after vaccination were only observed in animals vaccinated with s.c. BCG, 10(8)CFU oral BCG or a combination of 2 × 10(7)CFU oral BCG and CFP/Chitin/Gel 01. In conclusion, co-administration of a protein vaccine, administered by either systemic or mucosal routes with oral

  12. Vaccination against tuberculosis in badgers and cattle: an overview of the challenges, developments and current research priorities in Great Britain.

    PubMed

    Chambers, M A; Carter, S P; Wilson, G J; Jones, G; Brown, E; Hewinson, R G; Vordermeier, M

    2014-07-26

    Bovine tuberculosis (TB) is a significant threat to the cattle industry in England and Wales. It is widely acknowledged that a combination of measures targeting both cattle and wildlife will be required to eradicate bovine TB or reduce its prevalence until European official freedom status is achieved. Vaccination of cattle and/or badgers could contribute to bovine TB control in Great Britain, although there are significant gaps in our knowledge regarding the impact that vaccination would actually have on bovine TB incidence. Laboratory studies have demonstrated that vaccination with BCG can reduce the progression and severity of TB in both badgers and cattle. This is encouraging in terms of the prospect of a sustained vaccination programme achieving reductions in disease prevalence; however, developing vaccines for tackling the problem of bovine TB is challenging, time-consuming and resource-intensive, as this review article sets out to explain.

  13. Immune modulators with defined molecular targets: cornerstone to optimize rational vaccine design.

    PubMed

    Ebensen, Thomas; Guzmán, Carlos A

    2008-01-01

    Vaccination remains the most valuable tool for preventing infectious diseases. However, the performance of many existing vaccines should be improved and there are diseases for which vaccines are still not available. The use of well-defined antigens for the generation of subunit vaccines has led to products with an improved safety profile. However, purified antigens are usually poorly immunogenic, making essential the use of adjuvants. Despite the fact that adjuvants have been used to increase the immunogenicity of vaccines for more than 70 years, only a handful has been licensed for human use (e.g., aluminium salts, the micro-fluidized squalene-in-water emulsion MF59 and monophosphoryl lipid A). Thus, the development of new adjuvants which are able to promote broad and sustained immune responses at systemic and mucosal levels still remains as a major challenge in vaccinology. Recent advances in our understanding of the immune system have facilitated the identification of new biological targets for screening programs aimed at the discovery of novel immune stimulators. This resulted in the identification of new candidate adjuvants, which made possible the modulation of the immune responses elicited according to specific needs. A number of promising adjuvants which are currently under preclinical or clinical development will be described in this review. PMID:18376145

  14. Immune modulators with defined molecular targets: cornerstone to optimize rational vaccine design.

    PubMed

    Ebensen, Thomas; Guzmán, Carlos A

    2009-01-01

    Vaccination remains the most valuable tool for preventing infectious diseases. However, the performance of many existing vaccines should be improved and there are diseases for which vaccines are still not available. The use of well-defined antigens for the generation of subunit vaccines has led to products with an improved safety profile. However, purified antigens are usually poorly immunogenic, making essential the use of adjuvants. Despite the fact that adjuvants have been used to increase the immunogenicity of vaccines for more than 70 years, only a handful has been licensed for human use (e.g., aluminium salts, the micro-fluidized squalene-in-water emulsion MF59 and monophosphoryl lipid A). Thus, the development of new adjuvants which are able to promote broad and sustained immune responses at systemic and mucosal levels still remains as a major challenge in vaccinology. Recent advances in our understanding of the immune system have facilitated the identification of new biological targets for screening programs aimed at the discovery of novel immune stimulators. This resulted in the identification of new candidate adjuvants, which made possible the modulation of the immune responses elicited according to specific needs. A number of promising adjuvants which are currently under preclinical or clinical development will be described in this chapter. PMID:20047042

  15. Mycobacterium tuberculosis Rv2882c Protein Induces Activation of Macrophages through TLR4 and Exhibits Vaccine Potential

    PubMed Central

    Back, Yong Woo; Park, Hye-Soo; Bae, Hyun Shik; Choi, Chul Hee; Kim, Hwa-Jung

    2016-01-01

    Macrophages constitute the first line of defense against Mycobacterium tuberculosis and are critical in linking innate and adaptive immunity. Therefore, the identification and characterization of mycobacterial proteins that modulate macrophage function are essential for understanding tuberculosis pathogenesis. In this study, we identified the novel macrophage-activating protein, Rv2882c, from M. tuberculosis culture filtrate proteins. Recombinant Rv2882c protein activated macrophages to secrete pro-inflammatory cytokines and express co-stimulatory and major histocompatibility complex molecules via Toll-like receptor 4, myeloid differentiation primary response protein 88, and Toll/IL-1 receptor-domain-containing adaptor inducing IFN-beta. Mitogen-activated protein kinases and NF-κB signaling pathways were involved in Rv2882c-induced macrophage activation. Further, Rv2882c-treated macrophages induced expansion of the effector/memory T cell population and Th1 immune responses. In addition, boosting Bacillus Calmette-Guerin vaccination with Rv2882c improved protective efficacy against M. tuberculosis in our model system. These results suggest that Rv2882c is an antigen that could be used for tuberculosis vaccine development. PMID:27711141

  16. Pilot Study of Diagnostic Potential of the Mycobacterium tuberculosis Recombinant HBHA Protein in a Vaccinated Population in Finland

    PubMed Central

    Savolainen, Laura; Pusa, Liana; Kim, Hwa-Jung; Sillanpää, Heidi; Seppälä, Ilkka; Tuuminen, Tamara

    2008-01-01

    Background In recent years T cell based interferon gamma release assays (IGRA) have been developed for immunodiagnosis of M. tuberculosis infection. At present these assays do not discriminate between disease and latency. Therefore, more promising antigens and diagnostic tools are continuously being searched for tuberculosis immunodiagnostics. The heparin binding hemagglutinin (HBHA) is a surface protein of M. tuberculosis which promotes bacterial aggregation and adhesion to non-phagocytic cells. It has been previously assumed that native, methylated form of this protein would be a promising antigen to discriminate latent from active infection. Methodology and Principal Findings We performed a pilot investigation to study humoral and T-cell mediated immunological responses to recombinant HBHA produced in M. smegmatis or to synthetic peptides in patients with recent or past tuberculosis, with atypical mycobacteriosis, or in healthy vaccinated individuals. The T cell reactivities to HBHA were compared to the respective reactivities towards Purified Protein Derivative (PPD) and two surface secreted proteins, ie. Early Secretory Antigen Target-6 (ESAT-6) and Culture Filtrate Protein-10 (CFP-10). Our pilot results indicate that methylated recombinant HBHA induced a strong T cell mediated immune response and the production of IgG and IgM-class antibodies in all patient groups, most surprisingly in young Finnish vaccinees, as well. We observed a positive correlation between the reactivities to HBHA and non-specific PPD among all studied subjects. As expected, ESAT-6 and CFP-10 were the most powerful antigens to discriminate disease from immunity caused by vaccination. Conclusions On the basis of results of this exploratory investigation we raise concerns that in countries like Finland, where BCG vaccination was routinely used, HBHA utility might not be sufficient for diagnostics because of inability to explicitly discriminate tuberculosis infection from immunoreactivity

  17. A Dual TLR Agonist Adjuvant Enhances the Immunogenicity and Protective Efficacy of the Tuberculosis Vaccine Antigen ID93

    PubMed Central

    Orr, Mark T.; Beebe, Elyse A.; Hudson, Thomas E.; Moon, James J.; Fox, Christopher B.; Reed, Steven G.; Coler, Rhea N.

    2014-01-01

    With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4+ T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG. PMID:24404140

  18. Mycobacterium tuberculosis Rv0899 defines a family of membrane proteins widespread in nitrogen-fixing bacteria

    PubMed Central

    Marassi, Francesca M.

    2011-01-01

    The Mycobacterium tuberculosis membrane protein Rv0899 confers adaptation of the bacterium to acidic environments. Due to strong sequence homology of its C-terminus to bacterial OmpA-like domains, Rv0899 has been proposed to constitute an outer membrane porin of M. tuberculosis. However, OmpA-like domains are widespread in a wide variety of bacterial proteins with different functions. Furthermore, the three-dimensional structure of Rv0899 does not contain a transmembrane β-barrel, and recent evidence demonstrates that it does not have porin activity. Instead, the rv0899 gene is part of an operon (rv0899-rv0901) that is required for fast ammonia secretion, pH neutralization and growth of M. tuberculosis in acidic environments. The mechanism whereby these functions are accomplished is not known. To gain further functional insights, a targeted search of the genomic databases was performed for proteins with sequence similarity beyond the OmpA-like C-terminus. The results presented here, show that Rv0899-like proteins are widespread in bacteria with functions in nitrogen metabolism, adaptation to nutrient poor environments, and/or establishing symbiosis with the host organism, and appear to form a protein family. These findings suggest that M. tuberculosis Rv0899 may also assist similar processes and lend further support to its role in ammonia secretion and M. tuberculosis adaptation to the host environment. PMID:21905117

  19. Kinetics of the immune response profile in guinea pigs after vaccination with Mycobacterium bovis BCG and infection with Mycobacterium tuberculosis.

    PubMed

    Grover, Ajay; Taylor, Jennifer; Troudt, JoLynn; Keyser, Andrew; Arnett, Kimberly; Izzo, Linda; Rholl, Drew; Izzo, Angelo

    2009-11-01

    The guinea pig model of tuberculosis is used extensively in assessing novel vaccines, since Mycobacterium bovis BCG vaccination effectively prolongs survival after low-dose aerosol infection with virulent M. tuberculosis. To better understand how BCG extends time to death after pulmonary infection with M. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-gamma) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+ CD62Llow and CD8+ CD62Llow) and mRNA expression of IFN-gamma, tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-gamma mRNA expression but decreased TNF-alpha mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-gamma mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+ CD62Llow T cells at day 40, although the numbers of CD8+ CD62Llow T cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.

  20. Therapeutic vaccination against relevant high virulence clinical isolates of Mycobacterium tuberculosis.

    PubMed

    Shanley, Crystal A; Ireton, Gregory C; Baldwin, Susan L; Coler, Rhea N; Reed, Steven G; Basaraba, Randall J; Orme, Ian M

    2014-03-01

    The purpose of this study was to attempt to develop therapeutic or post-exposure vaccines that could slow progressive disease in guinea pigs infected by low dose aerosol with very high virulence Beijing isolates of Mycobacterium tuberculosis, currently classified as Category C biodefense pathogens by the NIH and CDC. After screening several candidates we focused on the use of three candidates; these were a pool of bacterial iron acquisition proteins, a pool of antigens recognized by T cells from chronically infected mice thought to represent proteins made by the bacillus in response to decreases in local oxygen tension, and a bacterial lipoprotein that is a potent TLR2 agonist. When delivered in a potent GLA-based adjuvant [targeting TLR4 and TLR9], in most cases we were unable to reduce the bacterial load in the lungs. However, the pathologic appearance of lungs from these animals showed that, while primary lesions were most unaffected and had become necrotic, the development of large, lung consolidating secondary lesions seemed to have been mostly prevented. In animals given both a priming vaccination and a boost the effects were prominent, and almost certainly contributed to significantly prolonged survival in these animals. In a biodefense situation, this prolonged survival would be potentially long enough to allow for the organism to be identified and a drug susceptibility profile determined.

  1. Therapeutic vaccination against relevant high virulence clinical isolates of Mycobacterium tuberculosis

    PubMed Central

    Shanley, Crystal A.; Ireton, Gregory C.; Baldwin, Susan L.; Coler, Rhea N.; Reed, Steven G.; Basaraba, Randall J.; Orme, Ian M.

    2014-01-01

    SUMMARY The purpose of this study was to attempt to develop therapeutic or post-exposure vaccines that could slow progressive disease in guinea pigs infected by low dose aerosol with very high virulence Beijing isolates of Mycobacterium tuberculosis, currently classified as Category C biodefense pathogens by the NIH and CDC. After screening several candidates we focused on the use of three candidates; these were a pool of bacterial iron acquisition proteins, a pool of antigens recognized by T cells from chronically infected mice thought to represent proteins made by the bacillus in response to decreases in local oxygen tension, and a bacterial lipoprotein that is a potent TLR2 agonist. When delivered in a potent GLA-based adjuvant[targeting TLR4 and TLR9], in most cases we were unable to reduce the bacterial load in the lungs. However, the pathologic appearance of lungs from these animals showed that, while primary lesions were most unaffected and had become necrotic, the development of large, lung consolidating secondary lesions seemed to have been mostly prevented. In animals given both a priming vaccination and a boost the effects were prominent, and almost certainly contributed to significantly prolonged survival in these animals. In a biodefense situation, this prolonged survival would be potentially long enough to allow for the organism to be identified and a drug susceptibility profile determined. PMID:24295653

  2. Developing aerosol vaccines for Mycobacterium tuberculosis: Workshop proceedings: National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA, April 9, 2014.

    PubMed

    2015-06-12

    On April 9, 2014, Aeras and the National Institute of Allergy and Infectious Diseases convened a workshop entitled "Developing Aerosol Vaccines for Mycobacterium tuberculosis" in Bethesda, MD. The purpose of the meeting was to explore the potential for developing aerosol vaccines capable of preventing infection with M. tuberculosis (Mtb), preventing the development of active tuberculosis (TB) among those latently infected with Mtb, or as immunotherapy for persons with active TB. The workshop was organized around four key questions relevant to developing and assessing aerosol TB vaccines: (1) What is the current knowledge about lung immune responses and early pathogenesis resulting after Mtb infection and what are the implications for aerosol TB vaccine strategies? (2) What are the technical issues surrounding aerosol vaccine delivery? (3) What is the current experience in aerosol TB vaccine development? and (4) What are the regulatory implications of developing aerosol vaccines, including those for TB? Lessons learned from the WHO effort to develop an aerosol measles vaccine served as a case example for overall discussions at the meeting. Workshop participants agreed that aerosol delivery represents a potentially important strategy in advancing TB vaccine development efforts. As no major regulatory, manufacturing or clinical impediments were identified, members of the workshop emphasized the need for greater support to further explore the potential for this delivery methodology, either alone or as an adjunct to traditional parenteral methods of vaccine administration.

  3. Developing vaccines to prevent sustained infection with Mycobacterium tuberculosis: Conference proceedings: National Institute of Allergy and Infectious Diseases, Rockville, Maryland USA, November 7, 2014.

    PubMed

    2015-06-12

    On November 7, 2014, Aeras and the National Institute of Allergy and Infectious Diseases convened a conference entitled "Vaccine Prevention of Sustained Mycobacterium tuberculosis Infection." The purpose of this meeting was to explore the biologic plausibility, potential public health and economic impact, and regulatory feasibility in attempting to develop a vaccine to prevent sustained infection with Mycobacterium tuberculosis (Mtb). Currently there are two main goals for tuberculosis (TB) vaccine development, to develop a vaccine that could serve as a booster to Bacille Calmette-Guérin (BCG) vaccination and prevent active TB in adolescents and adults, and to develop an improved vaccine to replace BCG in infants. Although prevention of sustained Mtb infection is being used as a proof of biological activity for vaccines in mid-Phase 2 development, there currently are no plans for pursuing a prevention of Mtb infection licensure indication for TB vaccines. Ultimately, pursuing a prevention of sustained Mtb infection indication for TB vaccines, in parallel with ongoing efforts to develop vaccines to prevent active TB disease, was deemed a potentially important effort, but would require further resources, particularly to improve diagnostic assays, to increase the regulatory feasibility of this endeavor.

  4. Prime-boost bacillus Calmette-Guérin vaccination with lentivirus-vectored and DNA-based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice.

    PubMed

    Xu, Ying; Yang, Enzhuo; Wang, Jianguang; Li, Rui; Li, Guanghua; Liu, Guoyuan; Song, Na; Huang, Qi; Kong, Cong; Wang, Honghai

    2014-10-01

    To prevent the global spread of tuberculosis (TB), more effective vaccines and vaccination strategies are urgently needed. As a result of the success of bacillus Calmette-Guérin (BCG) in protecting children against miliary and meningeal TB, the majority of individuals will have been vaccinated with BCG; hence, boosting BCG-primed immunity will probably be a key component of future vaccine strategies. In this study, we compared the ability of DNA-, protein- and lentiviral vector-based vaccines that express the antigens Ag85B and Rv3425 to boost the effects of BCG in the context of immunity and protection against Mycobacterium tuberculosis in C57BL/6 mice. Our results demonstrated that prime-boost BCG vaccination with a lentiviral vector expressing the antigens Ag85B and Rv3425 significantly enhanced immune responses, including T helper type 1 and CD8(+) cytotoxic T lymphocyte responses, compared with DNA- and protein-based vaccines. However, lentivirus-vectored and DNA-based vaccines greatly improved the protective efficacy of BCG against M. tuberculosis, as indicated by a lack of weight loss and significantly reduced bacterial loads and histological damage in the lung. Our study suggests that the use of lentiviral or DNA vaccines containing the antigens Ag85B and Rv3425 to boost BCG is a good choice for the rational design of an efficient vaccination strategy against TB.

  5. A human dendritic cell-based in vitro model to assess Mycobacterium tuberculosis SO2 vaccine immunogenicity.

    PubMed

    Etna, Marilena P; Giacomini, Elena; Severa, Martina; Pardini, Manuela; Aguilo, Nacho; Martin, Carlos; Coccia, Eliana M

    2014-01-01

    Among the tuberculosis (TB) vaccine candidates, SO2 is the prototype of the first live-attenuated vaccine that recently entered into clinical trials. To investigate the capacity of SO2 to stimulate an appropriate immune response in vitro within a human immunological context, a comparative analysis of the effects promoted by SO2, the current Bacille Calmette-Guerin (BCG) vaccine and Mycobacterium tuberculosis (Mtb) was conducted in human primary dendritic cells (DC), which are critical modulators of vaccine-induced immunity. In particular, we found that SO2 promotes the expression of maturation markers similarly to BCG but at a lower extent than Mtb. Moreover, SO2-infected DC released higher levels of interleukin (IL)-23 than BCG-infected cells, which account for the expansion of interferon (IFN)-γ-producing T cells in an IL-12-independent manner. In the autologous mixed leukocyte reaction setting, the expansion of IL-17-producing T cells was also observed in response to SO2 infection. Interestingly, apoptosis and autophagic flux, events required for the antigen presentation within MHC class II complex, were not affected in DC infected with SO2, conversely to what observed upon Mtb stimulation. Collectively, our results indicate that SO2 represents a promising TB vaccine candidate, which displays an attenuated phenotype and promotes in DC a stronger capacity to stimulate the Th response than BCG vaccine. Interestingly, the data obtained by using the human DC-based experimental setting mirrored the results derived from studies in animal models, suggesting that this system could be used for an efficient and rapid down-selection of new TB vaccine candidates, contributing to achieve the "3Rs" objective.

  6. Problems in defining a “case” of pulmonary tuberculosis in prevalence surveys*

    PubMed Central

    Narain, Raj; Nair, S. S.; Naganna, K.; Chandrasekhar, P.; Rao, G. Ramanatha; Lal, Pyare

    1968-01-01

    An analysis of data from two successive tuberculosis prevalence surveys (conducted at an interval of 18 months) in a random sample of villages in Bangalore District, South India, has shown that the term “a case of pulmonary tuberculosis” does not represent a single uniform entity, but rather embraces cases of several types, differing considerably in their mortality experience, tuberculin sensitivity, results of X-ray and sputum examinations, and in the reliability of their diagnosis. The status at the first survey of the cases found at the resurvey and that at resurvey of those found at the initial survey give an indication of changes with time. Such changes show considerable differences for the various types of cases and provide another dimension to study the differences among them. The authors consider that, in spite of the great need and importance of a single straightforward definition of a case, no such definition is suitable for all situations; there is no other option but to continue to use more than one definition. Although, theoretically, finding a single bacillus in the sputum should be adequate proof of pulmonary tuberculosis, it is shown that finding of a few bacilli, 3 or less, is probably far too often due to artefacts and should not be the basis for a diagnosis. The findings also well bear out the notion that positive radiological findings, in the absence of bacteriological confirmation, indicate, not pulmonary tuberculosis, but only a high risk of the disease. Direct microscopy appears to be a consistent index of disease but, in community surveys, has the limitations of missing a substantial proportion of cases and of adding some false cases. The extent of these limitations, so far as symptomatic patients in a community tuberculosis control programme are concerned, remains to be investigated. PMID:5306123

  7. Live attenuated Salmonella vaccines displaying regulated delayed lysis and delayed antigen synthesis to confer protection against Mycobacterium tuberculosis.

    PubMed

    Juárez-Rodríguez, María Dolores; Yang, Jiseon; Kader, Rebin; Alamuri, Praveen; Curtiss, Roy; Clark-Curtiss, Josephine E

    2012-02-01

    Live recombinant attenuated Salmonella vaccine (RASV) strains have great potential to induce protective immunity against Mycobacterium tuberculosis by delivering M. tuberculosis antigens. Recently, we reported that, in orally immunized mice, RASV strains delivering the M. tuberculosis early secreted antigenic target 6-kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10) antigens via the Salmonella type III secretion system (SopE amino-terminal region residues 1 to 80 with two copies of ESAT-6 and one copy of CFP-10 [SopE(Nt80)-E2C]) afforded protection against aerosol challenge with M. tuberculosis. Here, we constructed and evaluated an improved Salmonella vaccine against M. tuberculosis. We constructed translational fusions for the synthesis of two copies of ESAT-6 plus CFP-10 fused to the OmpC signal sequence (OmpC(SS)-E2C) and amino acids 44 to 338 of antigen 85A (Ag85A(294)) flanked by the signal sequence (SS) and C-terminal peptide (CT) of β-lactamase (Bla(SS)-Ag85A(294)-Bla(CT)) to enable delivery via the Salmonella type II secretion system. The genes expressing these proteins were cloned as an operon transcribed from P(trc) into isogenic Asd(+)/MurA(+) pYA3681 lysis vector derivatives with different replication origins (pBR, p15A, pSC101), resulting in pYA4890, pYA4891, and pYA4892 for SopE(Nt80)-E2C/Ag85A(294) synthesis and pYA4893 and pYA4894 for OmpC(SS)-E2C/Ag85A(294) synthesis. Mice orally immunized with the RASV χ11021 strain engineered to display regulated delayed lysis and regulated delayed antigen synthesis in vivo and harboring pYA4891, pYA4893, or pYA4894 elicited significantly greater humoral and cellular immune responses, and the RASV χ11021 strain afforded a greater degree of protection against M. tuberculosis aerosol challenge in mice than RASVs harboring any other Asd(+)/MurA(+) lysis plasmid and immunization with M. bovis BCG, demonstrating that RASV strains displaying regulated delayed lysis with delayed antigen synthesis

  8. Performance of QuantiFERON-TB Gold In-Tube test and Tuberculin Skin Test for diagnosis of latent tuberculosis infection in BCG vaccinated health care workers

    PubMed Central

    Babayigit, Cenk; Ozer, Burcin; Inandi, Tacettin; Ozer, Cahit; Duran, Nizami; Gocmen, Orhan

    2014-01-01

    Background Tuberculin skin test (TST) has been used for years as an aid in diagnosing latent tuberculosis infection (LTBI) but it suffers from a number of well-documented performance and logistic problems. Quantiferon-TB Gold In Tube test (QFT-GIT) has been reported to have better sensitivity and specifity than TST. In this study, it was aimed to compare the performance of a commercial IFN-γ release assay (QFT-GIT) with TST in the diagnosis of HCWs at risk for latent TB infection in BCG vaccinated population. Material/Methods Hundred healthy volunteer health care workers were enrolled. All were subjected to TST and QFT-GIT. Results were compared among Health Care Workers (HCWs) groups in terms of profession, workplace, working duration. Results TST is affected by previous BCG vaccinations and number of cases with QFT-GIT positivity is increased in accordance with the TST induration diameter range. QFT-GIT result was negative in 17 of 32 TST positive (≥15 mm) cases and positive in 4 of 61 cases whose TST diameters are between 6–14 mm, that is attritutable to previous BCG vaccination(s). It was negative in all cases with TST diameters between 0–5 mm. HCWs with positive QFT-GIT results were significantly older than the ones with negative results. Furthermore duration of work was significantly longer in QFT-GIT positive than in negative HCWs. Conclusions There was a moderate concordance between QFT-GIT and TST, when TST result was defined as positive with a ≥15 mm diameter of induration. We suggest that QFT-GIT can be used as an alternative to TST for detection of LTBI, especially in groups with high risk of LTBI and in population with routine BCG vaccination program. PMID:24681806

  9. Extraordinarily few organisms of a live recombinant BCG vaccine against tuberculosis induce maximal cell-mediated and protective immunity.

    PubMed

    Horwitz, Marcus A; Harth, Günter; Dillon, Barbara Jane; Maslesa-Galić, Sasa

    2006-01-23

    In previous studies, we have described a live recombinant BCG vaccine (rBCG30) overexpressing the 30 kDa major secretory protein of Mycobacterium tuberculosis that induces greater protective immunity against tuberculosis than the current vaccine in the demanding guinea pig model of pulmonary tuberculosis. In this study, we have investigated the impact of vaccine dose on the development of cell-mediated and protective immunity in the guinea pig model. We found that the protective efficacy against M. tuberculosis aerosol challenge of both BCG and rBCG30 was essentially dose-independent over a dose range of 10(1)-10(6) live organisms. As previously observed, rBCG30 was more potent, reducing colony-forming units (CFU) below the level observed in animals immunized with the parental BCG vaccine by 0.7 logs in the lungs and 1.0 logs in the spleen (P<0.0001). To gain a better understanding of the influence of dose on bacterial clearance and immunity, we assessed animals immunized with 10(1), 10(3), or 10(6)CFU of rBCG30. The higher the dose, the higher the peak CFU level achieved in animal organs. However, whereas humoral immune responses to the 30 kDa protein reflected the disparate CFU levels, cell-mediated immune responses did not; high and low doses of rBCG30 ultimately induced comparable peak lymphocyte proliferative responses and cutaneous delayed-type hypersensitivity responses to the 30 kDa protein. We estimate that the amount of the 30 kDa protein required to induce a strong cell-mediated immune response when delivered via 10 rBCG30 organisms is about 9 orders of magnitude less than that required when the protein is delivered in a conventional protein/adjuvant vaccine. This study demonstrates that a very low inoculum of rBCG30 organisms has the capacity to induce strong protective immunity against tuberculosis and that rBCG30 is an extremely potent delivery system for mycobacterial antigens.

  10. Effect of culling and vaccination on bovine tuberculosis infection in a European badger (Meles meles) population by spatial simulation modelling.

    PubMed

    Abdou, Marwa; Frankena, Klaas; O'Keeffe, James; Byrne, Andrew W

    2016-03-01

    The control of bovine tuberculosis (bTB) in cattle herds in the Republic of Ireland (ROI) is partially hindered by spill-back infection from wild badgers (Meles meles). The aim of this study was to determine the relative effects of interventions (combinations of culling and/or vaccination) on bTB dynamics in an Irish badger population. A spatial agent-based stochastic simulation model was developed to evaluate the effect of various control strategies for bovine tuberculosis in badgers: single control strategies (culling, selective culling, vaccination, and vaccine baits), and combined strategies (Test vaccinate/cull (TVC)), split area approaches using culling and vaccination, or selective culling and vaccination, and mixed scenarios where culling was conducted for five years and followed by vaccination or by a TVC strategy. The effect of each control strategy was evaluated over a 20-year period. Badger control was simulated in 25%, 50%, and 75% area (limited area strategy) or in the entire area (100%, wide area strategy). For endemic bTB, a culling strategy was successful in eradicating bTB from the population only if applied as an area-wide strategy. However, this was achieved only by risking the extinction of the badger population. Selective culling strategies (selective culling or TVC) mitigated this negative impact on the badger population's viability. Furthermore, both strategies (selective culling and TVC) allowed the badger population to recover gradually, in compensation for the population reduction following the initial use of removal strategies. The model predicted that vaccination can be effective in reducing bTB prevalence in badgers, when used in combination with culling strategies (i.e. TVC or other strategies). If fecundity was reduced below its natural levels (e.g. by using wildlife contraceptives), the effectiveness of vaccination strategies improved. Split-area simulations highlighted that interventions can have indirect effects (e.g. on

  11. Acceptance and palatability for domestic and wildlife hosts of baits designed to deliver a tuberculosis vaccine to wild boar piglets.

    PubMed

    Ballesteros, Cristina; Vicente, Joaquín; Morriss, Grant; Jockney, Ivor; Rodríguez, Oscar; Gortázar, Christian; de la Fuente, José

    2011-02-01

    Tuberculosis (TB) caused by Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex, is an important health problem worldwide. The control of TB through vaccination of wildlife reservoirs may potentially have advantages over other management strategies. The most practical approach to deliver vaccines to wildlife is using oral baits that are stable under field conditions and effective in reaching the target species. Baits were developed in our laboratory to deliver oral vaccines to wild boar piglets. However, these baits were well accepted by other wild species. Therefore, bait consumption by different M. bovis hosts was evaluated herein. The results showed that the baits were well accepted by cattle, feral pigs, and adult red deer whereas small mammals like badgers and possums showed varying bait acceptance. Bait acceptance by different species has the advantage of targeting more than one wildlife reservoir when they coexist in the same area and need to be vaccinated for TB control. However, bait delivery methods such as the use of selective feeders to target the desired species should be developed to avoid bait consumption by other species.

  12. Evaluation of Humoral Immunity to Mycobacterium tuberculosis-Specific Antigens for Correlation with Clinical Status and Effective Vaccine Development.

    PubMed

    Niki, Mamiko; Suzukawa, Maho; Akashi, Shunsuke; Nagai, Hideaki; Ohta, Ken; Inoue, Manabu; Niki, Makoto; Kaneko, Yukihiro; Morimoto, Kozo; Kurashima, Atsuyuki; Kitada, Seigo; Matsumoto, Sohkichi; Suzuki, Koichi; Hoshino, Yoshihiko

    2015-01-01

    Although tuberculosis remains a major global health problem, Bacille Calmette-Guérin (BCG) is the only available vaccine. However, BCG has limited applications, and a more effective vaccine is needed. Cellular mediated immunity (CMI) is thought to be the most important immune response for protection against Mycobacterium tuberculosis (Mtb). However, the recent failure of a clinical trial for a booster BCG vaccine and increasing evidence of antibody-mediated immunity prompted us to evaluate humoral immunity to Mtb-specific antigens. Using Enzyme-Linked ImmunoSpot and Enzyme-Linked ImmunoSorbent Assays, we observed less correlation of both CMI and IgG titers with patient clinical status, including serum concentration of C reactive protein. However, IgA titers against Mtb were significantly correlated with clinical status, suggesting that specific IgA antibodies protect against Mtb proliferation. In addition, in some cases, IgA antibody titers were significantly associated with the serum concentration of total albumin, which supports the idea that humoral immunity can be influenced by the nutritional status. Based on these observations, we propose that the induction of humoral immunity should be included as an option in TB vaccine development strategies. PMID:26568961

  13. Evaluation of Humoral Immunity to Mycobacterium tuberculosis-Specific Antigens for Correlation with Clinical Status and Effective Vaccine Development

    PubMed Central

    Niki, Mamiko; Suzukawa, Maho; Akashi, Shunsuke; Nagai, Hideaki; Ohta, Ken; Inoue, Manabu; Niki, Makoto; Kaneko, Yukihiro; Morimoto, Kozo; Kurashima, Atsuyuki; Kitada, Seigo; Matsumoto, Sohkichi; Suzuki, Koichi; Hoshino, Yoshihiko

    2015-01-01

    Although tuberculosis remains a major global health problem, Bacille Calmette-Guérin (BCG) is the only available vaccine. However, BCG has limited applications, and a more effective vaccine is needed. Cellular mediated immunity (CMI) is thought to be the most important immune response for protection against Mycobacterium tuberculosis (Mtb). However, the recent failure of a clinical trial for a booster BCG vaccine and increasing evidence of antibody-mediated immunity prompted us to evaluate humoral immunity to Mtb-specific antigens. Using Enzyme-Linked ImmunoSpot and Enzyme-Linked ImmunoSorbent Assays, we observed less correlation of both CMI and IgG titers with patient clinical status, including serum concentration of C reactive protein. However, IgA titers against Mtb were significantly correlated with clinical status, suggesting that specific IgA antibodies protect against Mtb proliferation. In addition, in some cases, IgA antibody titers were significantly associated with the serum concentration of total albumin, which supports the idea that humoral immunity can be influenced by the nutritional status. Based on these observations, we propose that the induction of humoral immunity should be included as an option in TB vaccine development strategies. PMID:26568961

  14. Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

    PubMed Central

    Reese, Valerie A.; Huang, Po-wei D.; Beebe, Elyse A.; Podell, Brendan K.; Reed, Steven G.; Coler, Rhea N.

    2015-01-01

    Mycobacterium tuberculosis HN878 represents a virulent clinical strain from the W-Beijing family, which has been tested in small animal models in order to study its virulence and its induction of host immune responses following infection. This isolate causes death and extensive lung pathology in infected C57BL/6 mice, whereas lab-adapted strains, such as M. tuberculosis H37Rv, do not. The use of this clinically relevant isolate of M. tuberculosis increases the possibilities of assessing the long-lived efficacy of tuberculosis vaccines in a relatively inexpensive small animal model. This model will also allow for the use of knockout mouse strains to critically examine key immunological factors responsible for long-lived, vaccine-induced immunity in addition to vaccine-mediated prevention of pulmonary immunopathology. In this study, we show that the ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) tuberculosis vaccine candidate, currently in human clinical trials, is able to elicit protection against M. tuberculosis HN878 by reducing the bacterial burden in the lung and spleen and by preventing the extensive lung pathology induced by this pathogen in C57BL/6 mice. PMID:26656121

  15. Tuberculosis

    MedlinePlus

    ... to address TB and HIV coinfection around the world? The President’s U.S. President's Emergency Plan for AIDS ... of those suffering from HIV/AIDS around the world. PEPFAR’s Global Fund to Fight AIDS, Tuberculosis and ...

  16. Effects of MVA85A vaccine on tuberculosis challenge in animals: systematic review

    PubMed Central

    Kashangura, Rufaro; Sena, Emily S; Young, Taryn; Garner, Paul

    2015-01-01

    Background: The existing Bacillus Calmette–Guérin (BCG) vaccination provides partial protection against tuberculosis (TB). The modified vaccinia ankara virus-expressing antigen 85A (MVA85A) aims to boost BCG immunity. We evaluated the animal evidence supporting the testing of MVA85A in humans. Methods: Our protocol included in vivo preclinical studies of the MVA85A booster with BCG compared with BCG alone, followed by a TB challenge. We used standard methods for systematic review of animal studies, and summarized mortality, measures of pathology and lung bacterial load. The comprehensive literature search was to September 2014. Two independent investigators assessed eligibility and performed data extraction. We assessed study quality and pooled bacteria load using random effect meta-analysis. Findings: We included eight studies in 192 animals. Three experiments were in mice, two in guinea pigs, two in macaques and one in calves. Overall, study quality was low with no randomization, baseline comparability not described and blinding not reported. For animal death (including euthanasia due to severe morbidity), studies were underpowered, and overall no benefit demonstrated. No difference was shown for lung pathology measured on an ordinal scale or bacterial load. The largest mortality trial carried out in macaques had more deaths in the MVA85A vaccine group, and was published after a trial in South Africa had started recruiting children. Conclusions: This independent assessment of the animal data does not provide evidence to support efficacy of MVA85A as a BCG booster. More rigorous conduct and reporting of preclinical research are warranted, and we believe the results of studies should be publicly available before embarking on trials in humans, irrespective of the findings. PMID:26351306

  17. A lentiviral vector-based therapeutic vaccine encoding Ag85B-Rv3425 potently increases resistance to acute tuberculosis infection in mice.

    PubMed

    Yang, Enzhuo; Wang, Feifei; Xu, Ying; Wang, Honghai; Hu, Yong; Shen, Hongbo; Chen, Zheng W

    2015-08-01

    Few treatment options for multidrug-resistant tuberculosis (TB) and extensively drug-resistant TB call attention to the development of novel therapeutic approaches for TB. Therapeutic vaccines are promising candidates because they can induce antigen-specific cellular immune responses, which play an important role in the elimination of Mycobacterium tuberculosis (MTB). In this study, a novel lentiviral vector therapeutic vaccine for delivering MTB-specific fusion protein Ag85B-Rv3425 was constructed. Results showed that one single-injection of this recombinant lentivirus vaccine could trigger antigen-specific Th1-type immune responses in mice. More importantly, mice with acute infection benefited a lot from a single-dose administration of this vaccine by markedly reduced MTB burdens in lungs and spleens as well as attenuated lesions in lungs compared with untreated mice. These results displayed good prospects of this novel vaccine for the immunotherapy of TB.

  18. Bovine Tuberculosis Vaccine Efficacy Studies: Neonatal Calves and White-tailed Deer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction Tuberculosis (TB) in humans and animals may result from exposure to bacilli within the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, M. pinnipedi, M. microti, M. caprae, or M. canetti)(#1). Mycobacterium bovis is the species most often isolated from ...

  19. Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence.

    PubMed

    Ortega, Corrie; Anderson, Lindsey N; Frando, Andrew; Sadler, Natalie C; Brown, Robert W; Smith, Richard D; Wright, Aaron T; Grundner, Christoph

    2016-02-18

    The transition from replication to non-replication underlies much of Mycobacterium tuberculosis (Mtb) pathogenesis, as non- or slowly replicating Mtb are responsible for persistence and poor treatment outcomes. Therapeutic targeting of non-replicating populations is a priority for tuberculosis treatment, but few drug targets in non-replicating Mtb are currently known. Here, we directly measured the activity of the highly diverse and druggable serine hydrolases (SHs) during active replication and non-replication using activity-based proteomics. We predict SH activity for 78 proteins, including 27 proteins with unknown function, and identify 37 SHs that remain active in the absence of replication, providing a set of candidate persistence targets. Non-replication was associated with major shifts in SH activity. These activity changes were largely independent of SH abundance, indicating extensive post-translational regulation of SHs. By probing a large cross-section of druggable Mtb enzyme space during replication and non-replication, we identify new SHs and suggest new persistence targets. PMID:26853625

  20. Modelling the cost-effectiveness of a new infant vaccine to prevent tuberculosis disease in children in South Africa

    PubMed Central

    2014-01-01

    Background Tuberculosis remains the leading cause of death in South Africa. A number of potential new TB vaccine candidates have been identified and are currently in clinical trials. One such candidate is MVA85A. This study aimed to estimate the cost-effectiveness of adding the MVA85A vaccine as a booster to the BCG vaccine in children from the perspective of the South African government. Methods The cost-effectiveness was assessed by employing Decision Analytic Modelling, through the use of a Markov model. The model compared the existing strategy of BCG vaccination to a new strategy in which infants receive BCG and a booster vaccine, MVA85A, at 4 months of age. The costs and outcomes of the two strategies are estimated through modelling the vaccination of a hypothetical cohort of newborns and following them from birth through to 10 years of age, employing 6-monthly cycles. Results The results of the cost-effectiveness analysis indicate that the MVA85A strategy is both more costly and more effective – there are fewer TB cases and deaths from TB than BCG alone. The South African government would need to spend an additional USD 1,105 for every additional TB case averted and USD 284,017 for every additional TB death averted. The threshold analysis shows that, if the efficacy of the MVA85A vaccine was 41.3% (instead of the current efficacy of 17.3%), the two strategies would have the same cost but more cases of TB and more deaths from TB would be prevented by adding the MVA85A vaccine to the BCG vaccine. In this case, the government chould consider the MVA85A strategy. Conclusions At the current level of efficacy, the MVA85A vaccine is neither effective nor cost-effective and, therefore, not a good use of limited resources. Nevertheless, this study contributes to developing a standardized Markov model, which could be used, in the future, to estimate the potential cost-effectiveness of new TB vaccines compared to the BCG vaccine, in children between the ages of 0

  1. Lipid-formulated bcg as an oral-bait vaccine for tuberculosis: vaccine stability, efficacy, and palatability to brushtail possums (Trichosurus vulpecula) in New Zealand.

    PubMed

    Cross, Martin L; Henderson, Ray J; Lambeth, Matthew R; Buddle, Bryce M; Aldwell, Frank E

    2009-07-01

    Bovine tuberculosis (Tb), due to infection with virulent Mycobacterium bovis, represents a threat to New Zealand agriculture due to vectorial transmission from wildlife reservoir species, principally the introduced Australian brushtail possum (Trichosurus vulpecula). An oral-delivery wildlife vaccine has been developed to immunize possums against Tb, based on formulation of the human Tb vaccine (M. bovis BCG) in edible lipid matrices. Here BCG bacilli were shown to be stable in lipid matrix formulation for over 8 mo in freezer storage, for 7 wk under room temperature conditions, and for 3-5 wk under field conditions in a forest/pasture margin habitat (when maintained in weatherproof bait-delivery sachets). Samples of the lipid matrix were flavored and offered to captive possums in a bait-preference study: a combination of 10% chocolate powder with anise oil was identified as the most effective attractant/palatability combination. In a replicated field study, 85-100% of wild possums were shown to access chocolate-flavored lipid pellets, when baits were applied to areas holding approximately 600-800 possums/km(2). Finally, in a controlled vaccination/challenge study, chocolate-flavored lipid vaccine samples containing 10(8) BCG bacilli were fed to captive possums, which were subsequently challenged via aerosol exposure to virulent M. bovis: vaccine immunogenicity was confirmed, and protection was identified by significantly reduced postchallenge weight loss in vaccinated animals compared to nonvaccinated controls. These studies indicate that, appropriately flavored, lipid delivery matrices may form effective bait vaccines for the control of Tb in wildlife.

  2. The mc2-CMX vaccine induces an enhanced immune response against Mycobacterium tuberculosis compared to Bacillus Calmette-Guérin but with similar lung inflammatory effects.

    PubMed

    Oliveira, Fábio Muniz de; Trentini, Monalisa Martins; Junqueira-Kipnis, Ana Paula; Kipnis, André

    2016-04-01

    Although the attenuated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine has been used since 1921, tuberculosis (TB) control still proceeds at a slow pace. The main reason is the variable efficacy of BCG protection against TB among adults, which ranges from 0-80%. Subsequently, the mc2-CMX vaccine was developed with promising results. Nonetheless, this recombinant vaccine needs to be compared to the standard BCG vaccine. The objective of this study was to evaluate the immune response induced by mc2-CMX and compare it to the response generated by BCG. BALB/c mice were immunised with both vaccines and challenged with Mycobacterium tuberculosis (Mtb). The immune and inflammatory responses were evaluated by ELISA, flow cytometry, and histopathology. Mice vaccinated with mc2-CMX and challenged with Mtb induced an increase in the IgG1 and IgG2 levels against CMX as well as recalled specific CD4+ T-cells that produced T-helper 1 cytokines in the lungs and spleen compared with BCG vaccinated and challenged mice. Both vaccines reduced the lung inflammatory pathology induced by the Mtb infection. The mc2-CMX vaccine induces a humoral and cellular response that is superior to BCG and is efficiently recalled after challenge with Mtb, although both vaccines induced similar inflammatory reductions.

  3. The mc2-CMX vaccine induces an enhanced immune response against Mycobacterium tuberculosis compared to Bacillus Calmette-Guérin but with similar lung inflammatory effects

    PubMed Central

    de Oliveira, Fábio Muniz; Trentini, Monalisa Martins; Junqueira-Kipnis, Ana Paula; Kipnis, André

    2016-01-01

    Although the attenuated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine has been used since 1921, tuberculosis (TB) control still proceeds at a slow pace. The main reason is the variable efficacy of BCG protection against TB among adults, which ranges from 0-80%. Subsequently, the mc2-CMX vaccine was developed with promising results. Nonetheless, this recombinant vaccine needs to be compared to the standard BCG vaccine. The objective of this study was to evaluate the immune response induced by mc2-CMX and compare it to the response generated by BCG. BALB/c mice were immunised with both vaccines and challenged withMycobacterium tuberculosis (Mtb). The immune and inflammatory responses were evaluated by ELISA, flow cytometry, and histopathology. Mice vaccinated with mc2-CMX and challenged with Mtb induced an increase in the IgG1 and IgG2 levels against CMX as well as recalled specific CD4+ T-cells that produced T-helper 1 cytokines in the lungs and spleen compared with BCG vaccinated and challenged mice. Both vaccines reduced the lung inflammatory pathology induced by the Mtb infection. The mc2-CMX vaccine induces a humoral and cellular response that is superior to BCG and is efficiently recalled after challenge with Mtb, although both vaccines induced similar inflammatory reductions. PMID:27074251

  4. Genetically defined race, but not sex, is associated with higher humoral and cellular immune responses to measles vaccination.

    PubMed

    Voigt, Emily A; Ovsyannikova, Inna G; Haralambieva, Iana H; Kennedy, Richard B; Larrabee, Beth R; Schaid, Daniel J; Poland, Gregory A

    2016-09-22

    In addition to host genetic and environmental factors, variations in immune responses to vaccination are influenced by demographic variables, such as race and sex. The influence of genetic race and sex on measles vaccine responses is not well understood, yet important for the development of much-needed improved measles vaccines with lower failure rates. We assessed associations between genetically defined race and sex with measles humoral and cellular immunity after measles vaccination in three independent and geographically distinct cohorts totaling 2872 healthy racially diverse children, older adolescents, and young adults. We found no associations between biological sex and either humoral or cellular immunity to measles vaccine, and no correlation between humoral and cellular immunity in these study subjects. Genetically defined race was, however, significantly associated with both measles vaccine-induced humoral and cellular immune responses, with subjects genetically classified as having African-American ancestry demonstrating significantly higher antibody and cell-mediated immune responses relative to subjects of Caucasian ancestry. This information may be useful in designing novel measles vaccines that are optimally effective across human genetic backgrounds. PMID:27591105

  5. A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection.

    PubMed

    Yuan, Xuefeng; Teng, Xindong; Jing, Yukai; Ma, Jilei; Tian, Maopeng; Yu, Qi; Zhou, Lei; Wang, Ruibo; Wang, Weihua; Li, Li; Fan, Xionglin

    2015-12-01

    Tuberculosis (TB) remains one of the most menacing infectious diseases, although attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine has been widely used to protect children against primary TB. There are increasing evidences that rapid growing and dormant Mycobacterium tuberculosis (M. tuberculosis) coexist in vivo after infection. However, BCG vaccine only elicits cell-mediated immune responses to secretory antigens expressed by rapid growing pathogen. BCG vaccine is thus unable to thwart the reactivation of latent tuberculosis infection (LTBI), and its protection wanes over age after neonatal immunization. In order to extend its ability for a durable protection, a novel recombinant BCG (rBCG) strain, named rBCG::XB, was constructed by overexpressing immunodominant multistage antigens of Ag85B and HspX, which are expressed by both rapid replicating and dormant M. tuberculosis. Long-term protective effect and immunogenicity of rBCG::XB were compared with the parental BCG in vaccinated C57BL/6 mice. Our results demonstrated that rBCG::XB provided the stronger and long-lasting protection against M. tuberculosis H37Rv intranasal infection than BCG. The rBCG::XB not only elicited the more durable multistage antigen-specific CD4(+)Th1-biased immune responses and specific polyfunctional CD4(+)T cells but also augmented the CD8(+) CTL effects against Ag85B in vivo. In particular, higher levels of CD4(+) TEM and CD8(+) TCM cells, dominated by IL2(+) CD4(+) and CD8(+) TCM cells, were obtained in the spleen of rBCG::XB vaccinated mice. Therefore, our findings indicate that rBCG::XB is a promising candidate to improve the efficacy of BCG.

  6. Indications to Hospital Admission and Isolation of Children With Possible or Defined Tuberculosis

    PubMed Central

    Vecchio, Andrea Lo; Bocchino, Marialuisa; Lancella, Laura; Gabiano, Clara; Garazzino, Silvia; Scotto, Riccardo; Raffaldi, Irene; Assante, Luca Rosario; Villani, Alberto; Esposito, Susanna; Guarino, Alfredo

    2015-01-01

    Abstract Tuberculosis (TB) is a re-emerging health problem in developed countries. This paper is part of large guidelines on the global management of TB in children, by a group of scientific societies. It describes the indications to hospitalization of children with suspected or diagnosed TB, the isolation measures, hospital discharge, and re-admission into the community. Using the Consensus Conference method, relevant publications in English were identified by means of a systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from their inception until 31 December 2014. Available data on indications to hospitalization were mainly indirect and largely derived from observational studies. They include: (1) host-related risk factors, the main being age <12 months, immune deficiencies, and malnutrition; (2) TB-related clinical conditions that resemble those of pneumonia but also include drug-resistance; and (3) social and logistic conditions. The latter are based on opinion and depend on local conditions. Analysis of the literature showed that patients hospitalized with suspected pulmonary TB should be put in precautionary respiratory isolation regardless of their age while they await diagnosis. The general conditions for re-admission into the community are at least 14 days of effective treatment and negative microscopic tests of 3 consecutive samples in previously microscopically positive patients. This is the first paper that provides indications to hospitalization of children with TB. Most recommendations are generally applicable in all developed countries. Some might need an adaptation to local setting, epidemiological, parameters, and availability of specific health-care facilities. PMID:26683914

  7. Protection against tuberculosis by a single intranasal administration of DNA-hsp65 vaccine complexed with cationic liposomes

    PubMed Central

    Rosada, Rogério S; Torre, Lucimara Gaziola de la; Frantz, Fabiani G; Trombone, Ana PF; Zárate-Bladés, Carlos R; Fonseca, Denise M; Souza, Patrícia RM; Brandão, Izaíra T; Masson, Ana P; Soares, Édson G; Ramos, Simone G; Faccioli, Lúcia H; Silva, Célio L; Santana, Maria HA; Coelho-Castelo, Arlete AM

    2008-01-01

    Background The greatest challenges in vaccine development include optimization of DNA vaccines for use in humans, creation of effective single-dose vaccines, development of delivery systems that do not involve live viruses, and the identification of effective new adjuvants. Herein, we describe a novel, simple technique for efficiently vaccinating mice against tuberculosis (TB). Our technique consists of a single-dose, genetic vaccine formulation of DNA-hsp65 complexed with cationic liposomes and administered intranasally. Results We developed a novel and non-toxic formulation of cationic liposomes, in which the DNA-hsp65 vaccine was entrapped (ENTR-hsp65) or complexed (COMP-hsp65), and used to immunize mice by intramuscular or intranasal routes. Although both liposome formulations induced a typical Th1 pattern of immune response, the intramuscular route of delivery did not reduce the number of bacilli. However, a single intranasal immunization with COMP-hsp65, carrying as few as 25 μg of plasmid DNA, leads to a remarkable reduction of the amount of bacilli in lungs. These effects were accompanied by increasing levels of IFN-γ and lung parenchyma preservation, results similar to those found in mice vaccinated intramuscularly four times with naked DNA-hsp65 (total of 400 μg). Conclusion Our objective was to overcome the significant obstacles currently facing DNA vaccine development. Our results in the mouse TB model showed that a single intranasal dose of COMP-hsp65 elicited a cellular immune response that was as strong as that induced by four intramuscular doses of naked-DNA. This formulation allowed a 16-fold reduction in the amount of DNA administered. Moreover, we demonstrated that this vaccine is safe, biocompatible, stable, and easily manufactured at a low cost. We believe that this strategy can be applied to human vaccines to TB in a single dose or in prime-boost protocols, leading to a tremendous impact on the control of this infectious disease. PMID

  8. Oral vaccination of badgers (Meles meles) against tuberculosis: comparison of the protection generated by BCG vaccine strains Pasteur and Danish.

    PubMed

    Murphy, Denise; Costello, Eamon; Aldwell, Frank E; Lesellier, Sandrine; Chambers, Mark A; Fitzsimons, Tara; Corner, Leigh A L; Gormley, Eamonn

    2014-06-01

    Vaccination of badgers by the subcutaneous, mucosal and oral routes with the Pasteur strain of Mycobacterium bovis bacille Calmette-Guérin (BCG) has resulted in significant protection against experimental infection with virulent M. bovis. However, as the BCG Danish strain is the only commercially licensed BCG vaccine for use in humans in the European Union it is the vaccine of choice for delivery to badger populations. As all oral vaccination studies in badgers were previously conducted using the BCG Pasteur strain, this study compared protection in badgers following oral vaccination with the Pasteur and the Danish strains. Groups of badgers were vaccinated orally with 10(8) colony forming units (CFU) BCG Danish 1331 (n = 7 badgers) or 10(8) CFU BCG Pasteur 1173P2 (n = 6). Another group (n = 8) served as non-vaccinated controls. At 12 weeks post-vaccination, the animals were challenged by the endobronchial route with 6 × 10(3) CFU M. bovis, and at 15 weeks post-infection, all of the badgers were euthanased. Vaccination with either BCG strain provided protection against challenge compared with controls. The vaccinated badgers had significantly fewer sites with gross pathology and significantly lower gross pathological severity scores, fewer sites with histological lesions and fewer sites of infection, significantly lower bacterial counts in the thoracic lymph node, and lower bacterial counts in the lungs than the control group. No differences were observed between either of the vaccine groups by any of the pathology and bacteriology measures. The ELISPOT analysis, measuring production of badger interferon - gamma (IFN-γ), was also similar across the vaccinated groups.

  9. Vaccination of white-tailed deer (Odocoileus virginianus) for protection against bovine tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine tuberculosis (bTB), caused by Mycobacterium bovis and other related species in the M. tuberculosis complex, pose a serious continual threat to the health and economic wellbeing of wildlife, livestock, and humans worldwide. Wildlife reservoirs of bTB play a very important role in the epidemio...

  10. Disruption of the SapM locus in Mycobacterium bovis BCG improves its protective efficacy as a vaccine against M. tuberculosis.

    PubMed

    Festjens, Nele; Bogaert, Pieter; Batni, Anjana; Houthuys, Erica; Plets, Evelyn; Vanderschaeghe, Dieter; Laukens, Bram; Asselbergh, Bob; Parthoens, Eef; De Rycke, Riet; Willart, Monique A; Jacques, Peggy; Elewaut, Dirk; Brouckaert, Peter; Lambrecht, Bart N; Huygen, Kris; Callewaert, Nico

    2011-04-01

    Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α-1,2-oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c(+) MHC-II(int) CD40(int) dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination.

  11. Disruption of the SapM locus in Mycobacterium bovis BCG improves its protective efficacy as a vaccine against M. tuberculosis

    PubMed Central

    Festjens, Nele; Bogaert, Pieter; Batni, Anjana; Houthuys, Erica; Plets, Evelyn; Vanderschaeghe, Dieter; Laukens, Bram; Asselbergh, Bob; Parthoens, Eef; De Rycke, Riet; Willart, Monique A; Jacques, Peggy; Elewaut, Dirk; Brouckaert, Peter; Lambrecht, Bart N; Huygen, Kris; Callewaert, Nico

    2011-01-01

    Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α-1,2-oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c+MHC-IIintCD40int dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination. PMID:21328541

  12. Evaluation of the safety and immunogenicity of a candidate tuberculosis vaccine, MVA85A, delivered by aerosol to the lungs of macaques.

    PubMed

    White, A D; Sibley, L; Dennis, M J; Gooch, K; Betts, G; Edwards, N; Reyes-Sandoval, A; Carroll, M W; Williams, A; Marsh, P D; McShane, H; Sharpe, S A

    2013-05-01

    Tuberculosis (TB) is a reemerging disease. The only available vaccine, Mycobacterium bovis BCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-of-concept data for further evaluation of this route of immunization for use in human clinical trials. PMID:23446219

  13. Safety and Immunogenicity of the Mycobacterium tuberculosis {Delta}lysA {Delta}panCD Vaccine in Domestic Cats Infected with Feline Immunodeficiency Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Feline immunodeficiency virus (FIV)+ and FIV- cats (n = 4/group) received 2 x 10**6 cfu Mycobacterium tuberculosis Delta-lysA Delta-panCD intramuscularly. Vaccination elicited antibody responses; albeit, at lower levels in FIV+ cats as compared to FIV- cats. Delayed-type hypersensitivity responses ...

  14. Factors Associated With Tuberculosis as an AIDS-Defining Disease in an Immigration Setting

    PubMed Central

    Martín, Vicente; García de Olalla, Patricia; Orcau, Angels; Caylà, Joan A

    2011-01-01

    Background Immigration can affect the evolution of TB as an AIDS-defining disease (AIDS–TB). Methods The Barcelona AIDS register for 1994–2005 was analyzed, and the global characteristics of AIDS–TB and AIDS–non-TB cases were compared. The Mantel-Haenszel test was used in the trend analysis, and logistic regression was used in the multivariate analysis. Results Of the 3600 cases studied, 1130 had both AIDS and TB. A declining trend in AIDS–TB rates was observed in both sexes among both immigrants and native residents. The percentage of AIDS–TB was significantly higher among immigrants (P = 0.02). The number of cases among immigrants remained constant over the period of study, but decreased among native residents. The sociodemographic and immunological characteristics associated with TB were male sex, age younger than 36 years, inner city residence, a record of incarceration, greater than 200 CD4+ T-cells/mm3, injecting drug use, heterosexual sex, and immigration from Latin America, the Caribbean, or sub-Saharan Africa. Conclusions The incidence of TB as an AIDS-defining disease decreased in Barcelona during a recent 10-year period in both native and immigrant populations. However, immigrants remain a high-risk group for AIDS–TB and should be targeted for surveillance and control of both diseases. PMID:21325728

  15. Flux Balance Analysis with Objective Function Defined by Proteomics Data-Metabolism of Mycobacterium tuberculosis Exposed to Mefloquine.

    PubMed

    Montezano, Daniel; Meek, Laura; Gupta, Rashmi; Bermudez, Luiz E; Bermudez, José C M

    2015-01-01

    We present a study of the metabolism of the Mycobacterium tuberculosis after exposure to antibiotics using proteomics data and flux balance analysis (FBA). The use of FBA to study prokaryotic organisms is well-established and allows insights into the metabolic pathways chosen by the organisms under different environmental conditions. To apply FBA a specific objective function must be selected that represents the metabolic goal of the organism. FBA estimates the metabolism of the cell by linear programming constrained by the stoichiometry of the reactions in an in silico metabolic model of the organism. It is assumed that the metabolism of the organism works towards the specified objective function. A common objective is the maximization of biomass. However, this goal is not suitable for situations when the bacterium is exposed to antibiotics, as the goal of organisms in these cases is survival and not necessarily optimal growth. In this paper we propose a new approach for defining the FBA objective function in studies when the bacterium is under stress. The function is defined based on protein expression data. The proposed methodology is applied to the case when the bacterium is exposed to the drug mefloquine, but can be easily extended to other organisms, conditions or drugs. We compare our method with an alternative method that uses experimental data for adjusting flux constraints. We perform comparisons in terms of essential enzymes and agreement using enzyme abundances. Results indicate that using proteomics data to define FBA objective functions yields less essential reactions with zero flux and lower error rates in prediction accuracy. With flux variability analysis we observe that overall variability due to alternate optima is reduced with the incorporation of proteomics data. We believe that incorporating proteomics data in the objective function used in FBA may help obtain metabolic flux representations that better support experimentally observed features

  16. Protection of Eurasian badgers (Meles meles) from tuberculosis after intra-muscular vaccination with different doses of BCG.

    PubMed

    Lesellier, Sandrine; Palmer, Si; Gowtage-Sequiera, Sonya; Ashford, Roland; Dalley, Deanna; Davé, Dipesh; Weyer, Ute; Salguero, F Javier; Nunez, Alejandro; Crawshaw, Timothy; Corner, Leigh A L; Hewinson, R Glyn; Chambers, Mark A

    2011-05-12

    Mycobacterium bovis infection is widespread in Eurasian badger (Meles meles) populations in Great Britain and the Republic of Ireland where they act as a wildlife reservoir of infection for cattle. Removal of infected badgers can significantly reduce the incidence of bovine tuberculosis (TB) in local cattle herds. However, control measures based on culling of native wildlife are contentious and may even be detrimental to disease control. Vaccinating badgers with bacillus Calmette-Guerin (BCG) has been shown to be efficacious against experimentally induced TB of badgers when administered subcutaneously and orally. Vaccination may be an alternative or complementary strategy to other disease control measures. As the subcutaneous route is impractical for vaccinating wild badgers and an oral vaccine bait formulation is currently unavailable, we evaluated the intramuscular (IM) route of BCG administration. It has been demonstrated that the IM route is safe in badgers. IM administration has the practical advantage of being relatively easy to perform on trapped wild badgers without recourse to chemical immobilisation. We report the evaluation of the efficacy of IM administration of BCG Danish strain 1331 at two different doses: the dose prescribed for adult humans (2-8×10(5)colony forming units) and a 10-fold higher dose. Vaccination generated a dose-dependent cell-mediated immune response characterised by the production of interferon-γ (IFNγ) and protection against endobronchial challenge with virulent M. bovis. Protection, expressed in terms of a significant reduction in the severity of disease, the number of tissues containing acid-fast bacilli, and reduced bacterial excretion was statistically significant with the higher dose only.

  17. The Protective Effect of the Mycobacterium bovis BCG Vaccine Is Increased by Coadministration with the Mycobacterium tuberculosis 72-Kilodalton Fusion Polyprotein Mtb72F in M. tuberculosis-Infected Guinea Pigs

    PubMed Central

    Brandt, Lise; Skeiky, Yasir A. W.; Alderson, Mark R.; Lobet, Yves; Dalemans, Wilfried; Turner, Oliver C.; Basaraba, Randall J.; Izzo, Angelo A.; Lasco, Todd M.; Chapman, Philip L.; Reed, Steven G.; Orme, Ian M.

    2004-01-01

    A tuberculosis vaccine candidate consisting of a 72-kDa polyprotein or fusion protein based upon the Mtb32 and Mtb39 antigens of Mycobacterium tuberculosis and designated Mtb72F was tested for its protective capacity as a potential adjunct to the Mycobacterium bovis BCG vaccine in the mouse and guinea pig models of this disease. Formulation of recombinant Mtb72F (rMtb72F) in an AS02A adjuvant enhanced the Th1 response to BCG in mice but did not further reduce the bacterial load in the lungs after aerosol challenge infection. In the more stringent guinea pig disease model, rMtb72F delivered by coadministration with BCG vaccination significantly improved the survival of these animals compared to BCG alone, with some animals still alive and healthy in their appearance at >100 weeks post-aerosol challenge. A similar trend was observed with guinea pigs in which BCG vaccination was boosted by DNA vaccination, although this increase was not statistically significant due to excellent protection conferred by BCG alone. Histological examination of the lungs of test animals indicated that while BCG controls eventually died from overwhelming lung consolidation, the majority of guinea pigs receiving BCG mixed with rMtb72F or boosted twice with Mtb72F DNA had mostly clear lungs with minimal granulomatous lesions. Lesions were still prominent in guinea pigs receiving BCG and the Mtb72F DNA boost, but there was considerable evidence of lesion healing and airway remodeling and reestablishment. These data support the hypothesis that the coadministration or boosting of BCG vaccination with Mtb72F may limit the lung consolidation seen with BCG alone and may promote lesion resolution and healing. Collectively, these data suggest that enhancing BCG is a valid vaccination strategy for tuberculosis that is worthy of clinical evaluation. PMID:15501795

  18. Action against vaccine-preventable infectious diseases and tuberculosis in Nomad Camps: the experience of a Local Health Unit in Rome.

    PubMed

    Spadea, A; Semyonov, L; Unim, B; Giraldi, G; Corda, B; D'Amici, A M; Ercole, A; Boccia, A; La Torre, G

    2014-01-01

    In Italy the highest incidence of Tuberculosis (TB) cases is in young adult migrants. In 2011, the sanitarystaff of the Local Health Unit (ASL) Roma A promoted a vaccination campaign conducting several public health interventions in Nomad Camps. After notification of a case of TB in the Camp of Via Salaria, out of 357 Mantoux skin tests performed, 93 were positive (26%); subsequently, 5 subjects with radiographic positivity were hospitalized. The vaccination campaign was carried out to prevent the spread of infectious diseases in immigrant communities at high risk of contagion and to avoid the consequent transmission in the host country. As a result, vaccinations coverage among the residents of the Camps increased: 367 vaccinated subjects (30% more than previous year) and 612 administered vaccinations.

  19. Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

    PubMed Central

    Eoh, Hyungjin; Rhee, Kyu Y.

    2014-01-01

    Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb’s ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb’s ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb’s methylcitrate cycle into a “dead end” pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B12-dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb’s ICLs and survival on fatty acids. PMID:24639517

  20. The defining characteristics of Web 2.0 and their potential influence in the online vaccination debate.

    PubMed

    Witteman, Holly O; Zikmund-Fisher, Brian J

    2012-05-28

    The emergence of Web 2.0 has led to more and more Web-based resources demonstrating three defining characteristics: user participation, openness and network effects. This paper discusses these characteristics in the context of the online vaccination debate, explores how they structurally alter the way people might interact with vaccination information online, and describes ways in which such characteristics support particular tendencies in human decision making processes. Specifically, user participation supports the influence of narratives and personal accounts, openness shapes expectations for greater levels of detail and movement toward models of informed decision making, and network effects demonstrate the social nature of decision making, the influence of like-minded others and thus, the pitfalls of polarization in the online vaccination debate. Web 2.0 means that concerns about vaccination information online must expand beyond simply the possibility that people might access information of varying quality to incorporate a more comprehensive understanding of how people use current Web functionality, how such usage influences expectations about information sources and decision making processes, and the implications for communication strategies about vaccination.

  1. Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis

    PubMed Central

    Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun

    2016-01-01

    M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death

  2. Assessment of Mycobacterium bovis Deleted in p27-p55 Virulence Operon as Candidate Vaccine against Tuberculosis in Animal Models

    PubMed Central

    Bianco, María V.; Clark, Simon; Blanco, Federico C.; Garbaccio, Sergio; García, Elizabeth; Cataldi, Angel A.; Bigi, Fabiana

    2014-01-01

    A Mycobacterium bovis knockout in p27-p55 operon was tested as an antituberculosis experimental vaccine in animal models. The mutant MbΔp27-p55 was significantly more attenuated in nude mice than its parental strain but more virulent than BCG Pasteur. Challenge experiments in mice and guinea pigs using M. bovis or M. tuberculosis strains showed similar protection conferred by MbΔp27-p55 mutant than BCG in terms of pathology and bacterial loads in spleen but lower protection than BCG in lungs. When tested in cattle, MbΔp27-p55 did not induce IL-2 expression and induced a very low production of IFNγ, suggesting that the lack of P27/P55 reduces the capacity of M. bovis of triggering an adequate Th1 response. PMID:24588000

  3. Assessment of Mycobacterium bovis deleted in p27-p55 virulence operon as candidate vaccine against tuberculosis in animal models.

    PubMed

    Bianco, María V; Clark, Simon; Blanco, Federico C; Garbaccio, Sergio; García, Elizabeth; Cataldi, Angel A; Williams, Ann; Bigi, Fabiana

    2014-01-01

    A Mycobacterium bovis knockout in p27-p55 operon was tested as an antituberculosis experimental vaccine in animal models. The mutant MbΔp27-p55 was significantly more attenuated in nude mice than its parental strain but more virulent than BCG Pasteur. Challenge experiments in mice and guinea pigs using M. bovis or M. tuberculosis strains showed similar protection conferred by MbΔp27-p55 mutant than BCG in terms of pathology and bacterial loads in spleen but lower protection than BCG in lungs. When tested in cattle, MbΔp27-p55 did not induce IL-2 expression and induced a very low production of IFNγ, suggesting that the lack of P27/P55 reduces the capacity of M. bovis of triggering an adequate Th1 response.

  4. A Birth Cohort Study of Maternal and Infant Serum PCB-153 and DDE Concentrations and Responses to Infant Tuberculosis Vaccination

    PubMed Central

    Jusko, Todd A.; De Roos, Anneclaire J.; Lee, Sue Y.; Thevenet-Morrison, Kelly; Schwartz, Stephen M.; Verner, Marc-André; Murinova, Lubica Palkovicova; Drobná, Beata; Kočan, Anton; Fabišiková, Anna; Čonka, Kamil; Trnovec, Tomas; Hertz-Picciotto, Irva; Lawrence, B. Paige

    2015-01-01

    Background: Reasons for the highly variable and often poor protection conferred by the Mycobacterium bovis bacille Calmette–Guérin (BCG) vaccine are multifaceted and poorly understood. Objectives: We aimed to determine whether early-life exposure to PCBs (polychlorinated biphenyls) and DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] reduces 6-month infant BCG vaccine response. Methods: Data came from families participating in a prospective birth cohort in eastern Slovakia. At birth, maternal and cord blood were collected for chemical analyses, and infants were immunized with BCG. Blood was collected from infants for chemical analyses and to determine 6-month BCG-specific immunoglobulin (Ig) G and IgA levels. Multivariable linear regression models were fit to examine chemical–BCG associations among approximately 500 mother–infant pairs, with adjustment for confounders. Results: The median 6-month infant concentration of the prevalent congener PCB-153 was 113 ng/g lipid [interquartile range (IQR): 37–248], and 388 ng/g lipid (IQR: 115–847) for DDE. Higher 6-month infant concentrations of PCB-153 and DDE were strongly associated with lower 6-month BCG-specific antibody levels. For instance, BCG-specific IgG levels were 37% lower for infants with PCB-153 concentrations at the 75th percentile compared to the 25th percentile (95% CI: –42, –32; p < 0.001). Results were similar in magnitude and precision for DDE. There was also evidence of PCB–DDE additivity, where exposure to both compounds reduced anti-BCG levels more than exposure to either compound alone. Conclusions: The associations observed in this study indicate that environmental exposures may be overlooked contributors to poorer responses to BCG vaccine. The overall association between these exposures and tuberculosis incidence is unknown. Citation: Jusko TA, De Roos AJ, Lee SY, Thevenet-Morrison K, Schwartz SM, Verner MA, Palkovicova Murinova L, Drobná B, Kočan A, Fabišiková A, Čonka K

  5. Immunogenicity and therapeutic effects of Ag85A/B chimeric DNA vaccine in mice infected with Mycobacterium tuberculosis.

    PubMed

    Liang, Yan; Wu, Xueqiong; Zhang, Junxian; Xiao, Li; Yang, Yourong; Bai, Xuejuan; Yu, Qi; Li, Zhongming; Bi, Lan; Li, Ning; Wu, Xiaoli

    2012-12-01

    The situation of tuberculosis (TB) is very severe in China. New therapeutic agents or regimens to treat TB are urgently needed. In this study, Mycobacterium tuberculosis-infected mice were given immunotherapy intramuscularly with Ag85A/B chimeric DNA or saline, plasmid vector pVAX1, or Mycobacterium vaccae vaccine. The mice treated with Ag85A/B chimeric DNA showed significantly higher numbers of T cells secreting interferon-gamma (IFN-γ), more IFN-γ in splenocyte culture supernatant, more Th1 and Tc1 cells, and higher ratios of Th1/Th2 and Tc1/Tc2 cells in whole blood, indicating a predominant Th1 immune response to treatment. Infected mice treated with doses of 100 μg Ag85A/B chimeric DNA had an extended time until death of 50% of the animals that was markedly longer than the saline and vector control groups, and the death rate at 1 month after the last dose was lower than that in the other groups. Compared with the saline group, 100 μg Ag85A/B chimeric DNA and 100 μg Ag85A DNA reduced the pulmonary bacterial loads by 0.79 and 0.45 logs, and the liver bacterial loads by 0.52 and 0.50 logs, respectively. Pathological changes in the lungs were less, and the lesions were more limited. These results show that Ag85A/B chimeric DNA was effective for the treatment of TB, significantly increasing the cellular immune response and inhibiting the growth of M. tuberculosis.

  6. A DNA vaccine against tuberculosis based on the 65 kDa heat-shock protein differentially activates human macrophages and dendritic cells

    PubMed Central

    Franco, Luís H; Wowk, Pryscilla F; Silva, Célio L; Trombone, Ana PF; Coelho-Castelo, Arlete AM; Oliver, Constance; Jamur, Maria C; Moretto, Edson L; Bonato, Vânia LD

    2008-01-01

    Background A number of reports have demonstrated that rodents immunized with DNA vaccines can produce antibodies and cellular immune responses presenting a long-lasting protective immunity. These findings have attracted considerable interest in the field of DNA vaccination. We have previously described the prophylactic and therapeutic effects of a DNA vaccine encoding the Mycobacterium leprae 65 kDa heat shock protein (DNA-HSP65) in a murine model of tuberculosis. As DNA vaccines are often less effective in humans, we aimed to find out how the DNA-HSP65 stimulates human immune responses. Methods To address this question, we analysed the activation of both human macrophages and dendritic cells (DCs) cultured with DNA-HSP65. Then, these cells stimulated with the DNA vaccine were evaluated regarding the expression of surface markers, cytokine production and microbicidal activity. Results It was observed that DCs and macrophages presented different ability to uptake DNA vaccine. Under DNA stimulation, macrophages, characterized as CD11b+/CD86+/HLA-DR+, produced high levels of TNF-alpha, IL-6 (pro-inflammatory cytokines), and IL-10 (anti-inflammatory cytokine). Besides, they also presented a microbicidal activity higher than that observed in DCs after infection with M. tuberculosis. On the other hand, DCs, characterized as CD11c+/CD86+/CD123-/BDCA-4+/IFN-alpha-, produced high levels of IL-12 and low levels of TNF-alpha, IL-6 and IL-10. Finally, the DNA-HSP65 vaccine was able to induce proliferation of peripheral blood lymphocytes. Conclusion Our data suggest that the immune response is differently activated by the DNA-HSP65 vaccine in humans. These findings provide important clues to the design of new strategies for using DNA vaccines in human immunotherapy. PMID:18208592

  7. A Multi-Antigenic Adenoviral-Vectored Vaccine Improves BCG-Induced Protection of Goats against Pulmonary Tuberculosis Infection and Prevents Disease Progression

    PubMed Central

    Pérez de Val, Bernat; Vidal, Enric; Villarreal-Ramos, Bernardo; Gilbert, Sarah C.; Andaluz, Anna; Moll, Xavier; Martín, Maite; Nofrarías, Miquel; McShane, Helen; Vordermeier, H. Martin; Domingo, Mariano

    2013-01-01

    The “One world, one health” initiative emphasizes the need for new strategies to control human and animal tuberculosis (TB) based on their shared interface. A good example would be the development of novel universal vaccines against Mycobacterium tuberculosis complex (MTBC) infection. This study uses the goat model, a natural TB host, to assess the protective effectiveness of a new vaccine candidate in combination with Bacillus Calmette-Guerin (BCG) vaccine. Thirty-three goat kids were divided in three groups: Group 1) vaccinated with BCG (week 0), Group 2) vaccinated with BCG and boosted 8 weeks later with a recombinant adenovirus expressing the MTBC antigens Ag85A, TB10.4, TB9.8 and Acr2 (AdTBF), and Group 3) unvaccinated controls. Later on, an endobronchial challenge with a low dose of M. caprae was performed (week 15). After necropsy (week 28), the pulmonary gross pathology was quantified using high resolution Computed Tomography. Small granulomatous pulmonary lesions (< 0.5 cm diameter) were also evaluated through a comprehensive qualitative histopathological analysis. M. caprae CFU were counted from pulmonary lymph nodes. The AdTBF improved the effects of BCG reducing gross lesion volume and bacterial load, as well as increasing weight gain. The number of Ag85A-specific gamma interferon-producing memory T-cells was identified as a predictor of vaccine efficacy. Specific cellular and humoral responses were measured throughout the 13-week post-challenge period, and correlated with the severity of lesions. Unvaccinated goats exhibited the typical pathological features of active TB in humans and domestic ruminants, while vaccinated goats showed only very small lesions. The data presented in this study indicate that multi-antigenic adenoviral vectored vaccines boosts protection conferred by vaccination with BCG. PMID:24278420

  8. A novel liposome adjuvant DPC mediates Mycobacterium tuberculosis subunit vaccine well to induce cell-mediated immunity and high protective efficacy in mice.

    PubMed

    Liu, Xun; Da, Zejiao; Wang, Yue; Niu, Hongxia; Li, Ruiying; Yu, Hongjuan; He, Shanshan; Guo, Ming; Wang, Yong; Luo, Yanping; Ma, Xingming; Zhu, Bingdong

    2016-03-01

    Tuberculosis (TB) is a serious disease around the world, and protein based subunit vaccine is supposed to be a kind of promising novel vaccine against it. However, there is no effective adjuvant available in clinic to activate cell-mediated immune responses which is required for TB subunit vaccine. Therefore, it is imperative to develop new adjuvant. Here we reported an adjuvant composed of dimethyl dioctadecylammonium (DDA), Poly I:C and cholesterol (DPC for short). DDA can form a kind of cationic liposome with the ability to deliver and present antigen and can induce Th1 type cell-mediated immune response. Poly I:C, a ligand of TLR3 receptor, could attenuate the pathologic reaction induced by following Mycobacterium tuberculosis challenge. Cholesterol, which could enhance rigidity of lipid bilayer, is added to DDA and Poly I:C to improve the stability of the adjuvant. The particle size and Zeta-potential of DPC were analyzed in vitro. Furthermore, DPC was mixed with a TB fusion protein ESAT6-Ag85B-MPT64(190-198)-Mtb8.4-Rv2626c (LT70) to construct a subunit vaccine. The subunit vaccine-induced immune responses and protective efficacy against M. tuberculosis H37Rv infection in C57BL/6 mice were investigated. The results showed that the DPC adjuvant with particle size of 400 nm and zeta potential of 40 mV was in good stability. LT70 in the adjuvant of DPC generated strong antigen-specific humoral and cell-mediated immunity, and induced long-term higher protective efficacy against M. tuberculosis infection (5.41 ± 0.38log10CFU) than traditional vaccine Bacillus Calmette-Guerin (BCG) (6.01 ± 0.33log10CFU) and PBS control (6.53 ± 0.26log10CFU) at 30 weeks post-vaccination. In conclusion, DPC would be a promising vaccine adjuvant with the ability to stimulate Th1 type cell-mediated immunity, and could be used in TB subunit vaccine.

  9. Increased B and T Cell Responses in M. bovis Bacille Calmette-Guérin Vaccinated Pigs Co-Immunized with Plasmid DNA Encoding a Prototype Tuberculosis Antigen

    PubMed Central

    Bruffaerts, Nicolas; Pedersen, Lasse E.; Vandermeulen, Gaëlle; Préat, Véronique; Stockhofe-Zurwieden, Norbert; Huygen, Kris; Romano, Marta

    2015-01-01

    The only tuberculosis vaccine currently available, bacille Calmette-Guérin (BCG) is a poor inducer of CD8+ T cells, which are particularly important for the control of latent tuberculosis and protection against reactivation. As the induction of strong CD8+ T cell responses is a hallmark of DNA vaccines, a combination of BCG with plasmid DNA encoding a prototype TB antigen (Ag85A) was tested. As an alternative animal model, pigs were primed with BCG mixed with empty vector or codon-optimized pAg85A by the intradermal route and boosted with plasmid delivered by intramuscular electroporation. Control pigs received unformulated BCG. The BCG-pAg85A combination stimulated robust and sustained Ag85A specific antibody, lymphoproliferative, IL-6, IL-10 and IFN-γ responses. IgG1/IgG2 antibody isotype ratio reflected the Th1 helper type biased response. T lymphocyte responses against purified protein derivative of tuberculin (PPD) were induced in all (BCG) vaccinated animals, but responses were much stronger in BCG-pAg85A vaccinated pigs. Finally, Ag85A-specific IFN-γ producing CD8+ T cells were detected by intracellular cytokine staining and a synthetic peptide, spanning Ag85A131-150 and encompassing two regions with strong predicted SLA-1*0401/SLA-1*0801 binding affinity, was promiscuously recognized by 6/6 animals vaccinated with the BCG-pAg85A combination. Our study provides a proof of concept in a large mammalian species, for a new Th1 and CD8+ targeting tuberculosis vaccine, based on BCG-plasmid DNA co-administration. PMID:26172261

  10. Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination.

    PubMed

    Ellebedy, Ali H; Jackson, Katherine J L; Kissick, Haydn T; Nakaya, Helder I; Davis, Carl W; Roskin, Krishna M; McElroy, Anita K; Oshansky, Christine M; Elbein, Rivka; Thomas, Shine; Lyon, George M; Spiropoulou, Christina F; Mehta, Aneesh K; Thomas, Paul G; Boyd, Scott D; Ahmed, Rafi

    2016-10-01

    Antigen-specific B cells bifurcate into antibody-secreting cells (ASCs) and memory B cells (MBCs) after infection or vaccination. ASCs (plasmablasts) have been extensively studied in humans, but less is known about B cells that become activated but do not differentiate into plasmablasts. Here we have defined the phenotype and transcriptional program of a subset of antigen-specific B cells, which we have called 'activated B cells' (ABCs), that were distinct from ASCs and were committed to the MBC lineage. We detected ABCs in humans after infection with Ebola virus or influenza virus and also after vaccination. By simultaneously analyzing antigen-specific ASCs and ABCs in human blood after vaccination against influenza virus, we investigated the clonal overlap and extent of somatic hypermutation (SHM) in the ASC (effector) and ABC (memory) lineages. Longitudinal tracking of vaccination-induced hemagglutinin (HA)-specific clones revealed no overall increase in SHM over time, which suggested that repeated annual immunization might have limitations in enhancing the quality of influenza-virus-specific antibody.

  11. Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination.

    PubMed

    Ellebedy, Ali H; Jackson, Katherine J L; Kissick, Haydn T; Nakaya, Helder I; Davis, Carl W; Roskin, Krishna M; McElroy, Anita K; Oshansky, Christine M; Elbein, Rivka; Thomas, Shine; Lyon, George M; Spiropoulou, Christina F; Mehta, Aneesh K; Thomas, Paul G; Boyd, Scott D; Ahmed, Rafi

    2016-10-01

    Antigen-specific B cells bifurcate into antibody-secreting cells (ASCs) and memory B cells (MBCs) after infection or vaccination. ASCs (plasmablasts) have been extensively studied in humans, but less is known about B cells that become activated but do not differentiate into plasmablasts. Here we have defined the phenotype and transcriptional program of a subset of antigen-specific B cells, which we have called 'activated B cells' (ABCs), that were distinct from ASCs and were committed to the MBC lineage. We detected ABCs in humans after infection with Ebola virus or influenza virus and also after vaccination. By simultaneously analyzing antigen-specific ASCs and ABCs in human blood after vaccination against influenza virus, we investigated the clonal overlap and extent of somatic hypermutation (SHM) in the ASC (effector) and ABC (memory) lineages. Longitudinal tracking of vaccination-induced hemagglutinin (HA)-specific clones revealed no overall increase in SHM over time, which suggested that repeated annual immunization might have limitations in enhancing the quality of influenza-virus-specific antibody. PMID:27525369

  12. Prospects in Mycobacterium bovis Bacille Calmette et Guérin (BCG) vaccine diversity and delivery: why does BCG fail to protect against tuberculosis?

    PubMed

    Moliva, Juan I; Turner, Joanne; Torrelles, Jordi B

    2015-09-22

    Mycobacterium tuberculosis (M.tb) infection leads to active tuberculosis (TB), a disease that kills one human every 18s. Current therapies available to combat TB include chemotherapy and the preventative vaccine Mycobacterium bovis Bacille Calmette et Guérin (BCG). Increased reporting of drug resistant M.tb strains worldwide indicates that drug development cannot be the primary mechanism for eradication. BCG vaccination has been used globally for protection against childhood and disseminated TB, however, its efficacy at protecting against pulmonary TB in adult and aging populations is highly variable. In this regard, the immune response generated by BCG vaccination is incapable of sterilizing the lung post M.tb infection as indicated by the large proportion of individuals with latent TB infection that have received BCG. Although many new TB vaccine candidates have entered the development pipeline, only a few have moved to human clinical trials; where they showed no efficacy and/or were withdrawn due to safety regulations. These trials highlight our limited understanding of protective immunity against the development of active TB. Here, we discuss current vaccination strategies and their impact on the generation and sustainability of protective immunity against TB.

  13. Poly(2-aminoethyl methacrylate) with well-defined chain-length for DNA vaccine delivery to dendritic cells

    PubMed Central

    Ji, Weihang; Panus, David; Palumbo, R. Noelle; Tang, Rupei; Wang, Chun

    2011-01-01

    Poly(2-aminoethyl methacrylate) (PAEM) homopolymers with defined chain-length and narrow molecular weight distribution were synthesized using atom transfer radical polymerization (ATRP), and a comprehensive study was conducted to evaluate the colloidal properties of PAEM/plasmid DNA polyplexes, the uptake and subcellular trafficking of polyplexes in antigen-presenting dendritic cells (DCs), and the biological performance of PAEM as a potential DNA vaccine carrier. PAEM of different chain-length (45, 75 and 150 repeating units) showed varying strength in condensing plasmid DNA into narrowly dispersed nanoparticles with very low cytotoxicity. Longer polymer chain-length resulted in higher levels of overall cellular uptake and nuclear uptake of plasmid DNA, but shorter polymer chains favored intracellular and intra-nuclear release of free plasmid from the polyplexes. Despite its simple chemical structure, PAEM transfected DCs very efficiently in vitro in media with or without serum and led to phenotypic maturation of DCs. When a model antigen-encoding ovalbumin plasmid was used, transfected DCs stimulated the activation of naïve CD8+ T cells to produce high levels of interferon-γ. The efficiency of transfection, DC maturation, and CD8+ T cell activation showed varying degrees of polymer chain-length dependence. These structurally defined cationic polymers may have much potential as efficient DNA vaccine carriers and immunostimulatory adjuvants. They may also serve as a model material system for elucidating structural and intracellular mechanisms of polymer-mediated DNA vaccine delivery. PMID:22082257

  14. Enhanced Immunogenicity of CD4+ T-Cell Responses and Protective Efficacy of a DNA-Modified Vaccinia Virus Ankara Prime-Boost Vaccination Regimen for Murine Tuberculosis

    PubMed Central

    McShane, Helen; Brookes, Roger; Gilbert, Sarah C.; Hill, Adrian V. S.

    2001-01-01

    DNA vaccines whose DNA encodes a variety of antigens from Mycobacterium tuberculosis have been evaluated for immunogenicity and protective efficacy. CD8+ T-cell responses and protection achieved in other infectious disease models have been optimized by using a DNA immunization to prime the immune system and a recombinant virus encoding the same antigen(s) to boost the response. A DNA vaccine (D) and recombinant modified vaccinia virus Ankara (M) in which the DNA encodes early secreted antigenic target 6 and mycobacterial protein tuberculosis 63 synthesized, and each was found to generate specific gamma interferon (IFN-γ)-secreting CD4+ T cells. Enhanced CD4+ IFN-γ T-cell responses were produced by both D-M and M-D immunization regimens. Significantly higher levels of IFN-γ were seen with a D-D-D-M immunization regimen. The most immunogenic regimens were assessed in a challenge study and found to produce protection equivalent to that produced by Mycobacterium bovis BCG. Thus, heterologous prime-boost regimens boost CD4+ as well as CD8+ T-cell responses, and the use of heterologous constructs encoding the same antigen(s) may improve the immunogenicity and protective efficacy of DNA vaccines against tuberculosis and other diseases. PMID:11159955

  15. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.

    PubMed

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M; Lucas, Megan; Spencer, John S; Amara, Rama Rao; Plikaytis, Bonnie B; Posey, James E; Sable, Suraj B

    2016-01-01

    Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans. PMID:27173443

  16. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.

    PubMed

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M; Lucas, Megan; Spencer, John S; Amara, Rama Rao; Plikaytis, Bonnie B; Posey, James E; Sable, Suraj B

    2016-05-13

    Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans.

  17. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis

    PubMed Central

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M.; Lucas, Megan; Spencer, John S.; Amara, Rama Rao; Plikaytis, Bonnie B.; Posey, James E.; Sable, Suraj B.

    2016-01-01

    Heterologous prime–boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32–52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime–Apa-subunit-boost strategy compared to Apa-subunit-prime–BCG-boost approach. However, parenteral BCG-prime–Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime–boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime–boost regimens against tuberculosis in humans. PMID:27173443

  18. Differential cellular recognition pattern to M. tuberculosis targets defined by IFN-γ and IL-17 production in blood from TB + patients from Honduras as compared to health care workers: TB and immune responses in patients from Honduras

    PubMed Central

    2013-01-01

    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. PMID:23497342

  19. Characterization of Francisella tularensis Schu S4 defined mutants as live-attenuated vaccine candidates.

    PubMed

    Santiago, Araceli E; Mann, Barbara J; Qin, Aiping; Cunningham, Aimee L; Cole, Leah E; Grassel, Christen; Vogel, Stefanie N; Levine, Myron M; Barry, Eileen M

    2015-08-01

    Francisella tularensis (Ft), the etiological agent of tularemia and a Tier 1 select agent, has been previously weaponized and remains a high priority for vaccine development. Ft tularensis (type A) and Ft holarctica (type B) cause most human disease. We selected six attenuating genes from the live vaccine strain (LVS; type B), F. novicida and other intracellular bacteria: FTT0507, FTT0584, FTT0742, FTT1019c (guaA), FTT1043 (mip) and FTT1317c (guaB) and created unmarked deletion mutants of each in the highly human virulent Ft strain Schu S4 (Type A) background. FTT0507, FTT0584, FTT0742 and FTT1043 Schu S4 mutants were not attenuated for virulence in vitro or in vivo. In contrast, Schu S4 gua mutants were unable to replicate in murine macrophages and were attenuated in vivo, with an i.n. LD50 > 10(5) CFU in C57BL/6 mice. However, the gua mutants failed to protect mice against lethal challenge with WT Schu S4, despite demonstrating partial protection in rabbits in a previous study. These results contrast with the highly protective capacity of LVS gua mutants against a lethal LVS challenge in mice, and underscore differences between these strains and the animal models in which they are evaluated, and therefore have important implications for vaccine development.

  20. Oral delivery of BCG Moreau Rio de Janeiro gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination.

    PubMed

    Clark, Simon O; Kelly, Dominic L F; Badell, Edgar; Castello-Branco, Luiz Roberto; Aldwell, Frank; Winter, Nathalie; Lewis, David J M; Marsh, Philip D

    2010-10-01

    There is a need for an improved vaccine to better control human tuberculosis (TB), as the only currently available TB vaccine, bacillus Calmette-Guerin (BCG) delivered parenterally, offers variable levels of efficacy. Therefore, recombinant strains expressing additional antigens are being developed alongside alternative routes to parenteral delivery. There is strong evidence that BCG Moreau (RdJ) is a safe and effective vaccine in humans when given by the oral route. This study compared the efficacy of a single oral dose of wild type BCG Moreau Rio de Janeiro (RdJ), or a recombinant RdJ strain expressing Ag85B-ESAT6 fusion protein, formulated with and without lipid to enhance oral delivery, with subcutaneous BCG Danish 1331 and saline control groups in a guinea pig aerosol infection model of pulmonary tuberculosis. Protection was measured as survival at 30 weeks post-challenge and reduced bacterial load and histopathology in lungs and spleen. Results showed that a single oral dose of BCG Moreau (RdJ) or recombinant BCG Moreau (RdJ)-Ag85B-ESAT6, formulated with or without lipid, gave protection equivalent to subcutaneously delivered BCG Danish in the 30 weeks post-challenge survival study. The orally delivered vaccines gave reduced pathology scores in the lungs (three of the four formulations) and spleens (all four formulations) compared to subcutaneously delivered BCG Danish. The oral wild type BCG Moreau (RdJ) in lipid and the unformulated oral wild type BCG Moreau (RdJ) vaccine also gave statistically lower bacterial loads in the lungs and spleens, respectively, compared to subcutaneously delivered BCG Danish. This study provides further evidence to show that lipid formulation does not impair vaccine efficacy and may enhance the delivery and stability of oral vaccines intended for use in countries with poor health infrastructure. Oral delivery also avoids needles (and associated cross-infection risks) and immunisation without the need for specially trained

  1. Prime-Boost Vaccination with rBCG/rAd35 Enhances CD8+ Cytolytic T-Cell Responses in Lesions from Mycobacterium Tuberculosis –Infected Primates

    PubMed Central

    Rahman, Sayma; Magalhaes, Isabelle; Rahman, Jubayer; Ahmed, Raija K; Sizemore, Donata R; Scanga, Charles A; Weichold, Frank; Verreck, Frank; Kondova, Ivanela; Sadoff, Jerry; Thorstensson, Rigmor; Spångberg, Mats; Svensson, Mattias; Andersson, Jan; Maeurer, Markus; Brighenti, Susanna

    2012-01-01

    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. PMID:22396020

  2. Vaccinations

    MedlinePlus

    ... vaccinated? For many years, a set of annual vaccinations was considered normal and necessary for dogs and ... to protect for a full year. Consequently, one vaccination schedule will not work well for all pets. ...

  3. Family history of immigration from a tuberculosis endemic country and low family income are associated with a higher BCG vaccination coverage in Ile-de-France region, France.

    PubMed

    Guthmann, Jean-Paul; Chauvin, Pierre; Le Strat, Yann; Soler, Marion; Fonteneau, Laure; Lévy-Bruhl, Daniel

    2013-11-19

    After withdrawal of multipuncture BCG device from the French market in January 2006, vaccination coverage (VC) with the intradermal device has dropped and since remained sub-optimal in Ile-de-France, the only region of mainland France where BCG is recommended to all children. We conducted a cross-sectional study to identify socio-economic factors associated with BCG VC in children of Paris metropolitan area born after January 2006. Two-stage random sampling was used to include 425 children up to 5 years old from Paris and its suburbs. Information was collected through face-to-face interviews and vaccination status confirmed by a vaccination document. Poisson regression analyzed the association between VC and potential determinants. VC of children from families with the lowest incomes (first quartile of family income/consumption unit (CU) (<883 €) was close to 100% regardless of family origin. In families with higher incomes (≥ 883 €/CU), VC was significantly higher among children born to families from a tuberculosis highly endemic country (98.2%) compared with other children (76.2%) (p=0.004). Children of low socio-economic background as well as those with a family history of immigration, regardless of family income, are correctly identified as being at high risk of tuberculosis and properly vaccinated with BCG in this area.

  4. Vaccines Directed Against Microorganisms or Their Products Present During Biofilm Lifestyle: Can We Make a Translation as a Broad Biological Model to Tuberculosis?

    PubMed Central

    Flores-Valdez, Mario A.

    2016-01-01

    Tuberculosis (TB) remains as a global public health problem. In recent years, experimental evidence suggesting the relevance of in vitro pellicle (a type of biofilm formed at the air-liquid interface) production as a phenotype mimicking aspects found by Mycobacterium tuberculosis-complex bacteria during in vivo infection has started to accumulate. There are still opportunities for better diagnostic tools, therapeutic molecules as well as new vaccine candidates to assist in TB control programs worldwide and particularly in less developed nations. Regarding vaccines, despite the availability of a live, attenuated strain (Mycobacterium bovis BCG) since almost a century ago, its variable efficacy and lack of protection against pulmonary and latent disease has prompted basic and applied research leading to preclinical and clinical evaluation of up to 15 new candidates. In this work, I present examples of vaccines based on whole cells grown as biofilms, or specific proteins expressed under such condition, and the effect they have shown in relevant animal models or directly in the natural host. I also discuss why it might be worthwhile to explore these approaches, for constructing and developing new vaccine candidates for testing their efficacy against TB. PMID:26834732

  5. Characterization of T cells that confer a high degree of protective immunity against tuberculosis in mice after vaccination with tumor cells expressing mycobacterial hsp65.

    PubMed Central

    Silva, C L; Silva, M F; Pietro, R C; Lowrie, D B

    1996-01-01

    Mice vaccinated by injection with tumor cells expressing the Mycobacterium leprae gene for hsp65 acquire a remarkably high degree of protection against challenge with Mycobacterium tuberculosis. We used limiting-dilution analysis to assess the frequency of CD4+ CD8- and CD4- CD8+ splenocytes responding to mycobacterial hsp65 in such vaccinated mice. Cells of both phenotypes were present at very high and equal frequencies (approximately 1:100). Vaccination with live Mycobacterium bovis BCG also increased the frequencies of both phenotypes of hsp65-reactive cells equally (to approximately 1:2,500), whereas vaccination procedures that were not protective, with either dead BCG, hsp65 protein in incomplete Freund's adjuvant, or hsp65 mixed with tumor cells, resulted in preferential increase in CD4+ CD8- cells. Twelve CD4+ CD8- and twelve CD4- CD8+ hsp65-responsive T-cell clones were obtained and characterized. All showed conventional antigen recognition via major histocompatibility complex class II and class I pathways but differed in secretion of gamma interferon and interleukin 4 and cytotoxicity. In tests of antimycobacterial activity against M. tuberculosis, both in infected macrophages in vitro and by adoptive transfer of protection with T-cell clones injected into irradiated mice, the most effective clones were the most cytotoxic and secretion of gamma interferon made only a secondary contribution. PMID:8698458

  6. Vaccines Directed Against Microorganisms or Their Products Present During Biofilm Lifestyle: Can We Make a Translation as a Broad Biological Model to Tuberculosis?

    PubMed

    Flores-Valdez, Mario A

    2016-01-01

    Tuberculosis (TB) remains as a global public health problem. In recent years, experimental evidence suggesting the relevance of in vitro pellicle (a type of biofilm formed at the air-liquid interface) production as a phenotype mimicking aspects found by Mycobacterium tuberculosis-complex bacteria during in vivo infection has started to accumulate. There are still opportunities for better diagnostic tools, therapeutic molecules as well as new vaccine candidates to assist in TB control programs worldwide and particularly in less developed nations. Regarding vaccines, despite the availability of a live, attenuated strain (Mycobacterium bovis BCG) since almost a century ago, its variable efficacy and lack of protection against pulmonary and latent disease has prompted basic and applied research leading to preclinical and clinical evaluation of up to 15 new candidates. In this work, I present examples of vaccines based on whole cells grown as biofilms, or specific proteins expressed under such condition, and the effect they have shown in relevant animal models or directly in the natural host. I also discuss why it might be worthwhile to explore these approaches, for constructing and developing new vaccine candidates for testing their efficacy against TB.

  7. Attenuated D2 16681-PDK53 vaccine: defining humoral and cell-mediated immunity.

    PubMed

    Rabablert, J; Yoksan, S

    2009-01-01

    Dengue viruses cause 50-100 million cases of acute febrile disease every year, including more than 500000 reported cases of the severe forms of the disease-dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Attempts to create conventional vaccines have been hampered by the lack of suitable experimental models, the need to provide protection against all four serotypes simultaneously and the possible involvement of virus-specific immune responses in severe disease. Live attenuated D2 16681-PDK53 vaccine was first developed from Mahidol University, Thailand. This vaccine induced both humoral and cell-mediated immunity and lack of reactogeneticity in humans. Infectious cDNA clones of the virulent D2 16681 virus and its attenuated D2 16681-PDK53 were constructed. The attenuated virus elicited neutralizing antibodies in mice and monkeys and developed viremia in monkeys. At molecular level, patterns of cytokines which are immunological mediators released from human mononuclear cells obtained from dengue naïve and immune donors infected with this attenuated virus compared with virulent virus were studied. In dengue naïve PBMC, the virulent and attenuated clones induced alternation in expression of 25 and 24 versus 13 and 18 genes out of 268 genes on day 1 and 3. In dengue immune PBMC, the virulent and attenuated clones induced alternation in expression of 33 and 38 versus 25 and 29 genes on days 1 and 3. Up-regulation of IL-1beta, IL-6, IL-8, IL-10, IFN-alpha, IFNgammaR, MIP-1alpha, MIP-1beta, MIP-2alpha, VEGF and down-regulation of IL-4, IL-4R, IL-RII, MIF, RANTES, IGF-1, GM-CSF-2 were shown. This review pointed out the infectious clones of the attenuated D2 16681-PDK53 was safe and induced both neutralizing antibodies in vivo and cytokine gene expression in vitro at molecular level. Furthermore, the phenotypic markers of ideal dengue vaccine could be included the alteration of cytokine gene expression and cytokine production in human mononuclear cells.

  8. Novel licensure pathways for expeditious introduction of new tuberculosis vaccines: a discussion of the adaptive licensure concept.

    PubMed

    Rustomjee, Roxana; Lockhart, Stephen; Shea, Jacqueline; Fourie, P Bernard; Hindle, Zoë; Steel, Gavin; Hussey, Gregory; Ginsberg, Ann; Brennan, Michael J

    2014-03-01

    The ultimate goal of vaccine development is licensure of a safe and efficacious product that has a well-defined manufacturing process resulting in a high quality product. In general, clinical development and regulatory approval occurs in a linear, sequential manner: Phase 1 - safety, immunogenicity; Phase 2 - immunogenicity, safety, dose ranging and preliminary efficacy; Phase 3 - definitive efficacy, safety, lot consistency; and, following regulatory approval, Phase 4 - post-marketing safety and effectiveness. For candidate TB vaccines, where correlates of protection are not yet identified, phase 2 and 3 efficacy of disease prevention trials are, by necessity, very large. Each trial would span 2-5 years, with full licensure expected only after 1 or even 2 decades of development. Given the urgent unmet need for a new TB vaccine, a satellite discussion was held at the International African Vaccinology Conference in Cape Town, South Africa in November 2012, to explore the possibility of expediting licensure by use of an "adaptive licensure" process, based on a risk/benefit assessment that is specific to regional needs informed by epidemiology. This may be appropriate for diseases such as TB, where high rates of morbidity, mortality, particularly in high disease burden countries, impose an urgent need for disease prevention. The discussion focused on two contexts: licensure within the South African regulatory environment - a high burden country where TB vaccine efficacy trials are on-going, and licensure by the United States FDA --a well-resourced regulatory agency where approval could facilitate global licensure of a novel TB vaccine. PMID:24360811

  9. Novel licensure pathways for expeditious introduction of new tuberculosis vaccines: a discussion of the adaptive licensure concept.

    PubMed

    Rustomjee, Roxana; Lockhart, Stephen; Shea, Jacqueline; Fourie, P Bernard; Hindle, Zoë; Steel, Gavin; Hussey, Gregory; Ginsberg, Ann; Brennan, Michael J

    2014-03-01

    The ultimate goal of vaccine development is licensure of a safe and efficacious product that has a well-defined manufacturing process resulting in a high quality product. In general, clinical development and regulatory approval occurs in a linear, sequential manner: Phase 1 - safety, immunogenicity; Phase 2 - immunogenicity, safety, dose ranging and preliminary efficacy; Phase 3 - definitive efficacy, safety, lot consistency; and, following regulatory approval, Phase 4 - post-marketing safety and effectiveness. For candidate TB vaccines, where correlates of protection are not yet identified, phase 2 and 3 efficacy of disease prevention trials are, by necessity, very large. Each trial would span 2-5 years, with full licensure expected only after 1 or even 2 decades of development. Given the urgent unmet need for a new TB vaccine, a satellite discussion was held at the International African Vaccinology Conference in Cape Town, South Africa in November 2012, to explore the possibility of expediting licensure by use of an "adaptive licensure" process, based on a risk/benefit assessment that is specific to regional needs informed by epidemiology. This may be appropriate for diseases such as TB, where high rates of morbidity, mortality, particularly in high disease burden countries, impose an urgent need for disease prevention. The discussion focused on two contexts: licensure within the South African regulatory environment - a high burden country where TB vaccine efficacy trials are on-going, and licensure by the United States FDA --a well-resourced regulatory agency where approval could facilitate global licensure of a novel TB vaccine.

  10. Fc-based delivery system enhances immunogenicity of a tuberculosis subunit vaccine candidate consisting of the ESAT-6:CFP-10 complex.

    PubMed

    Farsiani, Hadi; Mosavat, Arman; Soleimanpour, Saman; Sadeghian, Hamid; Akbari Eydgahi, Mohammad Reza; Ghazvini, Kiarash; Sankian, Mojtaba; Aryan, Ehsan; Jamehdar, Saeid Amel; Rezaee, Seyed Abdolrahim

    2016-06-21

    Tuberculosis (TB) remains a major global health threat despite chemotherapy and Bacilli Calmette-Guérin (BCG) vaccination. Therefore, a safer and more effective vaccine against TB is urgently needed. This study evaluated the immunogenicity of a recombinant fusion protein consisting of early secreted antigenic target protein 6 kDa (ESAT-6), culture filtrate protein 10 kDa (CFP-10) and the Fc-domain of mouse IgG2a as a novel subunit vaccine. The recombinant expression vectors (pPICZαA-ESAT-6:CFP-10:Fcγ2a and pPICZαA-ESAT-6:CFP-10:His) were transferred into Pichia pastoris. After SDS-PAGE and immunoblotting, the immunogenicity of the recombinant proteins was evaluated in mice. When both recombinant proteins (ESAT-6:CFP-10:Fcγ2a and ESAT-6:CFP-10:His) were used for vaccination, Th1-type cellular responses were induced producing high levels of IFN-γ and IL-12. However, the Fc-tagged recombinant protein induced more effective Th1-type cellular responses with a small increase in IL-4 as compared to the BCG and ESAT-6:CFP-10:His groups. Moreover, mice primed with BCG and then supplemented with ESAT-6:CFP-10:Fcγ2a produced the highest levels of IFN-γ and IL-12 in immunized groups. The findings indicate that when Fcγ2a is fused to the ESAT-6:CFP-10 complex, as a delivery vehicle, there could be an increase in the immunogenicity of this type of subunit vaccine. Therefore, additional investigations are necessary for the development of appropriate Fc-based tuberculosis vaccines. PMID:27138226

  11. A human type 5 adenovirus-based tuberculosis vaccine induces robust T cell responses in humans despite preexisting anti-adenovirus immunity.

    PubMed

    Smaill, Fiona; Jeyanathan, Mangalakumari; Smieja, Marek; Medina, Maria Fe; Thanthrige-Don, Niroshan; Zganiacz, Anna; Yin, Cindy; Heriazon, Armando; Damjanovic, Daniela; Puri, Laura; Hamid, Jemila; Xie, Feng; Foley, Ronan; Bramson, Jonathan; Gauldie, Jack; Xing, Zhou

    2013-10-01

    There is an urgent need to develop new tuberculosis (TB) vaccines to safely and effectively boost Bacille Calmette-Guérin (BCG)-triggered T cell immunity in humans. AdHu5Ag85A is a recombinant human type 5 adenovirus (AdHu5)-based TB vaccine with demonstrated efficacy in a number of animal species, yet it remains to be translated to human applications. In this phase 1 study, we evaluated the safety and immunogenicity of AdHu5Ag85A in both BCG-naïve and previously BCG-immunized healthy adults. Intramuscular immunization of AdHu5Ag85A was safe and well tolerated in both trial volunteer groups. Moreover, although AdHu5Ag85A was immunogenic in both trial volunteer groups, it much more potently boosted polyfunctional CD4(+) and CD8(+) T cell immunity in previously BCG-vaccinated volunteers. Furthermore, despite prevalent preexisting anti-AdHu5 humoral immunity in most of the trial volunteers, we found little evidence that such preexisting anti-AdHu5 immunity significantly dampened the potency of AdHu5Ag85A vaccine. This study supports further clinical investigations of the AdHu5Ag85A vaccine for human applications. It also suggests that the widely perceived negative effect of preexisting anti-AdHu5 immunity may not be universally applied to all AdHu5-based vaccines against different types of human pathogens.

  12. Testing the H56 Vaccine Delivered in 4 Different Adjuvants as a BCG-Booster in a Non-Human Primate Model of Tuberculosis.

    PubMed

    Billeskov, Rolf; Tan, Esterlina V; Cang, Marjorie; Abalos, Rodolfo M; Burgos, Jasmin; Pedersen, Bo Vestergaard; Christensen, Dennis; Agger, Else Marie; Andersen, Peter

    2016-01-01

    The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study's main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB. PMID:27525651

  13. Testing the H56 Vaccine Delivered in 4 Different Adjuvants as a BCG-Booster in a Non-Human Primate Model of Tuberculosis

    PubMed Central

    Billeskov, Rolf; Tan, Esterlina V.; Cang, Marjorie; Abalos, Rodolfo M.; Burgos, Jasmin; Pedersen, Bo Vestergaard; Christensen, Dennis; Agger, Else Marie; Andersen, Peter

    2016-01-01

    The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study’s main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB. PMID:27525651

  14. High Sequence Variability of the ppE18 Gene of Clinical Mycobacterium tuberculosis Complex Strains Potentially Impacts Effectivity of Vaccine Candidate M72/AS01E.

    PubMed

    Homolka, Susanne; Ubben, Tanja; Niemann, Stefan

    2016-01-01

    The development of an effective vaccine is urgently needed to fight tuberculosis (TB) which is still the leading cause of death from a single infectious agent worldwide. One of the promising vaccine candidates M72/AS01E consists of two proteins subunits PepA and PPE18 coded by Rv0125 and Rv1196. However, preliminary data indicate a high level of sequence variability among clinical Mycobacterium tuberculosis complex (MTBC) strains that might have an impact on the vaccine efficacy. To further investigate this finding, we determined ppE18 sequence variability in a well-characterized reference collection of 71 MTBC strains from 23 phylogenetic lineages representing the global MTBC diversity. In total, 100 sequence variations consisting of 96 single nucleotide polymorphisms (SNPs), three insertions and one deletion were detected resulting in 141 variable positions distributed over the entire gene. The majority of SNPs detected were non-synonymous (n = 68 vs. n = 28 synonymous). Strains from animal adapted lineages, e.g., M. bovis, showed a significant higher diversity than the human pathogens such as M. tuberculosis Haarlem. SNP patterns specific for different lineages as well as for deeper branches in the phylogeny could be identified. The results of our study demonstrate a high variability of the ppE18 gene even in the N-terminal domains that is normally highly conserved in ppe genes. As the N-terminal region interacts with TLR2 receptor inducing a protective anti-inflammatory immune response, genetic heterogeneity has a potential impact on the vaccine efficiency, however, this has to be investigated in future studies.

  15. U.S. College and University Student Health Screening Requirements for Tuberculosis and Vaccine-Preventable Diseases, 2012

    PubMed Central

    Jewett, A.; Bell, T; Cohen, NJ.; Buckley, K.; Leino, V.; Even, S.; Beavers, S.; Brown, C.; Marano, N.

    2016-01-01

    Objective Colleges are at risk for communicable disease outbreaks because of the high degree of person-to-person interactions and relatively crowded dormitory settings. This report describes the U.S. college student health screening requirements among U.S. resident and international students for tuberculosis (TB) and vaccine-preventable diseases (VPD) as it relates to the American College Health Association (ACHA) Guidelines. Methods/Participants In April 2012, U.S. college health administrators (N=2858) were sent online surveys to assess their respective school’s TB screening and immunization requirements. Results Surveys were completed by 308 (11%) schools. Most schools were aware of the ACHA immunization (78%) and TB screening (76%) guidelines. Schools reported having policies related to immunization screening (80.4%), immunization compliance (93%), TB screening (55%), and TB compliance (87%). Conclusion Most colleges were following ACHA guidelines. However, there are opportunities for improvement to fully utilize the recommendations and prevent outbreaks of communicable diseases among students in colleges. PMID:26730492

  16. A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults

    PubMed Central

    Satti, Iman; Hokey, David A.; Dheenadhayalan, Veerabadran; Stockdale, Lisa; Manjaly Thomas, Zita-Rose; Minhinnick, Alice; Wilkie, Morven; Vermaak, Samantha; Meyer, Joel; O’Shea, Matthew K.; Pau, Maria Grazia; Versteege, Isabella; Douoguih, Macaya; Hendriks, Jenny; Sadoff, Jerald; Landry, Bernard; Moss, Paul; McShane, Helen

    2015-01-01

    Background MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB. Methods In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402. Results Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A. Conclusions Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries. Trial Registration ClinicalTrials.gov NCT01683773. PMID:26529238

  17. Differential Mycobacterium bovis BCG Vaccine-Derived Efficacy in C3Heb/FeJ and C3H/HeOuJ Mice Exposed to a Clinical Strain of Mycobacterium tuberculosis

    PubMed Central

    Henao-Tamayo, Marcela; Obregón-Henao, Andrés; Creissen, Elizabeth; Shanley, Crystal; Orme, Ian

    2014-01-01

    The global epidemic caused by the bacterial pathogen Mycobacterium tuberculosis continues unabated. Moreover, the only available vaccine against tuberculosis, Mycobacterium bovis bacillus Calmette-Guérin (BCG), demonstrates variable efficacy. To respond to this global threat, new animal models that mimic the pathological disease process in humans are required for vaccine testing. One new model, susceptible C3Heb/FeJ mice, is similar to human tuberculosis in that these animals are capable of forming necrotic tubercle granulomas, in contrast to resistant C3H/HeOuJ mice. In this study, we evaluated the impact of prior BCG vaccination of C3Heb/FeJ and C3H/HeOuJ mice on exposure to a low-dose aerosol of Mycobacterium tuberculosis W-Beijing strain SA161. Both BCG-vaccinated murine strains demonstrated reduced bacterial loads 25 days after infection compared to controls, indicating vaccine efficacy. However, during chronic infection, vaccine efficacy waned in C3H/HeOuJ but not in C3Heb/FeJ mice. Protection in vaccinated C3Heb/FeJ mice was associated with reduced numbers of CD11b+ Gr1+ cells, increased numbers of effector and memory T cells, and an absence of necrotic granulomas. BCG vaccine efficacy waned in C3H/HeOuJ mice, as indicated by reduced expression of gamma interferon (IFN-γ) and increased expressions of interleukin-17 (IL-17), IL-10, and Foxp3 by T cells compared to C3Heb/FeJ mice. This is the first murine vaccine model system described to date that can be utilized to dissect differential vaccine-derived immune efficacy. PMID:25392011

  18. Differential Mycobacterium bovis BCG vaccine-derived efficacy in C3Heb/FeJ and C3H/HeOuJ mice exposed to a clinical strain of Mycobacterium tuberculosis.

    PubMed

    Henao-Tamayo, Marcela; Obregón-Henao, Andrés; Creissen, Elizabeth; Shanley, Crystal; Orme, Ian; Ordway, Diane J

    2015-01-01

    The global epidemic caused by the bacterial pathogen Mycobacterium tuberculosis continues unabated. Moreover, the only available vaccine against tuberculosis, Mycobacterium bovis bacillus Calmette-Guérin (BCG), demonstrates variable efficacy. To respond to this global threat, new animal models that mimic the pathological disease process in humans are required for vaccine testing. One new model, susceptible C3Heb/FeJ mice, is similar to human tuberculosis in that these animals are capable of forming necrotic tubercle granulomas, in contrast to resistant C3H/HeOuJ mice. In this study, we evaluated the impact of prior BCG vaccination of C3Heb/FeJ and C3H/HeOuJ mice on exposure to a low-dose aerosol of Mycobacterium tuberculosis W-Beijing strain SA161. Both BCG-vaccinated murine strains demonstrated reduced bacterial loads 25 days after infection compared to controls, indicating vaccine efficacy. However, during chronic infection, vaccine efficacy waned in C3H/HeOuJ but not in C3Heb/FeJ mice. Protection in vaccinated C3Heb/FeJ mice was associated with reduced numbers of CD11b(+) Gr1(+) cells, increased numbers of effector and memory T cells, and an absence of necrotic granulomas. BCG vaccine efficacy waned in C3H/HeOuJ mice, as indicated by reduced expression of gamma interferon (IFN-γ) and increased expressions of interleukin-17 (IL-17), IL-10, and Foxp3 by T cells compared to C3Heb/FeJ mice. This is the first murine vaccine model system described to date that can be utilized to dissect differential vaccine-derived immune efficacy.

  19. Bioinformatics of varicella-zoster virus: Single nucleotide polymorphisms define clades and attenuated vaccine genotypes

    PubMed Central

    Chow, Vincent T.; Tipples, Graham A.; Grose, Charles

    2012-01-01

    Varicella zoster virus (VZV) is one of the human herpesviruses. To date, over 40 complete VZV genomes have been sequenced and analyzed. The VZV genome contains around 125,000 base pairs including 70 open reading frames (ORFs). Enumeration of single nucleotide polymorphisms (SNPs) has determined that the following ORFs are the most variable (in descending order): 62, 22, 29, 28, 37, 21, 54, 31, 1 and 55. ORF 62 is the major immediate early regulatory VZV gene. Further SNP analysis across the entire genome has led to the observation that VZV strains can be broadly grouped into clades within a phylogenetic tree. VZV strains collected in Singapore provided important sequence data for construction of the phylogenetic tree. Currently 5 VZV clades are recognized; they have been designated clades 1 through 5. Clades 1 and 3 include European/North American strains; clade 2 includes Asian strains, especially from Japan; and clade 5 includes strains from India. Clade 4 includes some strains from Europe, but its geographic origins need further documentation.. Within clade 1, five variant viruses have been isolated with a missense mutation in the gE (ORF 68) glycoprotein; these strains have an altered increased cell spread phenotype. Bioinformatics analyses of the attenuated vaccine strains have also been performed, with a subsequent discovery of a stop-codon SNP in ORFO as a likely attenuation determinant. Taken together, these VZV bioinformatics analyses have provided enormous insights into VZV phylogenetics as well as VZV SNPs associated with attenuation. PMID:23183312

  20. Pulmonary immunity and durable protection induced by the ID93/GLA-SE vaccine candidate against the hyper-virulent Korean Beijing Mycobacterium tuberculosis strain K.

    PubMed

    Cha, Seung Bin; Kim, Woo Sik; Kim, Jong-Seok; Kim, Hongmin; Kwon, Kee Woong; Han, Seung Jung; Cho, Sang-Nae; Coler, Rhea N; Reed, Steven G; Shin, Sung Jae

    2016-04-27

    The majority of tuberculosis (TB) vaccine candidates advanced to clinical trials have been evaluated preclinically using laboratory-adapted strains. However, it has been proposed that challenge with clinical isolates in preclinical vaccine testing could provide further and more practical validation. Here, we tested the ID93/GLA-SE TB vaccine candidate against the clinical Mycobacterium tuberculosis (Mtb) strain K (Mtb K) belonging to the Beijing family, the most prevalent Mtb strain in South Korea. Mice immunized with ID93/GLA-SE exhibited a significant reduction in bacteria and reduced lung inflammation against Mtb K when compared to non-immunized controls. In addition, we analyzed the immune responses in the lungs of ID93/GLA-SE-immunized mice, and showed that ID93/GLA-SE was able to elicit sustained Th1-biased immune responses including antigen-specific multifunctional CD4(+) T cell co-producing IFN-γ, TNF-α, and IL-2 as well as a high magnitude of IFN-γ response for up to 10 weeks post-challenge. Notably, further investigation of T cell subsets in the lung following challenge showed remarkable generation of CD8(+) central memory T cells by ID93/GLA-SE-immunization. Our findings showed that ID93/GLA-SE vaccine confers a high level of robust protection against the hypervirulent Mtb Beijing infection which was characterized by pulmonary Th1-polarized T-cell immune responses. These findings may also provide relevant information for potential utility of this vaccine candidate in East-Asian countries where the Beijing genotype is highly prevalent.

  1. Cost-benefit analysis of vaccination against Mycobacterium avium ssp. paratuberculosis in dairy cattle, given its cross-reactivity with tuberculosis tests.

    PubMed

    Groenendaal, Huybert; Zagmutt, Francisco J; Patton, Elisabeth A; Wells, Scott J

    2015-09-01

    Johne's disease (JD), or paratuberculosis, is a chronic enteric disease of ruminants, caused by infection with Mycobacterium avium ssp. paratuberculosis (MAP). Johne's disease causes considerable economic losses to the US dairy industry, estimated to be over $200 million annually. Available control strategies include management measures to improve calf hygiene, test-and-cull strategies, and vaccination. Although the first 2 strategies have shown to reduce the prevalence of MAP, they require dedicated and long-term efforts from dairy producers, with often relatively slow progress. As a result, uptake of both strategies has not been as wide as expected given the economic benefits especially of improved hygiene. Vaccination has also been found to reduce the prevalence and economic losses of JD, but most economic estimates have been based on simulation of hypothetical vaccines. In addition, if an animal is vaccinated, cross-reactivity between MAP antibodies and bovine tuberculosis (BTB) antigens may occur, decreasing the specificity of BTB tests. Therefore, MAP vaccination would cause additional indirect costs to the BTB surveillance and control program. The objective of the present study was to use data from a MAP vaccine trial together with an epidemiologic and economic model to estimate the direct on-farm benefits of MAP vaccination and to estimate the indirect costs of MAP vaccination due to the cross-reactivity with BTB tests. Direct economic benefits of MAP vaccination were estimated at $8.03 (90% predictive interval: -$25.97 to $41.36) per adult animal per year, all accruing to the dairy producers. This estimate is likely an underestimation of the true direct benefits of MAP vaccination. In addition, indirect economic costs due to cross-reactivity were $2.14 per adult animal per year, making MAP vaccination economically attractive. Only in regions or states with a high frequency of BTB testing (because of, for example, Mycobacterium bovis outbreaks in a wild

  2. Cost-benefit analysis of vaccination against Mycobacterium avium ssp. paratuberculosis in dairy cattle, given its cross-reactivity with tuberculosis tests.

    PubMed

    Groenendaal, Huybert; Zagmutt, Francisco J; Patton, Elisabeth A; Wells, Scott J

    2015-09-01

    Johne's disease (JD), or paratuberculosis, is a chronic enteric disease of ruminants, caused by infection with Mycobacterium avium ssp. paratuberculosis (MAP). Johne's disease causes considerable economic losses to the US dairy industry, estimated to be over $200 million annually. Available control strategies include management measures to improve calf hygiene, test-and-cull strategies, and vaccination. Although the first 2 strategies have shown to reduce the prevalence of MAP, they require dedicated and long-term efforts from dairy producers, with often relatively slow progress. As a result, uptake of both strategies has not been as wide as expected given the economic benefits especially of improved hygiene. Vaccination has also been found to reduce the prevalence and economic losses of JD, but most economic estimates have been based on simulation of hypothetical vaccines. In addition, if an animal is vaccinated, cross-reactivity between MAP antibodies and bovine tuberculosis (BTB) antigens may occur, decreasing the specificity of BTB tests. Therefore, MAP vaccination would cause additional indirect costs to the BTB surveillance and control program. The objective of the present study was to use data from a MAP vaccine trial together with an epidemiologic and economic model to estimate the direct on-farm benefits of MAP vaccination and to estimate the indirect costs of MAP vaccination due to the cross-reactivity with BTB tests. Direct economic benefits of MAP vaccination were estimated at $8.03 (90% predictive interval: -$25.97 to $41.36) per adult animal per year, all accruing to the dairy producers. This estimate is likely an underestimation of the true direct benefits of MAP vaccination. In addition, indirect economic costs due to cross-reactivity were $2.14 per adult animal per year, making MAP vaccination economically attractive. Only in regions or states with a high frequency of BTB testing (because of, for example, Mycobacterium bovis outbreaks in a wild

  3. Optimization and scale-up of cell culture and purification processes for production of an adenovirus-vectored tuberculosis vaccine candidate.

    PubMed

    Shen, Chun Fang; Jacob, Danielle; Zhu, Tao; Bernier, Alice; Shao, Zhongqi; Yu, Xuefeng; Patel, Mehul; Lanthier, Stephane; Kamen, Amine

    2016-06-17

    Tuberculosis (TB) is the second leading cause of death by infectious disease worldwide. The only available TB vaccine is the Bacille Calmette-Guerin (BCG). However, parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. AdAg85A, an adenoviral vector expressing the mycobacterial protein Ag85A, is a new tuberculosis vaccine candidate, and has shown promising results in pre-clinical studies and phase I trial. This adenovirus vectored vaccine is produced using HEK 293 cell culture. Here we report on the optimization of cell culture conditions, scale-up of production and purification of the AdAg85A at different scales. Four commercial serum-free media were evaluated under various conditions for supporting the growth of HEK293 cell and production of AdAg85A. A culturing strategy was employed to take advantages of two culture media with respective strengths in supporting the cell growth and virus production, which enabled to maintain virus productivity at higher cell densities and resulted in more than two folds of increases in culture titer. The production of AdAg85A was successfully scaled up and validated at 60L bioreactor under the optimal conditions. The AdAg85A generated from the 3L and 60L bioreactor runs was purified through several purification steps. More than 98% of total cellular proteins was removed, over 60% of viral particles was recovered after the purification process, and purity of AdAg85A was similar to that of the ATCC VR-1516 Ad5 standard. Vaccination of mice with the purified AdAg85A demonstrated a very good level of Ag85A-specific antibody responses. The optimized production and purification conditions were transferred to a GMP facility for manufacturing of AdAg85A for generation of clinical grade material to support clinical trials. PMID:27154390

  4. Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG ΔureC::hly Improves Protection against Tuberculosis

    PubMed Central

    Gengenbacher, Martin; Nieuwenhuizen, Natalie; Vogelzang, Alexis; Liu, Haipeng; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Wagner, Ina; Mollenkopf, Hans-Joachim

    2016-01-01

    ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. PMID:27222470

  5. Deep sequencing analysis of the heterogeneity of seed and commercial lots of the bacillus Calmette-Guérin (BCG) tuberculosis vaccine substrain Tokyo-172.

    PubMed

    Wada, Takayuki; Maruyama, Fumito; Iwamoto, Tomotada; Maeda, Shinji; Yamamoto, Taro; Nakagawa, Ichiro; Yamamoto, Saburo; Ohara, Naoya

    2015-12-04

    BCG, only vaccine available to prevent tuberculosis, was established in the early 20th century by prolonged passaging of a virulent clinical strain of Mycobacterium bovis. BCG Tokyo-172, originally distributed within Japan in 1924, is one of the currently used reference substrains for the vaccine. Recently, this substrain was reported to contain two spontaneously arising, heterogeneous subpopulations (Types I and II). The proportions of the subpopulations changed over time in both distributed seed lots and commercial lots. To maintain the homogeneity of live vaccines, such variations and subpopulational mutations in lots should be restrained and monitored. We incorporated deep sequencing techniques to validate such heterogeneity in lots of the BCG Tokyo-172 substrain without cloning. By bioinformatics analysis, we not only detected the two subpopulations but also detected two intrinsic variations within these populations. The intrinsic variants could be isolated from respective lots as colonies cultured on plate media, suggesting analyses incorporating deep sequencing techniques are powerful, valid tools to detect mutations in live bacterial vaccine lots. Our data showed that spontaneous mutations in BCG vaccines could be easily monitored by deep sequencing without direct isolation of variants, revealing the complex heterogeneity of BCG Tokyo-172 and its daughter lots currently in use.

  6. Deep sequencing analysis of the heterogeneity of seed and commercial lots of the bacillus Calmette-Guérin (BCG) tuberculosis vaccine substrain Tokyo-172.

    PubMed

    Wada, Takayuki; Maruyama, Fumito; Iwamoto, Tomotada; Maeda, Shinji; Yamamoto, Taro; Nakagawa, Ichiro; Yamamoto, Saburo; Ohara, Naoya

    2015-01-01

    BCG, only vaccine available to prevent tuberculosis, was established in the early 20th century by prolonged passaging of a virulent clinical strain of Mycobacterium bovis. BCG Tokyo-172, originally distributed within Japan in 1924, is one of the currently used reference substrains for the vaccine. Recently, this substrain was reported to contain two spontaneously arising, heterogeneous subpopulations (Types I and II). The proportions of the subpopulations changed over time in both distributed seed lots and commercial lots. To maintain the homogeneity of live vaccines, such variations and subpopulational mutations in lots should be restrained and monitored. We incorporated deep sequencing techniques to validate such heterogeneity in lots of the BCG Tokyo-172 substrain without cloning. By bioinformatics analysis, we not only detected the two subpopulations but also detected two intrinsic variations within these populations. The intrinsic variants could be isolated from respective lots as colonies cultured on plate media, suggesting analyses incorporating deep sequencing techniques are powerful, valid tools to detect mutations in live bacterial vaccine lots. Our data showed that spontaneous mutations in BCG vaccines could be easily monitored by deep sequencing without direct isolation of variants, revealing the complex heterogeneity of BCG Tokyo-172 and its daughter lots currently in use. PMID:26635118

  7. Vaccines

    MedlinePlus Videos and Cool Tools

    Vaccinations are injections of antigens into the body. Once the antigens enter the blood, they circulate along ... suppressor T cells stop the attack. After a vaccination, the body will have a memory of an ...

  8. Immunomodulatory nanoparticles from elastin-like recombinamers: single-molecules for tuberculosis vaccine development.

    PubMed

    García-Arévalo, Carmen; Bermejo-Martín, Jesús F; Rico, Lucia; Iglesias, Verónica; Martín, Laura; Rodríguez-Cabello, J Carlos; Arias, F Javier

    2013-02-01

    This study investigates both the physicochemical properties and immunogenicity of a genetically engineered elastin-like block corecombinamer (ELbcR) containing a major membrane protein sequence from Mycobacterium tuberculosis. The recombinant production of this ELbcR allows the production of large quantities of safe, antigenic particle-based constructs that directly and reversibly self-assemble into highly biocompatible, multivalent, monodisperse, and stable nanovesicles with a diameter of 55 nm from the same gene product using a highly efficient and cost-effective inverse transition cycling (ITC) procedure. The compositional complexity of these vesicles is retained after secondary processes such as endotoxin removal, sterilization, and lyophilization. An initial pro-chemotactic cytokine response (IL-1β) followed by a pro-Th2/IL-5 response was observed in mice plasma following subcutaneous administration of the antigen-loaded nanovesicles in mice. This biphasic model of cytokine production was coupled with humoral isotype switching from IgM- to IgG-specific antibodies against the antigen, which was only observed in the presence of both the antigen and the polymer in the same construct and in the absence of additional adjuvants.

  9. [Vaccination perspectives].

    PubMed

    Saliou, P; Plotkin, S

    1994-01-01

    The aim of vaccinology is to improve the available vaccines and to develop new ones in the light of progress in immunology, molecular biology and biotechnologies. But it must go beyond this, and aim to protect all populations and control diseases, even eradicate them where possible. New vaccine strategies must be developed taking into account the epidemiology of diseases and the inherent logistic problems of implementing these strategies under local conditions. There are three major thrusts to the progress of the discipline. The improvement of the vaccines available. One of the drives of vaccinology is not only to deliver vaccines of increasing safety (replacement of the current vaccine for whooping cough with an acellular vaccine for example), but also to improve vaccine efficacy and immunogenicity (in particular for flu, tuberculosis, cholera and rabies vaccines). The optimisation of vaccination programmes and strategies for vaccinations. The ideal is to protect against the greatest possible number of diseases with the smallest number of vaccinations. The development of combinations of vaccines is central to this goal. The objective for the year 2000 is a hexavalent vaccine DTPP Hib HB. The development of new vaccines. Classic techniques continue to be successfully used (inactivated hepatitis A vaccine; attenuated live vaccines for chicken pox and dengue fever; conjugated polyosidic bacterial vaccines for meningococci and Streptococcus pneumoniae). However, it will become possible to prepare vaccines against most transmissible diseases using genetic engineering techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults

    PubMed Central

    Minhinnick, Alice; Satti, Iman; Harris, Stephanie; Wilkie, Morven; Sheehan, Sharon; Stockdale, Lisa; Thomas, Zita-Rose Manjaly; Lopez-Ramon, Raquel; Poulton, Ian; Lawrie, Alison; Vermaak, Samantha; Le Vert, Alexandre; Del Campo, Judith; Hill, Fergal; Moss, Paul; McShane, Helen

    2016-01-01

    Introduction There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. Methods In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. Results The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. Conclusion MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited. This trial was registered on clinicatrials.gov ref. NCT01879163. PMID:26854906

  11. The contribution of hydrogen peroxide resistance to virulence of Mycobacterium tuberculosis during the first six days after intravenous infection of normal and BCG-vaccinated guinea-pigs.

    PubMed Central

    Jackett, P. S.; Aber, V. R.; Mitchison, D. A.; Lowrie, D. B.

    1981-01-01

    The course of infection with Mycobacterium tuberculosis strains H37Rv, H37Ra and their isoniazid-resistant, hydrogen peroxide-susceptible mutants in guinea-pig spleen and lung were assessed by measuring changes in number of viable bacteria during the first and second 3-day intervals after i.v. infection of normal and BCG-vaccinated animals. Vaccination had no effect on bacterial survival in the first 3 days of infection. The peroxide-susceptible mutants were killed or inhibited more than their parent strains; in normal animals this enhanced susceptibility was expressed equally during the first and second 3-day intervals while in vaccinated animals the effect was greater in the second 3-day interval. The results suggest that hydrogen peroxide is generated in significant amounts in the environment of tubercle bacilli lodged in normal tissues and in enhanced amounts when acquired immunity becomes expressed after a few days' lodgement in the tissues of vaccinated animals. Thus hydrogen peroxide resistance may contribute to virulence by protecting against both normal resident and immunologically activated macrophages. PMID:6784743

  12. Comparison of the Membrane Proteome of Virulent Mycobacterium tuberculosis and the Attenuated Mycobacterium bovis BCG Vaccine Strain by Label-free Quantitative Proteomics

    PubMed Central

    Gunawardena, Harsha P.; Feltcher, Meghan E.; Wrobel, John A.; Gu, Sheng; Braunstein, Miriam; Chen, Xian

    2015-01-01

    The Mycobacterium tuberculosis (MTB) membrane is rich in antigens that are potential targets for diagnostics and the development of new vaccines. To better understand the mechanisms underlying MTB virulence and identify new targets for therapeutic intervention we investigated the differential composition of membrane proteomes between virulent M. tuberculosis H37Rv (MTB) and the Mycobacterium bovis BCG vaccine strain. To compare the membrane proteomes, we used LC-MS/MS analysis in combination with label-free quantitative (LFQ) proteomics, utilizing the area-under-curve (AUC) of the extracted ion chromatograms (XIC) of peptides obtained from m/z and retention time alignment of MS1 features. With this approach, we obtained relative abundance ratios for 2,203 identified membrane-associated proteins in high confidence. Of these proteins, 294 showed statistically significant differences of at least 2 fold, in relative abundance between MTB and BCG membrane fractions. Our comparative analysis detected several proteins associated with known genomic regions of difference between MTB and BCG as being absent, which validated the accuracy of our approach. In further support of our label-free quantitative data, we verified select protein differences by immunoblotting. To our knowledge we have generated the first comprehensive and high coverage profile of comparative membrane proteome changes between virulent MTB and its attenuated relative BCG, which helps elucidate the proteomic basis of the intrinsic virulence of the MTB pathogen. PMID:24093440

  13. Increased TNF-alpha/IFN-gamma/IL-2 and decreased TNF-alpha/IFN-gamma production by central memory T cells are associated with protective responses against bovine tuberculosis following BCG vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Central memory T cells (Tcm’s) and polyfunctional CD4 T responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by ...

  14. A single dose of a DNA vaccine encoding apa coencapsulated with 6,6'-trehalose dimycolate in microspheres confers long-term protection against tuberculosis in Mycobacterium bovis BCG-primed mice.

    PubMed

    Carlétti, Dyego; Morais da Fonseca, Denise; Gembre, Ana Flávia; Masson, Ana Paula; Weijenborg Campos, Lívia; Leite, Luciana C C; Rodrigues Pires, Andréa; Lannes-Vieira, Joseli; Lopes Silva, Célio; Bonato, Vânia Luiza Deperon; Horn, Cynthia

    2013-08-01

    Mycobacterium bovis BCG prime DNA (Mycobacterium tuberculosis genes)-booster vaccinations have been shown to induce greater protection against tuberculosis (TB) than BCG alone. This heterologous prime-boost strategy is perhaps the most realistic vaccination for the future of TB infection control, especially in countries where TB is endemic. Moreover, a prime-boost regimen using biodegradable microspheres seems to be a promising immunization to stimulate a long-lasting immune response. The alanine proline antigen (Apa) is a highly immunogenic glycoprotein secreted by M. tuberculosis. This study investigated the immune protection of Apa DNA vaccine against intratracheal M. tuberculosis challenge in mice on the basis of a heterologous prime-boost regimen. BALB/c mice were subcutaneously primed with BCG and intramuscularly boosted with a single dose of plasmid carrying apa and 6,6'-trehalose dimycolate (TDM) adjuvant, coencapsulated in microspheres (BCG-APA), and were evaluated 30 and 70 days after challenge. This prime-boost strategy (BCG-APA) resulted in a significant reduction in the bacterial load in the lungs, thus leading to better preservation of the lung parenchyma, 70 days postinfection compared to BCG vaccinated mice. The profound effect of this heterologous prime-boost regimen in the experimental model supports its development as a feasible strategy for prevention of TB.

  15. Hypersensitivity and vaccines: an update.

    PubMed

    Barbaud, Annick; Deschildre, Antoine; Waton, Julie; Raison-Peyron, Nadia; Tréchot, Philippe

    2013-04-01

    Allergic reactions to vaccines can be classified as sensitivity to one of the vaccine components, pseudo-allergic reactions, often after hyperimmunization, and exacerbation of atopic symptoms or vasculitis. Pseudo-allergic reactions, some possibly due to hyperimmunization, are probably more common than true allergies. Atopic reactions should not be confused with the "flash" phenomenon, defined as an exacerbation of an allergic reaction due to a reduction in the allergic reactivity threshold following the vaccine injection. BCGitis occurs frequently, and for this reason, guidelines for Bacillus Calmette-Guérin (BCG) have been modified. The vaccine is now reserved for people at risk of exposure to Mycobacterium tuberculosis. This review provides an update on the vaccination modalities for people allergic to eggs, on the assessment that should be performed when a reaction occurs due to tetanus vaccination, on the urticaria after hepatitis vaccination, on an aluminum granuloma, which is more and more frequent in young children, and vasculitis after flu vaccination and BCGitis. The side effects associated with new, recently released vaccines, such as anti-influenza A H1N1 or anti-human papilloma virus (HPV) will also be presented.

  16. Hypersensitivity and vaccines: an update.

    PubMed

    Barbaud, Annick; Deschildre, Antoine; Waton, Julie; Raison-Peyron, Nadia; Tréchot, Philippe

    2013-04-01

    Allergic reactions to vaccines can be classified as sensitivity to one of the vaccine components, pseudo-allergic reactions, often after hyperimmunization, and exacerbation of atopic symptoms or vasculitis. Pseudo-allergic reactions, some possibly due to hyperimmunization, are probably more common than true allergies. Atopic reactions should not be confused with the "flash" phenomenon, defined as an exacerbation of an allergic reaction due to a reduction in the allergic reactivity threshold following the vaccine injection. BCGitis occurs frequently, and for this reason, guidelines for Bacillus Calmette-Guérin (BCG) have been modified. The vaccine is now reserved for people at risk of exposure to Mycobacterium tuberculosis. This review provides an update on the vaccination modalities for people allergic to eggs, on the assessment that should be performed when a reaction occurs due to tetanus vaccination, on the urticaria after hepatitis vaccination, on an aluminum granuloma, which is more and more frequent in young children, and vasculitis after flu vaccination and BCGitis. The side effects associated with new, recently released vaccines, such as anti-influenza A H1N1 or anti-human papilloma virus (HPV) will also be presented. PMID:23238161

  17. Comparative analysis of Bacillus subtilis spores and monophosphoryl lipid A as adjuvants of protein-based mycobacterium tuberculosis-based vaccines: partial requirement for interleukin-17a for induction of protective immunity.

    PubMed

    Esparza-Gonzalez, Sandra C; Troy, Amber R; Izzo, Angelo A

    2014-04-01

    The development of adjuvants for vaccines has become an important area of research as the number of protein-based vaccines against infectious pathogens increases. Currently, there are a number of adjuvant-based Mycobacterium tuberculosis vaccines in clinical trials that have shown efficacy in animal models. Despite these novel adjuvants, there is still a need to design new and more versatile adjuvants that have minimal adverse side effects but produce robust long-lasting adaptive immune responses. To this end, we hypothesized that Bacillus subtilis spores may provide the appropriate innate signals that are required to generate such vaccine-mediated responses, which would be sufficient to reduce the mycobacterial burden after infection with M. tuberculosis. In addition, we compared the response generated by B. subtilis spores to that generated by monophosphoryl lipid A (MPL), which has been used extensively to test tuberculosis vaccines. The well-characterized, 6-kDa early secretory antigenic target of M. tuberculosis (ESAT-6; Rv3875) was used as a test antigen to determine the T cell activation potential of each adjuvant. Inoculated into mice, B. subtilis spores induced a strong proinflammatory response and Th1 immunity, similar to MPL; however, unlike MPL formulated with dimethyldioctadecylammonium (DDA) bromide, it failed to induce significant levels of interleukin-17A (IL-17A) and was unable to significantly reduce the mycobacterial burden after pulmonary infection with M. tuberculosis. Further analysis of the activity of MPL-DDA suggested that IL-17A was required for protective immunity. Taken together, the data emphasize the requirement for a network of cytokines that are essential for protective immunity.

  18. Comparative Analysis of Bacillus subtilis Spores and Monophosphoryl Lipid A as Adjuvants of Protein-Based Mycobacterium tuberculosis-Based Vaccines: Partial Requirement for Interleukin-17A for Induction of Protective Immunity

    PubMed Central

    Esparza-Gonzalez, Sandra C.; Troy, Amber R.

    2014-01-01

    The development of adjuvants for vaccines has become an important area of research as the number of protein-based vaccines against infectious pathogens increases. Currently, there are a number of adjuvant-based Mycobacterium tuberculosis vaccines in clinical trials that have shown efficacy in animal models. Despite these novel adjuvants, there is still a need to design new and more versatile adjuvants that have minimal adverse side effects but produce robust long-lasting adaptive immune responses. To this end, we hypothesized that Bacillus subtilis spores may provide the appropriate innate signals that are required to generate such vaccine-mediated responses, which would be sufficient to reduce the mycobacterial burden after infection with M. tuberculosis. In addition, we compared the response generated by B. subtilis spores to that generated by monophosphoryl lipid A (MPL), which has been used extensively to test tuberculosis vaccines. The well-characterized, 6-kDa early secretory antigenic target of M. tuberculosis (ESAT-6; Rv3875) was used as a test antigen to determine the T cell activation potential of each adjuvant. Inoculated into mice, B. subtilis spores induced a strong proinflammatory response and Th1 immunity, similar to MPL; however, unlike MPL formulated with dimethyldioctadecylammonium (DDA) bromide, it failed to induce significant levels of interleukin-17A (IL-17A) and was unable to significantly reduce the mycobacterial burden after pulmonary infection with M. tuberculosis. Further analysis of the activity of MPL-DDA suggested that IL-17A was required for protective immunity. Taken together, the data emphasize the requirement for a network of cytokines that are essential for protective immunity. PMID:24477855

  19. [VACCINES].

    PubMed

    Bellver Capella, Vincente

    2015-10-01

    Vaccines are an extraordinary instrument of immunization of the population against infectious diseases. Around them there are many ethical issues. One of the most debated is what to do with certain groups opposition to vaccination of their children. States have managed in different ways the conflict between the duty of vaccination and the refusal to use vaccines: some impose the vaccination and others simply promote it. In this article we deal with which of these two approaches is the most suitable from an ethical and legal point of view. We stand up for the second option, which is the current one in Spain, and we propose some measures which should be kept in mind to improve immunization programs.

  20. Autophagy-targeted vaccine of LC3-LpqH DNA and its protective immunity in a murine model of tuberculosis.

    PubMed

    Hu, Dong; Wu, Jing; Zhang, Rongbo; Chen, Liping; Chen, Zhaoquan; Wang, Xuefeng; Xu, Lifa; Xiao, Jian; Hu, Fengyu; Wu, Changyou

    2014-04-25

    The development of more effective antituberculosis vaccines would contribute to the control of the global problem of infection with Mycobacterium tuberculosis (MTB). Recently, the highlighted importance of autophagy in the host immune response against MTB has attracted the attention of researchers. However, the vaccines targeted at autophagy remain to be developed. In this study, we report on an autophagy-targeted vaccine of 19kDa MTB lipoprotein (LpqH) DNA that harbors another gene coding microtubule-associated protein light chain-3(LC3), which transports LpqH to autophagosomes and displays enhanced protective efficacy against MTB. After the transfection of pCMV-LpqH DNA, a significant increase LC3 II was detected in RAW264.7 cells, which was similar to that observed with treatment with rapamycin, a reagent used to induce autophagy. To target autophagy, the gene coding LC3, as a marked protein of autophagosome, was linked to the lpqH gene to express an LC3-LpqH fused protein. Interestingly, LC3-LpqH fused protein was determined to be transported to an autophagosome, which was demonstrated by the co-localization of GFP-LC3 with LC3-LpqH at autophagosomes. Notably, the mice immunized with LC3-LpqH/Ag85B displayed decreased mycobacterial loads in the lungs and spleen when challenged with virulent MTB by intravenous infection, which was consistent with increased IgG2a in serum and IFN-γ and IL-2 produced by splenocyte. In conclusion, our study demonstrates that an LC3-LpqH DNA vaccine could have autophagy as its target, which contributes to the enhancement of the Th1 immune response and vaccine protective efficacy.

  1. Vaxar: A Web-Based Database of Laboratory Animal Responses to Vaccinations and Its Application in the Meta-Analysis of Different Animal Responses to Tuberculosis Vaccinations

    PubMed Central

    Todd, Thomas; Dunn, Natalie; Xiang, Zuoshuang; He, Yongqun

    2016-01-01

    Animal models are indispensable for vaccine research and development. However, choosing which species to use and designing a vaccine study that is optimized for that species is often challenging. Vaxar (http://www.violinet.org/vaxar/) is a web-based database and analysis system that stores manually curated data regarding vaccine-induced responses in animals. To date, Vaxar encompasses models from 35 animal species including rodents, rabbits, ferrets, primates, and birds. These 35 species have been used to study more than 1300 experimentally tested vaccines for 164 pathogens and diseases significant to humans and domestic animals. The responses to vaccines by animals in more than 1500 experimental studies are recorded in Vaxar; these data can be used for systematic meta-analysis of various animal responses to a particular vaccine. For example, several variables, including animal strain, animal age, and the dose or route of either vaccination or challenge, might affect host response outcomes. Vaxar can also be used to identify variables that affect responses to different vaccines in a specific animal model. All data stored in Vaxar are publically available for web-based queries and analyses. Overall Vaxar provides a unique systematic approach for understanding vaccine-induced host immunity. PMID:27053566

  2. Protecting capacity against malaria of chemically defined tetramer forms based on the Plasmodium falciparum apical sushi protein as potential vaccine components.

    PubMed

    Vanegas, Magnolia; Bermúdez, Adriana; Guerrero, Yuly Andrea; Cortes-Vecino, Jesús Alfredo; Curtidor, Hernando; Patarroyo, Manuel Elkin; Lozano, José Manuel

    2014-08-15

    Developing novel generations of subunit-based antimalarial vaccines in the form of chemically-defined macromolecule systems for multiple antigen presentation represents a classical problem in the field of vaccine development. Many efforts involving synthesis strategies leading to macromolecule constructs have been based on dendrimer-like systems, the condensation of large building blocks and conventional asymmetric double dimer constructs, all based on lysine cores. This work describes novel symmetric double dimer and condensed linear constructs for presenting selected peptide multi-copies from the apical sushi protein expressed in Plasmodium falciparum. These molecules have been proved to be safe and innocuous, highly antigenic and have shown strong protective efficacy in rodents challenged with two Plasmodium species. Insights into systematic design, synthesis and characterisation have led to such novel antigen systems being used as potential platforms for developing new anti-malarial vaccine candidates.

  3. Protecting capacity against malaria of chemically defined tetramer forms based on the Plasmodium falciparum apical sushi protein as potential vaccine components.

    PubMed

    Vanegas, Magnolia; Bermúdez, Adriana; Guerrero, Yuly Andrea; Cortes-Vecino, Jesús Alfredo; Curtidor, Hernando; Patarroyo, Manuel Elkin; Lozano, José Manuel

    2014-08-15

    Developing novel generations of subunit-based antimalarial vaccines in the form of chemically-defined macromolecule systems for multiple antigen presentation represents a classical problem in the field of vaccine development. Many efforts involving synthesis strategies leading to macromolecule constructs have been based on dendrimer-like systems, the condensation of large building blocks and conventional asymmetric double dimer constructs, all based on lysine cores. This work describes novel symmetric double dimer and condensed linear constructs for presenting selected peptide multi-copies from the apical sushi protein expressed in Plasmodium falciparum. These molecules have been proved to be safe and innocuous, highly antigenic and have shown strong protective efficacy in rodents challenged with two Plasmodium species. Insights into systematic design, synthesis and characterisation have led to such novel antigen systems being used as potential platforms for developing new anti-malarial vaccine candidates. PMID:25063026

  4. A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults

    PubMed Central

    Kumarasamy, Nagalingeswaran; Poongulali, Selvamuthu; Bollaerts, Anne; Moris, Philippe; Beulah, Faith Esther; Ayuk, Leo Njock; Demoitié, Marie-Ange; Jongert, Erik; Ofori-Anyinam, Opokua

    2016-01-01

    Abstract Human immunodeficiency virus (HIV)-associated tuberculosis is a major public health threat. We evaluated the safety and immunogenicity of the candidate tuberculosis vaccine M72/AS01 in HIV-positive and HIV-negative Indian adults. Randomized, controlled observer-blind trial (NCT01262976). We assigned 240 adults (1:1:1) to antiretroviral therapy (ART)-stable, ART-naive, or HIV-negative cohorts. Cohorts were randomized 1:1 to receive M72/AS01 or placebo following a 0, 1-month schedule and followed for 12 months (time-point M13). HIV-specific and laboratory safety parameters, adverse events (AEs), and M72-specific T-cell-mediated and humoral responses were evaluated. Subjects were predominantly QuantiFERON-negative (60%) and Bacille Calmette–Guérin-vaccinated (73%). Seventy ART-stable, 73 ART-naive, and 60 HIV-negative subjects completed year 1. No vaccine-related serious AEs or ART-regimen adjustments, or clinically relevant effects on laboratory parameters, HIV-1 viral loads or CD4 counts were recorded. Two ART-naive vaccinees died of vaccine-unrelated diseases. M72/AS01 induced polyfunctional M72-specific CD4+ T-cell responses (median [interquartile range] at 7 days postdose 2: ART-stable, 0.9% [0.7–1.5]; ART-naive, 0.5% [0.2–1.0]; and HIV-negative, 0.6% [0.4–1.1]), persisting at M13 (0.4% [0.2–0.5], 0.09% [0.04–0.2], and 0.1% [0.09–0.2], respectively). Median responses were higher in the ART-stable cohort versus ART-naive cohort from day 30 onwards (P ≤ 0.015). Among HIV-positive subjects (irrespective of ART-status), median responses were higher in QuantiFERON-positive versus QuantiFERON-negative subjects up to day 30 (P ≤ 0.040), but comparable thereafter. Cytokine-expression profiles were comparable between cohorts after dose 2. At M13, M72-specific IgG responses were higher in ART-stable and HIV-negative vaccinees versus ART-naive vaccinees (P ≤ 0.001). M72/AS01 was well-tolerated and immunogenic in this population of

  5. Accuracy of the QuantiFERON-TB Gold in Tube for diagnosing tuberculosis in a young pediatric population previously vaccinated with Bacille Calmette-Guérin

    PubMed Central

    Vallada, Marcelo Genofre; Okay, Thelma Suely; Del Negro, Gilda Maria B.; Antonio, Claudio Amaral; Yamamoto, Lidia; Ramos, Sonia Regina T. S.

    2014-01-01

    Objective: To evaluate the accuracy of an interferongamma release assay (QuantiFERON-TB Gold in Tube) for diagnosing Mycobacterium tuberculosis infection in a young pediatric population. Methods: 195 children previously vaccinated with BCG were evaluated, being 184 healthy individuals with no clinical or epidemiological evidence of mycobacterial infection, and 11 with Mycobacterium tuberculosis infection, according to clinical, radiological, and laboratory parameters. A blood sample was obtained from each child and processed according to the manufacturer's instructions. The assay performance was evaluated by a Receiver Operating Characteristic (ROC) curve. Results: In the group of 184 non-infected children, 130 (70.6%) were under the age of four years (mean age of 35 months). In this group, 177 children (96.2%) had negative test results, six (3.2%) had indeterminate results, and one (0.5%) had a positive result. In the group of 11 infected children, the mean age was 58.5 months, and two of them (18%) had negative results. The ROC curve had an area under the curve of 0.88 (95%CI 0.82-0.92; p<0.001), disclosing a predictive positive value of 81.8% for the test (95%CI 46.3-97.4). The assay sensitivity was 81.8% (95%CI 48.2-97.2) and the specificity was 98.8% (95%CI 96-99.8). Conclusions: In the present study, the QuantiFERON-TB Gold in Tube performance for diagnosing M. tuberculosis infection was appropriate in a young pediatric population. PMID:24676183

  6. Synergistic effect of bacillus calmette guerin and a tuberculosis subunit vaccine in cationic liposomes: increased immunogenicity and protection.

    PubMed

    Dietrich, Jes; Billeskov, Rolf; Doherty, T Mark; Andersen, Peter

    2007-03-15

    In the present work, we evaluated a new TB vaccine approach based on a combination of the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine and a subunit vaccine consisting of the proteins Ag85B and ESAT-6. We demonstrate that in addition to its vaccine efficacy BCG is an immune modulator that can potentiate a Th1 immune response better than the well-known adjuvant mono phosphoryl lipid A, leading to enhanced recognition of the subunit vaccine Ag85B-ESAT-6. Importantly, adding a vehicle to the vaccine, such as the cationic liposome dimethyl dioctadecyl ammonium bromide (DDA), significantly increased the potentiating effect of BCG. This synergistic effect between BCG and Ag85B-ESAT-6/liposome required drainage to the same lymph node of all vaccine components but did not require direct mixing of the components and was therefore also observed when BCG and Ag85B-ESAT-6/liposome were given as separate injections at sites draining to the same lymph node. The resulting optimized vaccine protocol consisting of BCG and subunit in liposomes (injected side by side) followed by boosting with the subunit in conventional adjuvant resulted in an impressive increase in the protective efficacy of up to 7-fold compared with BCG alone and 3-fold compared with unaugmented BCG boosted by the subunit vaccine. Thus, these studies suggest an immunization strategy where a novel TB subunit vaccine is administered as part of the child vaccination program together with BCG in neonates and followed by subunit boosting.

  7. A candidate gene approach for the genetic analysis of susceptibility to tuberculosis

    SciTech Connect

    Morgan, K.; Liu, J.; Boothroyd, L.

    1994-09-01

    Tuberculosis is the most frequent and severe human disease caused by mycobacteria. In the mouse a candidate gene for innate resistance to mycobacteria (Bcg) was recently isolated and termed Nramp. We used SSCA and DNA sequencing to identify mutations in the human homologue, NRAMP, in chromosome region 2q35 in order to test if NRAMP contributes to susceptibility to tuberculosis. We have identified 16 sequence variants in or near NRAMP and defined haplotypes segregating in multiplex tuberculosis families from Canada, Columbia and Hong Kong. We defined a recessive susceptibility model for linkage analysis with four liability classes which take into account clinical status, age, exposure, and BCG vaccination. Our preliminary results support a role of NRAMP in tuberculosis susceptibility in an epidemic situation. This research was supported by grants from the Medical Research Council of Canada and the Canadian Genetic Diseases Network.

  8. Evaluation of Mycobacterium bovis double knockout mce2-phoP as candidate vaccine against bovine tuberculosis.

    PubMed

    García, Elizabeth; Bianco, María V; Gravisaco, María José; Rocha, Rosana V; Blanco, Federico C; Bigi, Fabiana

    2015-03-01

    In this study, a Mycobacterium bovis knockout strain in phoP-phoR and mce2 operons was tested as an antituberculosis experimental vaccine in animal models. The double mutant strain was significantly more attenuated than the wild type strain in inmunocompetent and inmunodeficient mice. Vaccination with the double mutant protected mice against challenge with a virulent M. bovis strain.

  9. Head space analysis to non-invasively distinguish between vaccinated and bovine tuberculosis-infected white-tailed deer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    White-tailed deer (WTD; Odocoileus virginianus) can act as a reservoir for bovine tuberculosis (bTB), caused by Mycobacterium bovis, and can be a source of infection in cattle. Presently, no method exists to noninvasively monitor the presence of bTB in wildlife. In addition, due to similarities betw...

  10. Mycobacterium tuberculosis Pathogenesis and Molecular Determinants of Virulence

    PubMed Central

    Smith, Issar

    2003-01-01

    Tuberculosis (TB), one of the oldest known human diseases. is still is one of the major causes of mortality, since two million people die each year from this malady. TB has many manifestations, affecting bone, the central nervous system, and many other organ systems, but it is primarily a pulmonary disease that is initiated by the deposition of Mycobacterium tuberculosis, contained in aerosol droplets, onto lung alveolar surfaces. From this point, the progression of the disease can have several outcomes, determined largely by the response of the host immune system. The efficacy of this response is affected by intrinsic factors such as the genetics of the immune system as well as extrinsic factors, e.g., insults to the immune system and the nutritional and physiological state of the host. In addition, the pathogen may play a role in disease progression since some M. tuberculosis strains are reportedly more virulent than others, as defined by increased transmissibility as well as being associated with higher morbidity and mortality in infected individuals. Despite the widespread use of an attenuated live vaccine and several antibiotics, there is more TB than ever before, requiring new vaccines and drugs and more specific and rapid diagnostics. Researchers are utilizing information obtained from the complete sequence of the M. tuberculosis genome and from new genetic and physiological methods to identify targets in M. tuberculosis that will aid in the development of these sorely needed antitubercular agents. PMID:12857778

  11. Effect of bacillus Calmette-Guérin vaccination on CD4+Foxp3+ T cells during acquired immune response to Mycobacterium tuberculosis infection.

    PubMed

    Henao-Tamayo, Marcela I; Obregón-Henao, Andres; Arnett, Kimberly; Shanley, Crystal A; Podell, Brendan; Orme, Ian M; Ordway, Diane J

    2016-04-01

    Increasing information has shown that many newly emerging strains of Mycobacterium tuberculosis, including the highly prevalent and troublesome Beijing family of strains, can potently induce the emergence of Foxp3(+)CD4 Tregs Although the significance of this is still not fully understood, we have previously provided evidence that the emergence of this population can significantly ablate the protective effect of BCG vaccination, causing progressive fatal disease in the mouse model. However, whether the purpose of this response is to control inflammation or to directly dampen the acquired immune response is still unclear. In the present study, we have shown, using both cell depletion and adoptive transfer strategies, that Tregs can have either properties. Cell depletion resulted in a rapid, but transient, decrease in the lung bacterial load, suggesting release or temporary re-expansion of effector immunity. Transfer of Tregs into Rag2(-/-)or marked congenic mice worsened the disease course and depressed cellular influx of effector T cells into the lungs. Tregs from infected donors seemed to preferentially depress the inflammatory response and granulocytic influx. In contrast, those from BCG-vaccinated and then challenged donors seemed more focused on depression of acquired immunity. These qualitative differences might be related to increasing knowledge reflecting the plasticity of the Treg response.

  12. Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus

    PubMed Central

    Behar, Samuel M.; Carpenter, Stephen M.; Booty, Matthew G.; Barber, Daniel L.; Jayaraman, Pushpa

    2014-01-01

    Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease – the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. PMID:25311810

  13. KLRG1 and PD-1 expression are increased on T-cells following tuberculosis-treatment and identify cells with different proliferative capacities in BCG-vaccinated adults.

    PubMed

    Boer, Mardi C; van Meijgaarden, Krista E; Goletti, Delia; Vanini, Valentina; Prins, Corine; Ottenhoff, Tom H M; Joosten, Simone A

    2016-03-01

    In cancer and chronic infectious diseases, immune checkpoint-blockade of inhibitory receptors can enhance T-cell immunity. In tuberculosis (TB), a chronic infectious disease, prolonged antigen exposure can potentially drive terminal T-cell differentiation towards functional 'exhaustion': in human TB T-cells express PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein-4). However, in murine TB not PD-1 but rather killer cell lectin-like receptor subfamily-G1 (KLRG1) was a superior indicator of terminal T-cell differentiation. We therefore compared expression of KLRG1, PD-1 and CTLA-4 on T-cells in different stages of human TB, and also analysed their induction following BCG-vaccination. KLRG1, PD-1 and CTLA-4-expression were highest on in vitro BCG-stimulated CD4(+) T-cells following recent TB-treatment; KLRG1 and PD-1-expression on CD4(+) T-cells in active--but not latent--TB were only slightly increased compared to healthy donors. BCG-vaccination induced KLRG1-expression on BCG-stimulated CD8(+) but not CD4(+) T-cells, while neither PD-1 nor CTLA-4-expression increased. KLRG1-expressing CD8(+) T-cells exhibited markedly decreased proliferation, whereas PD-1(+) T-cells proliferated after in vitro BCG-stimulation. Thus, we demonstrate the presence of increased KLRG1-expressing T-cells in TB-treated individuals, and present KLRG1 as a marker of decreased human T-cell proliferation following BCG-vaccination. These results expand our understanding of cell-mediated immune control of mycobacterial infections.

  14. [Construction of fusion gene vaccine of WT1 multi-epitope fused with stimulating epitope of mycobacterium tuberculosis heat shock protein 70 and its expression and immunogenicity].

    PubMed

    Tian, Wei-Wei; Qiao, Zhen-Hua; Yang, Lin-Hua; Wang, Hong-Wei; Tang, Yan-Hong; Bian, Si-Cheng

    2011-04-01

    This study was purposed to construct a fusion DNA vaccine containing WT1 multi-epitope and stimulating epitope of mycobacterium tuberculosis heat shock protein 70 and to detect its expression and immunogenicity. On the basis of published data, a multi-epitope gene (Multi-WT1) containing three HLA *0201-restricted CTL epitopes: one HLA*2402-restricted CTL epitope, two Th epitopes and one universal Th Pan-DR epitope (PADRE) was constructed. DNA-coding sequence was modified by Computer-Aided Design (CAD) to optimize proteasome-mediated epitope processing through the introduction of different amino acid spacer sequences. The synthetic nucleotide sequence was then inserted into an eukaryotic vector to construct the plasmid pcDNA3.1-WT1.For enhancing CTL activity, HSP70 fragment including stimulatory domain P407-426 was amplified by PCR from mycobacterial HSP70 gene and cloned into pcDNA3.1(+). Then Multi-WT1 was fused to the N-terminal of pcDNA3.1-mHSP70(407-426) to make the multi-epitope fusion gene vaccine pcDNA3.1-WT1-mHSP70(407-426). HEK-293T cells were transfected with this vaccine and the expressed product was identified by RT-PCR. Enzyme-linked immunospot assay (ELISPOT) was used to evaluate the immunological responses elicited by vaccine. The results showed that the most of WT1 epitopes could be correctly cleaved which was confirmed by software Net Chop 3.1 and PAPROCIanalysis. RT-PCR showed correct expression of target gene in HEK293T cells and ELISPOT showed specific T-cell responses. It is concluded that the eukaryotic expression vector PcDNA3.1-WT1-mHSP70(407-426) fusion gene has been successfully constructed and the immunity response is also elicited, which is a good candidate for further research of DNA vaccine.

  15. Prime-boost vaccination with Bacillus Calmette Guerin and a recombinant adenovirus co-expressing CFP10, ESAT6, Ag85A and Ag85B of Mycobacterium tuberculosis induces robust antigen-specific immune responses in mice.

    PubMed

    Li, Wu; Li, Min; Deng, Guangcun; Zhao, Liping; Liu, Xiaoming; Wang, Yujiong

    2015-08-01

    Tuberculosis (TB) remains to be a prevalent health issue worldwide. At present, Mycobacterium bovis Bacillus Calmette Guerin (BCG) is the singular anti-TB vaccine available for the prevention of disease in humans; however, this vaccine only provides limited protection against Mycobacterium tuberculosis (Mtb) infection. Therefore, the development of alternative vaccines and strategies for increasing the efficacy of vaccination against TB are urgently required. The present study aimed to evaluate the ability of a recombinant adenoviral vector (Ad5-CEAB) co-expressing 10-kDa culture filtrate protein, 6-kDa early-secreted antigenic target, antigen 85 (Ag85)A and Ag85B of Mtb to boost immune responses following primary vaccination with BCG in mice. The mice were first subcutaneously primed with BCG and boosted with two doses of Ad5-CEAB via an intranasal route. The immunological effects of Ad5-CEAB boosted mice primed with BCG were then evaluated using a series of immunological indexes. The results demonstrated that the prime-boost strategy induced a potent antigen-specific immune response, which was primarily characterized by an enhanced T cell response and increased production of cytokines, including interferon-γ, tumor necrosis factor-α and interleukin-2, in mice. In addition, this vaccination strategy was demonstrated to have an elevated humoral response with increased concentrations of antigen-specific bronchoalveolar lavage secretory immunoglobulin (Ig)A and serum IgG in mice compared with those primed with BCG alone. These data suggested that the regimen of subcutaneous BCG prime and mucosal Ad5-CEAB boost was a novel strategy for inducing a broad range of antigen-specific immune responses to Mtb antigens in vivo, which may provide a promising strategy for further development of adenoviral-based vaccine against Mtb infection.

  16. Defining Catastrophic Costs and Comparing Their Importance for Adverse Tuberculosis Outcome with Multi-Drug Resistance: A Prospective Cohort Study, Peru

    PubMed Central

    Wingfield, Tom; Boccia, Delia; Tovar, Marco; Gavino, Arquímedes; Zevallos, Karine; Montoya, Rosario; Lönnroth, Knut; Evans, Carlton A.

    2014-01-01

    Background Even when tuberculosis (TB) treatment is free, hidden costs incurred by patients and their households (TB-affected households) may worsen poverty and health. Extreme TB-associated costs have been termed “catastrophic” but are poorly defined. We studied TB-affected households' hidden costs and their association with adverse TB outcome to create a clinically relevant definition of catastrophic costs. Methods and Findings From 26 October 2002 to 30 November 2009, TB patients (n = 876, 11% with multi-drug-resistant [MDR] TB) and healthy controls (n = 487) were recruited to a prospective cohort study in shantytowns in Lima, Peru. Patients were interviewed prior to and every 2–4 wk throughout treatment, recording direct (household expenses) and indirect (lost income) TB-related costs. Costs were expressed as a proportion of the household's annual income. In poorer households, costs were lower but constituted a higher proportion of the household's annual income: 27% (95% CI = 20%–43%) in the least-poor houses versus 48% (95% CI = 36%–50%) in the poorest. Adverse TB outcome was defined as death, treatment abandonment or treatment failure during therapy, or recurrence within 2 y. 23% (166/725) of patients with a defined treatment outcome had an adverse outcome. Total costs ≥20% of household annual income was defined as catastrophic because this threshold was most strongly associated with adverse TB outcome. Catastrophic costs were incurred by 345 households (39%). Having MDR TB was associated with a higher likelihood of incurring catastrophic costs (54% [95% CI = 43%–61%] versus 38% [95% CI = 34%–41%], p<0.003). Adverse outcome was independently associated with MDR TB (odds ratio [OR] = 8.4 [95% CI = 4.7–15], p<0.001), previous TB (OR = 2.1 [95% CI = 1.3–3.5], p = 0.005), days too unwell to work pre-treatment (OR = 1.01 [95% CI = 1.00–1.01], p = 0.02), and catastrophic costs (OR = 1

  17. Pulmonary Mycobacterium bovis BCG Vaccination Confers Dose-Dependent Superior Protection Compared to That of Subcutaneous Vaccination

    PubMed Central

    Aguilo, Nacho; Toledo, Ana Maria; Lopez-Roman, Eva Maria; Perez-Herran, Esther; Gormley, Eamonn; Rullas-Trincado, Joaquin; Angulo-Barturen, Iñigo

    2014-01-01

    Worldwide, the Mycobacterium bovis BCG vaccine is one of the most widely used vaccines. However, it appears to be ineffective in preventing pulmonary tuberculosis. Here, we show that pulmonary BCG vaccination of mice with a broad dose range provides superior protection against Mycobacterium tuberculosis challenge compared to that of subcutaneous vaccination. PMID:24501340

  18. Defining a protective epitope on factor H binding protein, a key meningococcal virulence factor and vaccine antigen.

    PubMed

    Malito, Enrico; Faleri, Agnese; Lo Surdo, Paola; Veggi, Daniele; Maruggi, Giulietta; Grassi, Eva; Cartocci, Elena; Bertoldi, Isabella; Genovese, Alessia; Santini, Laura; Romagnoli, Giacomo; Borgogni, Erica; Brier, Sébastien; Lo Passo, Carla; Domina, Maria; Castellino, Flora; Felici, Franco; van der Veen, Stijn; Johnson, Steven; Lea, Susan M; Tang, Christoph M; Pizza, Mariagrazia; Savino, Silvana; Norais, Nathalie; Rappuoli, Rino; Bottomley, Matthew J; Masignani, Vega

    2013-02-26

    Mapping of epitopes recognized by functional monoclonal antibodies (mAbs) is essential for understanding the nature of immune responses and designing improved vaccines, therapeutics, and diagnostics. In recent years, identification of B-cell epitopes targeted by neutralizing antibodies has facilitated the design of peptide-based vaccines against highly variable pathogens like HIV, respiratory syncytial virus, and Helicobacter pylori; however, none of these products has yet progressed into clinical stages. Linear epitopes identified by conventional mapping techniques only partially reflect the immunogenic properties of the epitope in its natural conformation, thus limiting the success of this approach. To investigate antigen-antibody interactions and assess the potential of the most common epitope mapping techniques, we generated a series of mAbs against factor H binding protein (fHbp), a key virulence factor and vaccine antigen of Neisseria meningitidis. The interaction of fHbp with the bactericidal mAb 12C1 was studied by various epitope mapping methods. Although a 12-residue epitope in the C terminus of fHbp was identified by both Peptide Scanning and Phage Display Library screening, other approaches, such as hydrogen/deuterium exchange mass spectrometry (MS) and X-ray crystallography, showed that mAb 12C1 occupies an area of ∼1,000 Å(2) on fHbp, including >20 fHbp residues distributed on both N- and C-terminal domains. Collectively, these data show that linear epitope mapping techniques provide useful but incomplete descriptions of B-cell epitopes, indicating that increased efforts to fully characterize antigen-antibody interfaces are required to understand and design effective immunogens.

  19. Defining a protective epitope on factor H binding protein, a key meningococcal virulence factor and vaccine antigen

    PubMed Central

    Malito, Enrico; Faleri, Agnese; Lo Surdo, Paola; Veggi, Daniele; Maruggi, Giulietta; Grassi, Eva; Cartocci, Elena; Bertoldi, Isabella; Genovese, Alessia; Santini, Laura; Romagnoli, Giacomo; Borgogni, Erica; Brier, Sébastien; Lo Passo, Carla; Domina, Maria; Castellino, Flora; Felici, Franco; van der Veen, Stijn; Johnson, Steven; Lea, Susan M.; Tang, Christoph M.; Pizza, Mariagrazia; Savino, Silvana; Norais, Nathalie; Rappuoli, Rino; Bottomley, Matthew J.; Masignani, Vega

    2013-01-01

    Mapping of epitopes recognized by functional monoclonal antibodies (mAbs) is essential for understanding the nature of immune responses and designing improved vaccines, therapeutics, and diagnostics. In recent years, identification of B-cell epitopes targeted by neutralizing antibodies has facilitated the design of peptide-based vaccines against highly variable pathogens like HIV, respiratory syncytial virus, and Helicobacter pylori; however, none of these products has yet progressed into clinical stages. Linear epitopes identified by conventional mapping techniques only partially reflect the immunogenic properties of the epitope in its natural conformation, thus limiting the success of this approach. To investigate antigen–antibody interactions and assess the potential of the most common epitope mapping techniques, we generated a series of mAbs against factor H binding protein (fHbp), a key virulence factor and vaccine antigen of Neisseria meningitidis. The interaction of fHbp with the bactericidal mAb 12C1 was studied by various epitope mapping methods. Although a 12-residue epitope in the C terminus of fHbp was identified by both Peptide Scanning and Phage Display Library screening, other approaches, such as hydrogen/deuterium exchange mass spectrometry (MS) and X-ray crystallography, showed that mAb 12C1 occupies an area of ∼1,000 Å2 on fHbp, including >20 fHbp residues distributed on both N- and C-terminal domains. Collectively, these data show that linear epitope mapping techniques provide useful but incomplete descriptions of B-cell epitopes, indicating that increased efforts to fully characterize antigen–antibody interfaces are required to understand and design effective immunogens. PMID:23396847

  20. Peptide-specific T helper cells identified by MHC class II tetramers differentiate into several subtypes upon immunization with CAF01 adjuvanted H56 tuberculosis vaccine formulation.

    PubMed

    Prota, Gennaro; Christensen, Dennis; Andersen, Peter; Medaglini, Donata; Ciabattini, Annalisa

    2015-11-27

    CD4(+) T-cell priming is an essential step in vaccination due to the key role of T helper cells in driving both effector and memory immune responses. Here we have characterized in C57BL/6 mice the T helper subtype differentiation among tetramer-specific CD4(+) T cells primed by subcutaneous immunization with the tuberculosis vaccine antigen H56 plus the adjuvant CAF01. Peptide-specific population identified by the MHC class II tetramers differentiated into several T helper subtypes upon antigen encounter, and the frequency of subpopulations differed according to their localization. Th1 (CXCR3(+)T-bet(+)), Tfh (CXCR5(+)PD-1(+)Bcl-6(+)) and RORγt(+) cells were induced in the lymph nodes draining the immunization site (dLN), while Th1 cells were the predominant subtype in the spleen. In addition, CD4(+) T cells co-expressing multiple T-cell lineage-specifying transcription factors were also detected. In the lungs, most of the tetramer-binding T cells were RORγt(+), while Tfh and Th1 cells were absent. After boosting, a higher frequency of tetramer-binding cells co-expressing the markers CD44 and CD127 was detected compared to primed cells, and cells showed a prevalent Th1 phenotype in both dLN and spleens, while Tfh cells were significantly reduced. In conclusion, these data demonstrate that parenteral immunization with H56 and CAF01 elicits a distribution of antigen-specific CD4(+) T cells in both lymphoid tissues and lungs, and gives rise to multiple T helper subtypes, that differ depending on localization and following reactivation.

  1. Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment.

    PubMed

    Alyahya, S Anisah; Nolan, Scott T; Smith, Cara M R; Bishai, William R; Sadoff, Jerald; Lamichhane, Gyanu

    2015-01-01

    To investigate if bacterial persistence during TB drug treatment could be overcome by modulation of host immunity, we adapted a clinically-relevant model developed for the evaluation of new drugs and examined if immunotherapy with two adenoviral vaccines, Ad35-TBS (AERAS-402) and Ad26-TBS, could shorten therapy in mice. Even though immunotherapy resulted in strong splenic IFN-γ responses, no effect on bacterial replication in the lungs was seen. Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-γ, TNF-α and IL-2, suggesting that immunization failed to induce immunity in the lungs. In this model, we show that IFN-γ levels were not associated with protection against disease relapse. The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies. PMID:25996375

  2. Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment

    PubMed Central

    Alyahya, S. Anisah; Nolan, Scott T.; Smith, Cara M. R.; Bishai, William R.; Sadoff, Jerald; Lamichhane, Gyanu

    2015-01-01

    To investigate if bacterial persistence during TB drug treatment could be overcome by modulation of host immunity, we adapted a clinically-relevant model developed for the evaluation of new drugs and examined if immunotherapy with two adenoviral vaccines, Ad35-TBS (AERAS-402) and Ad26-TBS, could shorten therapy in mice. Even though immunotherapy resulted in strong splenic IFN-γ responses, no effect on bacterial replication in the lungs was seen. Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-γ, TNF-α and IL-2, suggesting that immunization failed to induce immunity in the lungs. In this model, we show that IFN-γ levels were not associated with protection against disease relapse. The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies. PMID:25996375

  3. Defining risk groups to yellow fever vaccine-associated viscerotropic disease in the absence of denominator data.

    PubMed

    Seligman, Stephen J; Cohen, Joel E; Itan, Yuval; Casanova, Jean-Laurent; Pezzullo, John C

    2014-02-01

    Several risk groups are known for the rare but serious, frequently fatal, viscerotropic reactions following live yellow fever virus vaccine (YEL-AVD). Establishing additional risk groups is hampered by ignorance of the numbers of vaccinees in factor-specific risk groups thus preventing their use as denominators in odds ratios (ORs). Here, we use an equation to calculate ORs using the prevalence of the factor-specific risk group in the population who remain well. The 95% confidence limits and P values can also be calculated. Moreover, if the estimate of the prevalence is imprecise, discrimination analysis can indicate the prevalence at which the confidence interval results in an OR of ∼1 revealing if the prevalence might be higher without yielding a non-significant result. These methods confirm some potential risk groups for YEL-AVD and cast doubt on another. They should prove useful in situations in which factor-specific risk group denominator data are not available.

  4. Protection against Mycobacterium tuberculosis Infection Offered by a New Multistage Subunit Vaccine Correlates with Increased Number of IFN-γ+IL-2+ CD4+ and IFN-γ+ CD8+ T Cells

    PubMed Central

    Wang, Xiaochun; Zhang, Jingyan; Liang, Jinping; Zhang, Ying; Teng, Xindong; Yuan, Xuefeng; Fan, Xionglin

    2015-01-01

    Protein subunit vaccines present a compelling new area of research for control of tuberculosis (TB). Based on the interaction between Mycobacterium tuberculosis and its host, five stage-specific antigens of M. tuberculosis that participate in TB pathogenesis—Rv1813, Rv2660c, Ag85B, Rv2623, and HspX—were selected. These antigens were verified to be recognized by T cells from a total of 42 whole blood samples obtained from active TB patients, patients with latent TB infections (LTBIs), and healthy control donors. The multistage polyprotein A1D4 was developed using the selected five antigens as a potentially more effective novel subunit vaccine. The immunogenicity and protective efficacy of A1D4 emulsified in the adjuvant MTO [monophosphoryl lipid A (MPL), trehalose-6,6′-dibehenate (TDB), components of MF59] was compared with Bacillus Calmette-Guerin (BCG) in C57BL/6 mice. Our results demonstrated that A1D4/MTO could provide more significant protection against M. tuberculosis infection than the PBS control or MTO adjuvant alone judging from the A1D4-specific Th1-type immune response; however, its efficacy was inferior to BCG as demonstrated by the bacterial load in the lung and spleen, and by the pathological changes in the lung. Antigen-specific single IL-2-secreting cells and different combinations with IL-2-secreting CD4+ T cells were beneficial and correlated with BCG vaccine-induced protection against TB. Antigen-specific IFN-γ+IL-2+ CD4+ T cells were the only effective biomarker significantly induced by A1D4/MTO. Among all groups, A1D4/MTO immunization also conferred the highest number of antigen-specific single IFN-γ+ and IFN-γ+TNF-α+ CD4+ T cells, which might be related to the antigen load in vivo, and single IFN-γ+ CD8+ T cells by mimicking the immune patterns of LTBIs or curable TB patients. Our strategy seems promising for the development of a TB vaccine based on multistage antigens, and subunit antigen A1D4 suspended in MTO adjuvant warrants

  5. Increased TNF-α/IFN-γ/IL-2 and Decreased TNF-α/IFN-γ Production by Central Memory T Cells Are Associated with Protective Responses against Bovine Tuberculosis Following BCG Vaccination

    PubMed Central

    Maggioli, Mayara F.; Palmer, Mitchell V.; Thacker, Tyler C.; Vordermeier, Hans Martin; McGill, Jodi L.; Whelan, Adam O.; Larsen, Michelle H.; Jacobs, William R.; Waters, W. Ray

    2016-01-01

    Central memory T cell (Tcm) and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector/memory populations from bacille Calmette–Guerin (BCG) vaccinated and non-vaccinated calves by flow cytometry prior to and after aerosol challenge with virulent Mycobacterium bovis. Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and M. bovis-infected calves, only differing in magnitude (i.e., infected > vaccinated). BCG vaccination, however, did alter the kinetics of the ensuing response to virulent M. bovis infection. Early after challenge (3 weeks post-infection), non-vaccinates had greater antigen-specific interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α) and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains) were detected in memory subsets, as well as in effector cells, as early as 3 weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden, while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB. PMID:27799930

  6. Bacillus Calmette-Guerin (BCG) Vaccine

    MedlinePlus

    TheraCys® BCG ... TICE® BCG ... WHY is this medicine prescribed?BCG vaccine provides immunity or protection against tuberculosis (TB). The vaccine may be given to persons at high risk of developing TB. ...

  7. Defining Risk Groups to Yellow Fever Vaccine-Associated Viscerotropic Disease in the Absence of Denominator Data

    PubMed Central

    Seligman, Stephen J.; Cohen, Joel E.; Itan, Yuval; Casanova, Jean-Laurent; Pezzullo, John C.

    2014-01-01

    Several risk groups are known for the rare but serious, frequently fatal, viscerotropic reactions following live yellow fever virus vaccine (YEL-AVD). Establishing additional risk groups is hampered by ignorance of the numbers of vaccinees in factor-specific risk groups thus preventing their use as denominators in odds ratios (ORs). Here, we use an equation to calculate ORs using the prevalence of the factor-specific risk group in the population who remain well. The 95% confidence limits and P values can also be calculated. Moreover, if the estimate of the prevalence is imprecise, discrimination analysis can indicate the prevalence at which the confidence interval results in an OR of ∼1 revealing if the prevalence might be higher without yielding a non-significant result. These methods confirm some potential risk groups for YEL-AVD and cast doubt on another. They should prove useful in situations in which factor-specific risk group denominator data are not available. PMID:24394480

  8. Protective effect of Bacillus Calmette-Guerin (BCG) vaccination in children with extra-pulmonary tuberculosis, but not the pulmonary disease. A case-control study in Rosario, Argentina.

    PubMed

    Bonifachich, Elena; Chort, Monica; Astigarraga, Ana; Diaz, Nora; Brunet, Beatriz; Pezzotto, Stella Maris; Bottasso, Oscar

    2006-04-01

    A hospital-based case-control study was carried out at the Vilela Children's Hospital in Rosario, Argentina, to measure the protection conferred by BCG vaccination against tuberculosis (TB). The study included 148 newly diagnosed cases of TB (75 males and 73 females, mean age 3.34+/-2.97 years, S.D.), 134 of them with pulmonary TB and 14 cases with extra-pulmonary disease. Controls (425 males and 357 females, 3.39+/-2.98 years) were selected randomly among children who attended to the Hospital showing, neither respiratory diseases nor any other infectious illnesses. Information on BCG vaccination history was assessed from scars or immunisation records. All participants were negative to human immunodeficiency virus and belonged to the lower and upper-lower socioeconomic status, being similar in place of residence and ethnic characteristics. Rate of vaccinated children was 92.6% of cases and 94.5% of controls (3.4 and 3.9% of them without scars, respectively). Regarding the total cases, the protective association between BCG and TB was statistically insignificant, as was for the pulmonary form. Among cases with extra-pulmonary disease, vaccine effectiveness attained significance [79% (95% CI=26-94)], no matter their age, sex or nutritional status. BCG vaccination exerted a beneficial role in extra-pulmonary TB, even in children not seriously undernourished.

  9. Multidrug-resistant to extensively drug resistant tuberculosis: what is next?

    PubMed

    Jain, Amita; Dixit, Pratima

    2008-11-01

    Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory,co-morbitidy of HIV and tuberculosis,new anti-TB drug regimens, better diagnostic tests,international standards for second line drugs (SLD)-susceptibility testing,invention of newer anti- tubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB. PMID:19208985

  10. Acceptability of BCG vaccination.

    PubMed

    Mande, R

    1977-01-01

    The acceptability of BCG vaccination varies a great deal according to the country and to the period when the vaccine is given. The incidence of complications has not always a direct influence on this acceptability, which depends, for a very large part, on the risk of tuberculosis in a given country at a given time.

  11. Emerging Vaccine Technologies

    PubMed Central

    Loomis, Rebecca J.; Johnson, Philip R.

    2015-01-01

    Vaccination has proven to be an invaluable means of preventing infectious diseases by reducing both incidence of disease and mortality. However, vaccines have not been effectively developed for many diseases including HIV-1, hepatitis C virus (HCV), tuberculosis and malaria, among others. The emergence of new technologies with a growing understanding of host-pathogen interactions and immunity may lead to efficacious vaccines against pathogens, previously thought impossible. PMID:26343196

  12. Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain

    PubMed Central

    Cha, Seung Bin; Kim, Hongmin; Kwon, Kee Woong; Kim, So Jeong; Han, Seung Jung; Choi, Soo Young; Cho, Sang-Nae; Park, Jong-Hwan; Shin, Sung Jae

    2016-01-01

    Identification of vaccine target antigens (Ags) that induce Ag-specific Th1 immunity is the first step toward the development of a tuberculosis vaccine. Here, we evaluated the Mycobacterium tuberculosis (Mtb) protein Rv3628, a soluble inorganic pyrophosphatase, as a vaccine target and characterized the molecular details of its interaction with dendritic cells (DCs). Rv3628 activated DCs, increasing their expression of cell surface molecules and augmenting their production of TNF-α, IL-1β, IL-6, and IL-12p70. Rv3628 mediated these effects by binding to TLR2 and activating downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. Rv3628-stimulated DCs induced the expansion of OVA-specific CD4+ and CD8+ T cells, which secreted IFN-γ and IL-2. Rv3628-specific effector/memory T cells expanded to a similar extent as those stimulated with ESAT-6 Ag in samples of lung and spleen cells collected from Mtb-infected mice. Finally, an Rv3628 subunit vaccine adjuvanted with dimethyldioctadecylammonium liposomes containing monophosphoryl lipid-A caused significant reductions in bacterial counts and lung inflammation after challenge with the hyper-virulent Mtb K strain. Importantly, protective efficacy was correlated with the generation of Rv3628-specific CD4+ T cells co-producing IFN-γ, TNF-α and IL-2 and exhibiting an elevated IFN-γ recall response. Thus, Rv3628 polarizes DCs toward a Th1 phenotype and promotes protective immunity against Mtb infection. PMID:27097115

  13. A rare cause of small bowel perforation by intestinal and peritoneal tuberculosis.

    PubMed

    Uranüs, S

    1990-02-01

    Tuberculosis of the intestine and peritoneum has become a rare disease. This is the result of a general decrease in pulmonary and extrapulmonary tuberculosis, rigorous BCG vaccination programs, and the eradication of tuberculosis in cattle. A case of tuberculosis in this frequent location, which was discovered unexpectedly during an emergency laparotomy, is reportet.

  14. Reprogramming the T Cell Response to Tuberculosis.

    PubMed

    Woodworth, Joshua S; Andersen, Peter

    2016-02-01

    Coscolla, Copin et al. recently used comparative genomics of M. tuberculosis (Mtb) strains to show that most human T cell-recognized epitopes are hyperconserved, but bona fide variable epitopes also exist. This identification of two sets of antigens implies opposing evolutionary processes and will have an important impact on tuberculosis (TB) vaccine strategy and design.

  15. Single Nucleotide Polymorphisms That Cause Structural Changes in the Cyclic AMP Receptor Protein Transcriptional Regulator of the Tuberculosis Vaccine Strain Mycobacterium bovis BCG Alter Global Gene Expression without Attenuating Growth▿

    PubMed Central

    Hunt, Debbie M.; Saldanha, José W.; Brennan, John F.; Benjamin, Pearline; Strom, Molly; Cole, Jeffrey A.; Spreadbury, Claire L.; Buxton, Roger S.

    2008-01-01

    Single nucleotide polymorphisms (SNPs) are present in the global transcriptional regulator cyclic AMP (cAMP) receptor protein (CRP) of the attenuated vaccine strain Mycobacterium bovis, bacillus Calmette-Guérin (BCG). We have found that these SNPs resulted in small but significant changes in the expression of a number of genes in M. tuberculosis when a deletion of the Rv3676 CRP was complemented by the BCG allele, compared to complementation by the M. tuberculosis allele. We can explain these changes in gene expression by modeling the structure of the mycobacterial protein on the known structure of CRP from Escherichia coli. Thus, the SNP change in the DNA-binding domain, Lys178, is predicted to form a hydrogen bond with the phosphate backbone of the DNA, as does the equivalent residue in E. coli, whereas Glu178 in M. tuberculosis/M. bovis does not, thus explaining the stronger binding reported for CRP of BCG to CRP-binding sites in mycobacterial DNA. In contrast, the SNP change in the nucleotide binding domain (Leu47Pro) is predicted to result in the loss of one hydrogen bond, which is accommodated by the structure, and would not therefore be expected to cause any change in function relating to cAMP binding. The BCG allele fully complemented the growth defect caused by the deletion of the Rv3676 protein in M. tuberculosis, both in vitro and in macrophage and mouse infections, suggesting that these SNPs do not play any role in the attenuation of BCG. However, they may have allowed BCG to grow better under the in vitro-selective conditions used in its derivation from the M. bovis wild type. PMID:18332206

  16. Rv3351c, a Mycobacterium tuberculosis gene that affects bacterial growth and alveolar epithelial cell viability.

    PubMed

    Pavlicek, Rebecca L; Fine-Coulson, Kari; Gupta, Tuhina; Quinn, Frederick D; Posey, James E; Willby, Melisa; Castro-Garza, Jorge; Karls, Russell K

    2015-12-01

    Despite the interactions known to occur between various lower respiratory tract pathogens and alveolar epithelial cells (AECs), few reports examine factors influencing the interplay between Mycobacterium tuberculosis bacilli and AECs during infection. Importantly, in vitro studies have demonstrated that the M. tuberculosis hbha and esxA gene products HBHA and ESAT6 directly or indirectly influence AEC survival. In this report, we identify Rv3351c as another M. tuberculosis gene that impacts the fate of both the pathogen and AEC host. Intracellular replication of an Rv3351c mutant in the human AEC type II pneumocyte cell line A549 was markedly reduced relative to the complemented mutant and parent strain. Deletion of Rv3351c diminished the release of lactate dehydrogenase and decreased uptake of trypan blue vital stain by host cells infected with M. tuberculosis bacilli, suggesting attenuated cytotoxic effects. Interestingly, an isogenic hbha mutant displayed reductions in AEC killing similar to those observed for the Rv3351c mutant. This opens the possibility that multiple M. tuberculosis gene products interact with AECs. We also observed that Rv3351c aids intracellular replication and survival of M. tuberculosis in macrophages. This places Rv3351c in the same standing as HBHA and ESAT6, which are important factors in AECs and macrophages. Defining the mechanism(s) by which Rv3351c functions to aid pathogen survival within the host may lead to new drug or vaccine targets.

  17. Antigens for CD4 and CD8 T Cells in Tuberculosis

    PubMed Central

    Lindestam Arlehamn, Cecilia S.; Lewinsohn, David; Sette, Alessandro; Lewinsohn, Deborah

    2014-01-01

    Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (MTB), represents an important cause of morbidity and mortality worldwide for which an improved vaccine and immunodiagnostics are urgently needed. CD4+ and CD8+ T cells play an important role in host defense to TB. Definition of the antigens recognized by these T cells is critical for improved understanding of the immunobiology of TB and for development of vaccines and diagnostics. Herein, the antigens and epitopes recognized by classically HLA class I– and II–restricted CD4+ and CD8+ T cells in humans infected with MTB are reviewed. Immunodominant antigens and epitopes have been defined using approaches targeting particular TB proteins or classes of proteins and by genome-wide discovery approaches. Antigens and epitopes recognized by classically restricted CD4+ and CD8+ T cells show extensive breadth and diversity in MTB-infected humans. PMID:24852051

  18. Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis.

    PubMed

    Coppola, Mariateresa; van den Eeden, Susan J F; Wilson, Louis; Franken, Kees L M C; Ottenhoff, Tom H M; Geluk, Annemieke

    2015-09-01

    Responsible for 9 million new cases of active disease and nearly 2 million deaths each year, tuberculosis (TB) remains a global health threat of overwhelming dimensions. Mycobacterium bovis BCG, the only licensed vaccine available, fails to confer lifelong protection and to prevent reactivation of latent infection. Although 15 new vaccine candidates are now in clinical trials, an effective vaccine against TB remains elusive, and new strategies for vaccination are vital. BCG vaccination fails to induce immunity against Mycobacterium tuberculosis latency antigens. Synthetic long peptides (SLPs) combined with adjuvants have been studied mostly for therapeutic cancer vaccines, yet not for TB, and proved to induce efficient antitumor immunity. This study investigated an SLP derived from Rv1733c, a major M. tuberculosis latency antigen which is highly expressed by "dormant" M. tuberculosis and well recognized by T cells from latently M. tuberculosis-infected individuals. In order to assess its in vivo immunogenicity and protective capacity, Rv1733c SLP in CpG was administered to HLA-DR3 transgenic mice. Immunization with Rv1733c SLP elicited gamma interferon-positive/tumor necrosis factor-positive (IFN-γ(+)/TNF(+)) and IFN-γ(+) CD4(+) T cells and Rv1733c-specific antibodies and led to a significant reduction in the bacterial load in the lungs of M. tuberculosis-challenged mice. This was observed both in a pre- and in a post-M. tuberculosis challenge setting. Moreover, Rv1733c SLP immunization significantly boosted the protective efficacy of BCG, demonstrating the potential of M. tuberculosis latency antigens to improve BCG efficacy. These data suggest a promising role for M. tuberculosis latency antigen Rv1733c-derived SLPs as a novel TB vaccine approach, both in a prophylactic and in a postinfection setting.

  19. Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis

    PubMed Central

    Coppola, Mariateresa; van den Eeden, Susan J. F.; Wilson, Louis; Franken, Kees L. M. C.; Ottenhoff, Tom H. M.

    2015-01-01

    Responsible for 9 million new cases of active disease and nearly 2 million deaths each year, tuberculosis (TB) remains a global health threat of overwhelming dimensions. Mycobacterium bovis BCG, the only licensed vaccine available, fails to confer lifelong protection and to prevent reactivation of latent infection. Although 15 new vaccine candidates are now in clinical trials, an effective vaccine against TB remains elusive, and new strategies for vaccination are vital. BCG vaccination fails to induce immunity against Mycobacterium tuberculosis latency antigens. Synthetic long peptides (SLPs) combined with adjuvants have been studied mostly for therapeutic cancer vaccines, yet not for TB, and proved to induce efficient antitumor immunity. This study investigated an SLP derived from Rv1733c, a major M. tuberculosis latency antigen which is highly expressed by “dormant” M. tuberculosis and well recognized by T cells from latently M. tuberculosis-infected individuals. In order to assess its in vivo immunogenicity and protective capacity, Rv1733c SLP in CpG was administered to HLA-DR3 transgenic mice. Immunization with Rv1733c SLP elicited gamma interferon-positive/tumor necrosis factor-positive (IFN-γ+/TNF+) and IFN-γ+ CD4+ T cells and Rv1733c-specific antibodies and led to a significant reduction in the bacterial load in the lungs of M. tuberculosis-challenged mice. This was observed both in a pre- and in a post-M. tuberculosis challenge setting. Moreover, Rv1733c SLP immunization significantly boosted the protective efficacy of BCG, demonstrating the potential of M. tuberculosis latency antigens to improve BCG efficacy. These data suggest a promising role for M. tuberculosis latency antigen Rv1733c-derived SLPs as a novel TB vaccine approach, both in a prophylactic and in a postinfection setting. PMID:26202436

  20. Enhancement of Vaccine Efficacy by Expression of a TLR5 Ligand in the Defined Live Attenuated Francisella tularensis subsp. novicida Strain U112▲iglB::fljB

    PubMed Central

    Cunningham, Aimee L.; Dang, Kim Minh; Yu, Jieh-Juen; Guentzel, M. Neal; Heidner, Hans; Klose, Karl E.; Arulanandam, Bernard P.

    2014-01-01

    Oral vaccination with the defined live attenuated Francisella novicida vaccine strain U112▲iglB has been demonstrated to induce protective immunity against pulmonary challenge with the highly human virulent F. tularensis strain SCHU S4. However, this vaccination regimen requires a booster dose in mice and exhibits 50% protective efficacy in the Fischer 344 rat model. To enhance the efficacy of this vaccine strain, we engineered U112▲iglB to express the Salmonella typhimurium FljB flagellin D1 domain, a TLR5 agonist. The U112▲iglB::fljB strain was highly attenuated for intracellular macrophage replication, and although the FljB protein was expressed within the cytosol, it exhibited TLR5 activation in a TLR5-expressing HEK cell line. Additionally, infection of splenocytes and lymphocytes with U112▲iglB::fljB induced significantly greater TNF-α production than infection with U112▲iglB. Oral vaccination with U112▲iglB::fljB also induced significantly greater protection than U112ΔiglB against pulmonary SCHU S4 challenge in rats. The enhanced protection was accompanied by higher IgG2a production and serum-mediated reduction of Francisella infectivity. Thus, the U112▲iglB::fljB strain may serve as a potential vaccine candidate against pneumonic tularemia. PMID:25050972

  1. Tuberculosis and mass gatherings-opportunities for defining burden, transmission risk, and the optimal surveillance, prevention, and control measures at the annual Hajj pilgrimage.

    PubMed

    Zumla, Alimuddin; Saeed, Abdulaziz Bin; Alotaibi, Badriah; Yezli, Saber; Dar, Osman; Bieh, Kingsley; Bates, Matthew; Tayeb, Tamara; Mwaba, Peter; Shafi, Shuja; McCloskey, Brian; Petersen, Eskild; Azhar, Esam I

    2016-06-01

    Tuberculosis (TB) is now the most common infectious cause of death worldwide. In 2014, an estimated 9.6 million people developed active TB. There were an estimated three million people with active TB including 360000 with multidrug-resistant TB (MDR-TB) who were not diagnosed, and such people continue to fuel TB transmission in the community. Accurate data on the actual burden of TB and the transmission risk associated with mass gatherings are scarce and unreliable due to the small numbers studied and methodological issues. Every year, an estimated 10 million pilgrims from 184 countries travel to the Kingdom of Saudi Arabia (KSA) to perform the Hajj and Umrah pilgrimages. A large majority of pilgrims come from high TB burden and MDR-TB endemic areas and thus many may have undiagnosed active TB, sub-clinical TB, and latent TB infection. The Hajj pilgrimage provides unique opportunities for the KSA and the 184 countries from which pilgrims originate, to conduct high quality priority research studies on TB under the remit of the Global Centre for Mass Gatherings Medicine. Research opportunities are discussed, including those related to the definition of the TB burden, transmission risk, and the optimal surveillance, prevention, and control measures at the annual Hajj pilgrimage. The associated data are required to develop international recommendations and guidelines for TB management and control at mass gathering events. PMID:26873277

  2. Tuberculosis and mass gatherings-opportunities for defining burden, transmission risk, and the optimal surveillance, prevention, and control measures at the annual Hajj pilgrimage.

    PubMed

    Zumla, Alimuddin; Saeed, Abdulaziz Bin; Alotaibi, Badriah; Yezli, Saber; Dar, Osman; Bieh, Kingsley; Bates, Matthew; Tayeb, Tamara; Mwaba, Peter; Shafi, Shuja; McCloskey, Brian; Petersen, Eskild; Azhar, Esam I

    2016-06-01

    Tuberculosis (TB) is now the most common infectious cause of death worldwide. In 2014, an estimated 9.6 million people developed active TB. There were an estimated three million people with active TB including 360000 with multidrug-resistant TB (MDR-TB) who were not diagnosed, and such people continue to fuel TB transmission in the community. Accurate data on the actual burden of TB and the transmission risk associated with mass gatherings are scarce and unreliable due to the small numbers studied and methodological issues. Every year, an estimated 10 million pilgrims from 184 countries travel to the Kingdom of Saudi Arabia (KSA) to perform the Hajj and Umrah pilgrimages. A large majority of pilgrims come from high TB burden and MDR-TB endemic areas and thus many may have undiagnosed active TB, sub-clinical TB, and latent TB infection. The Hajj pilgrimage provides unique opportunities for the KSA and the 184 countries from which pilgrims originate, to conduct high quality priority research studies on TB under the remit of the Global Centre for Mass Gatherings Medicine. Research opportunities are discussed, including those related to the definition of the TB burden, transmission risk, and the optimal surveillance, prevention, and control measures at the annual Hajj pilgrimage. The associated data are required to develop international recommendations and guidelines for TB management and control at mass gathering events.

  3. Tuberculosis (TB)

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis Research The New Challenge for TB Research NIAID ... HIV/AIDS Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Research Agenda (PDF) TB Research at NIAID Research ...

  4. Tuberculosis (TB)

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis (TB) Overview In developed countries, such as the ... thought to be infected with TB bacteria, Mycobacterium tuberculosis ( Mtb ). TB is a chronic bacterial infection. It ...

  5. Investments in tuberculosis research - what are the gaps?

    PubMed

    Khan, Mishal S; Fletcher, Helen; Coker, Richard

    2016-01-01

    Through decades of research, numerous studies have generated robust evidence about effective interventions for tuberculosis control. Yet, the global annual decline in incidence of approximately 1 % is evidence that current approaches and investment strategies are not sufficient. In this article, we assess recent tuberculosis research funding and discuss two critical gaps in funding and in scientific evidence from topics that have been left off the research priority agenda.We first examine research and development funding goals in the 2011-2015 Global Plan to Stop Tuberculosis and analyze disbursements to different research areas by funders worldwide in 2014. We then summarize, through a compilation of published literature and consultation with 35 researchers across multiple disciplines in the London School of Hygiene and Tropical Medicine TB Centre, priorities identified by the tuberculosis research community. Finally, we compare researchers' priority areas to the global funding agendas and activities.Our analysis shows that, among the five key research areas defined in the 2011-2015 Global Plan - namely drugs, basic science, vaccines, diagnostics and operational research - drug discovery and basic science on Mycobacterium tuberculosis accounted for 60 % of the $2 billion annual funding target. None of the research areas received the recommended level of funding. Operational research, which had the lowest target, received 66 % of its target funding, whereas new diagnostics received only 19 %. Although many of the priority research questions identified by researchers fell within the Global Plan categories, our analysis highlights important areas that are not explicitly mentioned in the current plan. These priority research areas included improved understanding of tuberculosis transmission dynamics, the role of social protection and social determinants, and health systems and policy research.While research priorities are increasingly important in light of the

  6. Investments in tuberculosis research - what are the gaps?

    PubMed

    Khan, Mishal S; Fletcher, Helen; Coker, Richard

    2016-01-01

    Through decades of research, numerous studies have generated robust evidence about effective interventions for tuberculosis control. Yet, the global annual decline in incidence of approximately 1 % is evidence that current approaches and investment strategies are not sufficient. In this article, we assess recent tuberculosis research funding and discuss two critical gaps in funding and in scientific evidence from topics that have been left off the research priority agenda.We first examine research and development funding goals in the 2011-2015 Global Plan to Stop Tuberculosis and analyze disbursements to different research areas by funders worldwide in 2014. We then summarize, through a compilation of published literature and consultation with 35 researchers across multiple disciplines in the London School of Hygiene and Tropical Medicine TB Centre, priorities identified by the tuberculosis research community. Finally, we compare researchers' priority areas to the global funding agendas and activities.Our analysis shows that, among the five key research areas defined in the 2011-2015 Global Plan - namely drugs, basic science, vaccines, diagnostics and operational research - drug discovery and basic science on Mycobacterium tuberculosis accounted for 60 % of the $2 billion annual funding target. None of the research areas received the recommended level of funding. Operational research, which had the lowest target, received 66 % of its target funding, whereas new diagnostics received only 19 %. Although many of the priority research questions identified by researchers fell within the Global Plan categories, our analysis highlights important areas that are not explicitly mentioned in the current plan. These priority research areas included improved understanding of tuberculosis transmission dynamics, the role of social protection and social determinants, and health systems and policy research.While research priorities are increasingly important in light of the

  7. Bovine Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tuberculosis (TB) in animals and humans may result from exposure to bacilli within the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, M. pinnipedii, M. microti, M. caprae, or M. canetti). Mycobacterium bovis is the species most often isolated from tuberculous catt...

  8. Vaccination: The Present and the Future

    PubMed Central

    Sadanand, Saheli

    2011-01-01

    Vaccines have undoubtedly saved the lives of millions, and along with improved sanitation, they remain one of the cornerstones of modern medicine. Many diseases that were once widespread are now eradicated, but vaccine programs face ongoing challenges. Safety concerns as well as limited funding have led to pockets of reduced vaccine coverage around the world ― including in developed countries. Chronic and recurrent diseases such as human immunodeficiency virus (HIV), tuberculosis, and malaria remain without effective vaccines. This review will briefly describe vaccines and the two major issues faced by modern vaccination programs: insufficient vaccine coverage and developing effective vaccines for chronic and recurrent diseases. PMID:22180673

  9. Tuberculosis update: will good news become bad news?

    PubMed

    Efferen, L S

    1997-03-01

    Recent efforts to reestablish control of tuberculosis have resulted in some success. However, deaths from tuberculosis continue to increase worldwide. Molecular techniques have dominated investigators' efforts to improve diagnostic methods and therapeutic options. Unfortunately, no significant advances in the development of new drugs have occurred. Ongoing attempts to develop more effective vaccines hold some preliminary promise, but delineation of the protective antigens on Mycobacterium tuberculosis and the development of a vaccine for use in humans is considered decades away from clinical use. The lack of political commitment worldwide and the potential loss of support nationally remain major obstacles to the establishment of effective and long-lasting tuberculosis control.

  10. Vaccines against poverty.

    PubMed

    MacLennan, Calman A; Saul, Allan

    2014-08-26

    With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an exciting time for vaccines against poverty, that is, vaccines against diseases that disproportionately affect low- and middle-income countries (LMICs). The Global Burden of Disease Study 2010 has helped better understand which vaccines are most needed. In 2012, US$1.3 billion was spent on research and development for new vaccines for neglected infectious diseases. However, the majority of this went to three diseases: HIV/AIDS, malaria, and tuberculosis, and not neglected diseases. Much of it went to basic research rather than development, with an ongoing decline in funding for product development partnerships. Further investment in vaccines against diarrheal diseases, hepatitis C, and group A Streptococcus could lead to a major health impact in LMICs, along with vaccines to prevent sepsis, particularly among mothers and neonates. The Advanced Market Commitment strategy of the Global Alliance for Vaccines and Immunisation (GAVI) Alliance is helping to implement vaccines against rotavirus and pneumococcus in LMICs, and the roll out of the MenAfriVac meningococcal A vaccine in the African Meningitis Belt represents a paradigm shift in vaccines against poverty: the development of a vaccine primarily targeted at LMICs. Global health vaccine institutes and increasing capacity of vaccine manufacturers in emerging economies are helping drive forward new vaccines for LMICs. Above all, partnership is needed between those developing and manufacturing LMIC vaccines and the scientists, health care professionals, and policy makers in LMICs where such vaccines will be implemented.

  11. Function and Potentials of M. tuberculosis Epitopes

    PubMed Central

    Ivanyi, Juraj

    2014-01-01

    Study of the function of epitopes of Mycobacterium tuberculosis antigens contributed significantly toward better understanding of the immunopathogenesis and to efforts for improving infection and disease control. Characterization of genetically permissively presented immunodominant epitopes has implications for the evolution of the host–parasite relationship, development of immunodiagnostic tests, and subunit prophylactic vaccines. Knowledge of the determinants of cross-sensitization, relevant to other pathogenic or environmental mycobacteria and to host constituents has advanced. Epitope-defined IFNγ assay kits became established for the specific detection of infection with tubercle bacilli both in humans and cattle. The CD4 T-cell epitope repertoire was found to be more narrow in patients with active disease than in latently infected subjects. However, differential diagnosis of active TB could not be made reliably merely on the basis of epitope recognition. The mechanisms by which HLA polymorphism can influence the development of multibacillary tuberculosis (TB) need further analysis of epitopes, recognized by Th2 helper cells for B-cell responses. Future vaccine development would benefit from better definition of protective epitopes and from improved construction and formulation of subunits with enhanced immunogenicity. Epitope-defined serology, due to its operational advantages is suitable for active case finding in selected high disease incidence populations, aiming for an early detection of infectious cases and hence for reducing the transmission of infection. The existing knowledge of HLA class I binding epitopes could be the basis for the construction of T-cell receptor-like ligands for immunotherapeutic application. Continued analysis of the functions of mycobacterial epitopes, recognized by T cells and antibodies, remains a fertile avenue in TB research. PMID:24715888

  12. Perforin- and Granzyme-Mediated Cytotoxic Effector Functions Are Essential for Protection against Francisella tularensis following Vaccination by the Defined F. tularensis subsp. novicida ΔfopC Vaccine Strain

    PubMed Central

    Sanapala, Shilpa; Yu, Jieh-Juen; Murthy, Ashlesh K.; Li, Weidang; Guentzel, M. Neal; Chambers, James P.; Klose, Karl E.

    2012-01-01

    A licensed vaccine against Francisella tularensis is currently not available. Two Francisella tularensis subsp. novicida (herein referred to by its earlier name, Francisella novicida) attenuated strains, the ΔiglB and ΔfopC strains, have previously been evaluated as potential vaccine candidates against pneumonic tularemia in experimental animals. F. novicida ΔiglB, a Francisella pathogenicity island (FPI) mutant, is deficient in phagosomal escape and intracellular growth, whereas F. novicida ΔfopC, lacking the outer membrane lipoprotein FopC, which is required for evasion of gamma interferon (IFN-γ)-mediated signaling, is able to escape and replicate in the cytosol. To dissect the difference in protective immune mechanisms conferred by these two vaccine strains, we examined the efficacy of the F. novicida ΔiglB and ΔfopC mutants against pulmonary live-vaccine-strain (LVS) challenge and found that both strains provided comparable protection in wild-type, major histocompatibility complex class I (MHC I) knockout, and MHC II knockout mice. However, F. novicida ΔfopC-vaccinated but not F. novicida ΔiglB-vaccinated perforin-deficient mice were more susceptible and exhibited greater bacterial burdens than similarly vaccinated wild-type mice. Moreover, perforin produced by natural killer (NK) cells and release of granzyme contributed to inhibition of LVS replication within macrophages. This NK cell-mediated LVS inhibition was enhanced with anti-F. novicida ΔfopC immune serum, suggesting antibody-dependent cell-mediated cytotoxicity (ADCC) in F. novicida ΔfopC-mediated protection. Overall, this study provides additional immunological insight into the basis for protection conferred by live attenuated F. novicida strains with different phenotypes and supports further investigation of this organism as a vaccine platform for tularemia. PMID:22493083

  13. Transformative tools for tackling tuberculosis.

    PubMed

    Gardiner, Jennifer L; Karp, Christopher L

    2015-10-19

    The world is in need of more effective approaches to controlling tuberculosis. The development of improved control strategies has been hampered by deficiencies in the tools available for detecting Mycobacterium tuberculosis and defining the dynamic consequences of the interaction of M. tuberculosis with its human host. Key needs include a highly sensitive, specific nonsputum diagnostic; biomarkers predictive of responses to therapy; correlates of risk for disease development; and host response-independent markers of M. tuberculosis infection. Tools able to sensitively detect and quantify total body M. tuberculosis burden might well be transformative across many needed use cases. Here, we review the current state of the field, paying particular attention to needed changes in experimental paradigms that would facilitate the discovery, validation, and development of such tools.

  14. Transformative tools for tackling tuberculosis

    PubMed Central

    2015-01-01

    The world is in need of more effective approaches to controlling tuberculosis. The development of improved control strategies has been hampered by deficiencies in the tools available for detecting Mycobacterium tuberculosis and defining the dynamic consequences of the interaction of M. tuberculosis with its human host. Key needs include a highly sensitive, specific nonsputum diagnostic; biomarkers predictive of responses to therapy; correlates of risk for disease development; and host response–independent markers of M. tuberculosis infection. Tools able to sensitively detect and quantify total body M. tuberculosis burden might well be transformative across many needed use cases. Here, we review the current state of the field, paying particular attention to needed changes in experimental paradigms that would facilitate the discovery, validation, and development of such tools. PMID:26458772

  15. Construction of an attenuated Salmonella enterica serovar Paratyphi A vaccine strain harboring defined mutations in htrA and yncD.

    PubMed

    Zhu, Chunyue; Xiong, Kun; Chen, Zhijin; Hu, Xiaomei; Li, Jianhua; Wang, Yiran; Rao, Xiancai; Cong, Yanguang

    2015-08-01

    The global epidemic features of enteric fever have changed greatly in recent years. The incidence of enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased. In some areas of Asia, infections with S. Paratyphi A have exceeded those with S. Typhi, resulting in S. Paratyphi A becoming the main causative agent of enteric fever. However, two currently licensed typhoid vaccines do not confer adequate cross-protection against S. Paratyphi A infection. Therefore, development of specific vaccines against enteric fever caused by S. Paratyphi A is urgently needed. In the present study, an attenuated strain was constructed by double deletion of the htrA and yncD genes in a wild-type strain of S. Paratyphi A and its safety and immunogenicity assessed. In a mouse model, the 50% lethal dose of the double deletion mutant and the wild-type strain were 3.0 × 10(8) CFU and 1.9 × 10(3) CFU, respectively, suggesting that the double deletion resulted in remarkably decreased bacterial virulence. Bacterial colonization of the double deletion mutant in the livers and spleens of infected mice was strikingly less than that of the wild-type strain. A single nasal administration of the attenuated vaccine candidate elicited high concentrations of anti-LPS and anti-flagellin IgG in a mouse model and protected immunized mice against lethal challenge with the wild-type strain. Thus, our findings suggest that the attenuated vaccine strain is a promising candidate worthy of further evaluation both as a human enteric fever vaccine and as a vaccine delivery vector for heterologous antigens. PMID:26084199

  16. Synthetically defined glycoprotein vaccines: current status and future directions†This perspective is dedicated to the memory of Professor David Y. Gin.

    PubMed Central

    Nilo, Alberto; Castagner, Bastien; Boutureira, Omar; Berti, Francesco

    2013-01-01

    Primary examples in vaccine design have shown good levels of carbohydrate-specific antibody generation when raised using extracted or fully synthetic capsular polysaccharide glycans covalently coupled to a protein carrier. Herein, we cover recent clinical developments of carbohydrate-based vaccines and describe how novel cutting-edge methodology for the total synthesis of oligosaccharides and for the precise placement of carbohydrates at pre-determined sites within a protein may be used to further improve the safety and efficacy of glycovaccines. PMID:25893089

  17. Knowledge and Awareness of Tuberculosis among Pre-University Students in Trinidad.

    ERIC Educational Resources Information Center

    Orrett, Fitzroy A.; Shurland, Simone M.

    2001-01-01

    Surveyed pre-university high school students in Trinidad regarding their awareness and knowledge of tuberculosis. Results indicated that while most students had heard of tuberculosis, knowledge levels were generally poor regarding the major presenting features of tuberculosis, vaccination and treatment, and the impact of overcrowded living…

  18. Common Mental Disorders Associated with Tuberculosis: A Matched Case-Control Study

    PubMed Central

    de Araújo, Gleide Santos; Pereira, Susan Martins; dos Santos, Darci Neves; Marinho, Jamocyr Moura; Rodrigues, Laura Cunha; Barreto, Mauricio Lima

    2014-01-01

    Introduction Despite the availability of treatment and a vaccine, tuberculosis continues to be a public health problem worldwide. Mental disorders might contribute to the burden of the disease. Objective The objective of this study was to investigate the association between common mental disorders and tuberculosis. Methods A matched case-control study was conducted. The study population included symptomatic respiratory patients who attended three referral hospitals and six community clinics in the city of Salvador, Brazil. A doctor’s diagnosis defined potential cases and controls. Cases were newly diagnosed tuberculosis cases, and controls were symptomatic respiratory patients for whom tuberculosis was excluded as a diagnosis by the attending physician. Cases and controls were ascertained in the same clinic. Data collection occurred between August 2008 and April 2010. The study instruments included a structured interview, a self-reporting questionnaire for the identification of common mental disorders, and a questionnaire for alcoholism. An univariate analysis included descriptive procedures (with chi-square statistics), and a multivariate analysis used conditional logistic regression. Results The mean age of the cases was 38 years, and 61% of the cases were males. After adjusting for potential confounders, the odds of tuberculosis were significantly higher in patients dignosed with a common mental disorder (OR: 1.34; 95% CI 1.05–1.70). Conclusion There appears to be a positive and independent association between common mental disorders and tuberculosis; further epidemiological studies are required to increase our understanding of the possible biological and social mechanisms responsible for this association. Independent of the direction of the association, this finding has implications for the provision of care for mental disorders and for tuberculosis. PMID:24937319

  19. Immunoregulatory functions and expression patterns of PE/PPE family members: Roles in pathogenicity and impact on anti-tuberculosis vaccine and drug design.

    PubMed

    Ahmed, Asma; Das, Arghya; Mukhopadhyay, Sangita

    2015-06-01

    The Mycobacterium tuberculosis genome was sequenced more than 15 years ago. It revealed a lot of interesting information, one of which was that 10% of the total coding capacity of the M. tuberculosis genome is dedicated to the PE/PPE family. There is a gradual expansion of these proteins from nonpathogenic to pathogenic mycobacteria, and there is increasing evidence that PE/PPE proteins play important roles in mycobacterial pathogenesis. In this review, we discuss PE/PPE proteins, their close functional association with the ESX clusters, their immunomodulatory functions, and their important roles in mycobacterial virulence. In addition, we have attempted to review and compile information available in the literature detailing the expression patterns of PE/PPE family members in different mycobacterial species and also during infection. Our attempt has been to provide a succinct overview of this interesting family.

  20. Human genetics of tuberculosis: a long and winding road

    PubMed Central

    Abel, Laurent; El-Baghdadi, Jamila; Bousfiha, Ahmed Aziz; Casanova, Jean-Laurent; Schurr, Erwin

    2014-01-01

    Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses. PMID:24821915

  1. Tuberculosis (TB): Treatment

    MedlinePlus

    ... Departments & Divisions Home Conditions Tuberculosis Treating Tuberculosis Treating Tuberculosis Make an Appointment Refer a Patient Ask a ... bones is treated longer. NEXT: Preventive Treatment Diagnosing Tuberculosis History of TB Our Specialists Charles L. Daley, ...

  2. Comparison of the vaccine efficacy of gamma-irradiated Schistosoma japonicum cercariae with the defined antigen Sj62(IrV-5) in pigs.

    PubMed

    Bickle, Q D; Bøgh, H O; Johansen, M V; Zhang, Y

    2001-09-12

    Development of a vaccine against Schistosoma japonicum which can protect both man and the domestic animal zoonotic reservoirs of infection would be an invaluable tool in attempts to control this infection in those areas in which conventional control methods have failed to break transmission. The pig is a natural host of S. japonicum and because of its anatomical and immunological similarities to humans, it is a potentially valuable host for studies on S. japonicum in particular and schistosomes in general. Radiation-attenuated cercariae are highly effective in inducing immunity in experimental schistosomosis and there are promising reports of partial protection against schistosomes with recombinant-derived individual antigens. In the present study we have set out to establish a protocol for inducing protection with gamma-irradiated cercariae in pigs and to assess the protective capacity of recombinant and naked DNA formulations of Sj62, a 62kDa region of S. japonicum myosin. The corresponding S. mansoni version or Sj62, recombinant IrV-5, has previously been implicated in irradiated vaccine immunity in S. mansoni infections and has been shown to induce high levels of immunity in a variety of hosts. Groups of pigs were immunised three times at 2-week intervals with 2000 cercariae irradiated at 20krad, with Sj62 as a recombinant (rSj62) incorporated in Freund's adjuvant, a micellar preparation, or as a naked DNA construct. Vaccination with irradiated cercariae did not induce significant anti-Sj62 antibody but following intramuscular challenge with 2000 cercariae, the vaccinated pigs showed >95% resistance as assessed by reduced faecal egg output, worm tissue egg burdens and also reduced septal fibrosis. Immunisation with each of the Sj62 formulations induced significant anti-Sj62 antibody responses, the highest titre (>12,800) being with the Freund's preparation but none of the Sj62-immunised groups showed significant resistance to challenge. The data suggest that Sj

  3. [Strategies for BCG vaccination 1947 - 94].

    PubMed

    Harthug, Henrik

    2016-06-01

    The tuberculosis reform of 1947 stipulated a clear responsibility of the state to combat tuberculosis. This entailed sanctions directed at individuals, as well as compulsory vaccination. Universal vaccination was to be achieved through extensive information work that emphasised the responsibility of the individual. The decline in the disease, the dawning of human rights thinking and the decline of professional boards in public administration help to explain the downgrading of compulsory vaccination over time.

  4. Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects

    PubMed Central

    Rock, R. Bryan; Olin, Michael; Baker, Cristina A.; Molitor, Thomas W.; Peterson, Phillip K.

    2008-01-01

    Summary: Tuberculosis of the central nervous system (CNS) is a highly devastating form of tuberculosis, which, even in the setting of appropriate antitubercular therapy, leads to unacceptable levels of morbidity and mortality. Despite the development of promising molecular diagnostic techniques, diagnosis of CNS tuberculosis relies largely on microbiological methods that are insensitive, and as such, CNS tuberculosis remains a formidable diagnostic challenge. Insights into the basic neuropathogenesis of Mycobacterium tuberculosis and the development of an appropriate animal model are desperately needed. The optimal regimen and length of treatment are largely unknown, and with the rising incidence of multidrug-resistant strains of M. tuberculosis, the development of well-tolerated and effective antibiotics remains a continued need. While the most widely used vaccine in the world largely targets this manifestation of tuberculosis, the BCG vaccine has not fulfilled the promise of eliminating CNS tuberculosis. We put forth this review to highlight the current understanding of the neuropathogenesis of M. tuberculosis, to discuss certain epidemiological, clinical, diagnostic, and therapeutic aspects of CNS tuberculosis, and also to underscore the many unmet needs in this important field. PMID:18400795

  5. Pathology of bovine tuberculosis.

    PubMed

    Domingo, M; Vidal, E; Marco, A

    2014-10-01

    Bovine tuberculosis (bTB) is a chronic granulomatous caseous-necrotising inflammatory process that mainly affects the lungs and their draining lymph nodes (Ln.). The pathological changes associated with bTB infection reflect the interplay between the host defence mechanisms and the mycobacterial virulence factors and the balance between the immunologic protective responses and the damaging inflammatory processes. Inhalation is the most common infection route and causes lesions of the nasopharynx and lower respiratory tract, including its associated lymph nodes. The initial infection (primary complex) may be followed by chronic (post-primary) tuberculosis or may be generalised. Goat tuberculosis often produces liquefactive necrosis and caverns, similarly to human TB. The assessment of the severity of TB lesions is crucial for vaccine trials. Semi-quantitative gross lesion scoring systems have been developed for cattle, but imaging technology has allowed the development of more standardised, objective, and quantitative methods, such as multi-detector computed tomography (MDCT), which provides quantitative measures of lesion volume. PMID:24731532

  6. The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection

    PubMed Central

    Seddon, James A; Paton, James; Nademi, Zohreh; Keane, Denis; Williams, Bhanu; Williams, Amanda; Welch, Steven B; Liebeschutz, Sue; Riddell, Anna; Bernatoniene, Jolanta; Patel, Sanjay; Martinez-Alier, Nuria; McMaster, Paddy; Kampmann, Beate

    2016-01-01

    Background Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity. Methods Children <15 years old were recruited from 11 sites in the UK between January 2011 and December 2014 if exposed in their home to a source case with sputum smear or culture positive TB. Demographic details were collected and TST and IGRA undertaken. The impact of BCG vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity. Results Of 422 children recruited (median age 69 months; IQR: 32–113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child. Discussion BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children. PMID:27335104

  7. Vaccines and global health.

    PubMed

    Greenwood, Brian; Salisbury, David; Hill, Adrian V S

    2011-10-12

    Vaccines have made a major contribution to global health in recent decades but they could do much more. In November 2011, a Royal Society discussion meeting, 'New vaccines for global health', was held in London to discuss the past contribution of vaccines to global health and to consider what more could be expected in the future. Papers presented at the meeting reviewed recent successes in the deployment of vaccines against major infections of childhood and the challenges faced in developing vaccines against some of the world's remaining major infectious diseases such as human immunodeficiency virus (HIV), malaria and tuberculosis. The important contribution that development of more effective veterinary vaccines could make to global health was also addressed. Some of the social and financial challenges to the development and deployment of new vaccines were reviewed. The latter issues were also discussed at a subsequent satellite meeting, 'Accelerating vaccine development', held at the Kavli Royal Society International Centre. Delegates at this meeting considered challenges to the more rapid development and deployment of both human and veterinary vaccines and how these might be addressed. Papers based on presentations at the discussion meeting and a summary of the main conclusions of the satellite meeting are included in this issue of Philosophical Transactions of the Royal Society B.

  8. Disseminated tuberculosis

    MedlinePlus

    Tuberculosis (TB) infection can develop after breathing in droplets sprayed into the air from a cough or sneeze by ... bacterium. The resulting lung infection is called primary TB. The usual site of TB is the lungs ( ...

  9. Influence of phthiocerol dimycocerosate on CD4(+) T cell priming and persistence during Mycobacterium tuberculosis infection.

    PubMed

    Pinto, Rachel; Nambiar, Jonathan K; Leotta, Lisa; Counoupas, Claudio; Britton, Warwick J; Triccas, James A

    2016-07-01

    The characterisation of mycobacterial factors that influence or modulate the host immune response may aid the development of more efficacious TB vaccines. We have previously reported that Mycobacterium tuberculosis deficient in export of Phthiocerol Dimycocerosates (DIM) (MT103(ΔdrrC)) is more attenuated than wild type M. tuberculosis and provides sustained protective immunity compared to the existing BCG vaccine. Here we sought to define the correlates of immunity associated with DIM deficiency by assessing the impact of MT103(ΔdrrC) delivery on antigen presenting cell (APC) function and the generation of CD4(+) T cell antigen-specific immunity. MT103(ΔdrrC) was a potent activator of bone marrow derived dendritic cells, inducing significantly greater expression of CD86 and IL-12p40 compared to BCG or the MT103 parental strain. This translated to an increased ability to initiate early in vivo priming of antigen-specific CD4(+) T cells compared to BCG with enhanced release of IFN-γ and TNF upon antigen-restimulation. The heightened immunity induced by MT103(ΔdrrC) correlated with greater persistence within the spleen compared to BCG, however both MT103(ΔdrrC) and BCG were undetectable in the lung at 70 days post-vaccination. In immunodeficient RAG (-/-) mice, MT103(ΔdrrC) was less virulent than the parental MT103 strain, yet MT103(ΔdrrC) infected mice succumbed more rapidly compared to BCG-infected animals. These results suggest that DIM translocation plays a role in APC stimulation and CD4(+) T cell activation during M. tuberculosis infection and highlights the potential of DIM-deficient strains as novel TB vaccine candidates. PMID:27450001

  10. Tuberculosis care: an evaluability study

    PubMed Central

    Coelho, Ardigleusa Alves; Martiniano, Cláudia Santos; Brito, Ewerton Willian Gomes; Negrão, Oswaldo Gomes Corrêa; Arcêncio, Ricardo Alexandre; Uchôa, Severina Alice da Costa

    2014-01-01

    OBJECTIVE: to verify whether the tuberculosis control program (TCP) is evaluable and to examine the feasibility of building an evaluation model in apriority municipality for the control of tuberculosis. METHOD: this evaluability study was conducted in a municipality in northeastern Brazil. For data collection, documental analysis and interviews with key informants were performed. For indicator validation, the nominal group technique was adopted. RESULTS: the details of TCP were described, and both the logical model and the classification framework for indicators were developed and agreed up on, with the goal of characterizing the structural elements of the program, defining the structure and process indicators, and formulating the evaluation questions. CONCLUSION: TCP is evaluable. Based on logical operational analysis, it was possible to evaluate the adequacy of the program goals for the control of tuberculosis. Therefore, the performance of a summative evaluation is recommended, with a focus on the analysis of the effects of tuberculosis control interventions on decreasing morbidity and mortality. PMID:25493675

  11. Global routine vaccination coverage, 2014.

    PubMed

    Subaiya, Saleena; Dumolard, Laure; Lydon, Patrick; Gacic-Dobo, Marta; Eggers, Rudolf; Conklin, Laura

    2015-11-13

    The year 2014 marked the 40th anniversary of the World Health Organization’s (WHO) Expanded Program on Immunization, which was established to ensure equitable access to routine immunization services (1). Since 1974, global coverage with the four core vaccines (Bacille Calmette- Guérin vaccine [BCG; for protection against tuberculosis], diphtheria-tetanus-pertussis [DTP] vaccine, poliovirus vaccine, and measles vaccine) has increased from <5% to ≥85%, and additional vaccines have been added to the recommended schedule. Coverage with the 3rd dose of DTP vaccine (DTP3) by age 12 months is an indicator of immunization program performance because it reflects completion of the basic infant immunization schedule; coverage with other vaccines, including the 3rd dose of poliovirus vaccine (polio3); the 1st dose of measles-containing vaccine (MCV1) is also assessed. Estimated global DTP3 coverage has remained at 84%–86% since 2009, with estimated 2014 coverage at 86%. Estimated global coverage for the 2nd routine dose of measles-containing vaccine (MCV2) was 38% by age 24 months and 56% when older age groups were included, similar to levels reported in 2013 (36% and 55%, respectively). To reach and sustain high immunization coverage in all countries, adequate vaccine stock management and additional opportunities for immunization, such as through routine visits in the second year of life, are integral components to strengthening immunization programs and reducing morbidity and mortality from vaccine preventable diseases. PMID:26562454

  12. [Assessment of BCG vaccine practices].

    PubMed

    Lechiche, C; Charpille, M; Saissi, G; Sotto, A

    2016-01-01

    Tuberculosis is a major public health problem. In France, the vaccine against tuberculosis (Bacillus Calmette-Guerin, BCG) is in decline. This decline is firstly due to changes in BGG administration that were implemented in 2006 and secondly because of new recommandations in 2007 that ended compulsory vaccination. To determine their position on this vaccine, in 2013-2014 we asked general practitioners, pediatricians, and Maternal and Infantile Protection Center physicians in the Gard and Herault departments (in Southern France) why this vaccine was not administered and their suggestions for improvement. Most of these doctors (73.9%) stated that they did not oppose this vaccination for children. They expressed concern about potential side effects, technical problems (intradermic injection, multi-dose bottles) and parents' refusal. One quarter of these physicians would have preferred that this vaccine remains compulsory and one third that this vaccine be administered in the maternity hospital. They also requested simplified criteria for patient eligibility, technical improvements (training for intradermal injection, single-dose vaccine) and more information for the public concerning this vaccination.

  13. Molecular signatures of vaccine adjuvants.

    PubMed

    Olafsdottir, Thorunn; Lindqvist, Madelene; Harandi, Ali M

    2015-09-29

    Mass vaccination has saved millions of human lives and improved the quality of life in both developing and developed countries. The emergence of new pathogens and inadequate protection conferred by some of the existing vaccines such as vaccines for tuberculosis, influenza and pertussis especially in certain age groups have resulted in a move from empirically developed vaccines toward more pathogen tailored and rationally engineered vaccines. A deeper understanding of the interaction of innate and adaptive immunity at molecular level enables the development of vaccines that selectively target certain type of immune responses without excessive reactogenicity. Adjuvants constitute an imperative element of modern vaccines. Although a variety of candidate adjuvants have been evaluated in the past few decades, only a limited number of vaccine adjuvants are currently available for human use. A better understanding of the mode of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in shaping a desired immune response. Recent advancement in systems biology powered by the emerging cutting edge omics technology has led to the identification of molecular signatures rapidly induced after vaccination in the blood that correlate and predict a later protective immune response or vaccine safety. This can pave ways to prospectively determine the potency and safety of vaccines and adjuvants. This review is intended to highlight the importance of big data analysis in advancing our understanding of the mechanisms of actions of adjuvants to inform rational development of future human vaccines. PMID:25989447

  14. [Hospital infection control practice for tuberculosis].

    PubMed

    Suzuki, Katsuhiro

    2002-11-01

    In Japan, annual incidence rate of tuberculosis was 31.0/10,000 population in 2000. But that of some hot spots, such as Osaka prefecture(61.5/10,000), were still high. Hospital infection control practice for tuberculosis in such a endemic area was discussed in this review. The tuberculosis infection-control program should be based on a hierarchy of control measures. The first level was local control practice in the area, the second level was administrative controls in the hospital, the third level was engineering control to prevent the spread of infectious doplet nuclei, and the fourth level was personal protection, such as N95 respirators. Because of general vaccination policy with BCG, detection of persons infected by M. tuberculosis were rather difficult in Japan, by using tuberculin skin test. In such a circumstance, how to select health care workers to whom chemoprophylaxis with isoniazid should be administered was also discussed. PMID:12440125

  15. Virulence factors of the Mycobacterium tuberculosis complex

    PubMed Central

    Forrellad, Marina A.; Klepp, Laura I.; Gioffré, Andrea; Sabio y García, Julia; Morbidoni, Hector R.; Santangelo, María de la Paz; Cataldi, Angel A.; Bigi, Fabiana

    2013-01-01

    The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world. PMID:23076359

  16. BCG vaccine-induced lupus vulgaris.

    PubMed

    Izumi, A K; Matsunaga, J

    1982-03-01

    A case of intradermal BCG vaccination was complicated by a lupus-like tuberculosis cutis progressive for over 30 years. The patient had been vaccinated twice with BCG in the affected site. A review of other BCG vaccine-induced cases of lupus vulgaris indicates that the incidence of this complication is markedly increased following multiple BCG vaccinations, but is rare following a single BCG vaccination. In our patient a skin biopsy specimen was characteristic for lupus vulgaris. Acid-fast stains from the tissue and cultures from the affected site were negative. The patient was successfully treated with rifampin.

  17. HPV vaccine

    MedlinePlus

    ... Gardasil; Cervarix; HPV2; HPV4; Vaccine to prevent cervical cancer; Genital warts - HPV vaccine; Cervical dysplasia - HPV vaccine; Cervical cancer - HPV vaccine; Cancer of the cervix - HPV vaccine; ...

  18. Tuberculosis Infection and Latent Tuberculosis

    PubMed Central

    2016-01-01

    Active tuberculosis (TB) has a greater burden of TB bacilli than latent TB and acts as an infection source for contacts. Latent tuberculosis infection (LTBI) is the state in which humans are infected with Mycobacterium tuberculosis without any clinical symptoms, radiological abnormality, or microbiological evidence. TB is transmissible by respiratory droplet nucleus of 1–5 µm in diameter, containing 1–10 TB bacilli. TB transmission is affected by the strength of the infectious source, infectiousness of TB bacilli, immunoresistance of the host, environmental stresses, and biosocial factors. Infection controls to reduce TB transmission consist of managerial activities, administrative control, engineering control, environmental control, and personal protective equipment provision. However, diagnosis and treatment for LTBI as a national TB control program is an important strategy on the precondition that active TB is not missed. Therefore, more concrete evidences for LTBI management based on clinical and public perspectives are needed. PMID:27790271

  19. Co-evolution of Mycobacterium tuberculosis and Homo sapiens

    PubMed Central

    Brites, Daniela; Gagneux, Sebastien

    2015-01-01

    The causative agent of human tuberculosis (TB), Mycobacterium tuberculosis, is an obligate pathogen that evolved to exclusively persist in human populations. For M. tuberculosis to transmit from person to person, it has to cause pulmonary disease. Therefore, M. tuberculosis virulence has likely been a significant determinant of the association between M. tuberculosis and humans. Indeed, the evolutionary success of some M. tuberculosis genotypes seems at least partially attributable to their increased virulence. The latter possibly evolved as a consequence of human demographic expansions. If co-evolution occurred, humans would have counteracted to minimize the deleterious effects of M. tuberculosis virulence. The fact that human resistance to infection has a strong genetic basis is a likely consequence of such a counter-response. The genetic architecture underlying human resistance to M. tuberculosis remains largely elusive. However, interactions between human genetic polymorphisms and M. tuberculosis genotypes have been reported. Such interactions are consistent with local adaptation and allow for a better understanding of protective immunity in TB. Future ‘genome-to-genome’ studies, in which locally associated human and M. tuberculosis genotypes are interrogated in conjunction, will help identify new protective antigens for the development of better TB vaccines. PMID:25703549

  20. Mycobacterium tuberculosis PPE protein Rv0256c induces strong B cell response in tuberculosis patients.

    PubMed

    Abraham, Philip Raj; Latha, Gaddam Suman; Valluri, Vijaya Lakshmi; Mukhopadhyay, Sangita

    2014-03-01

    Tuberculosis (TB) is one of the most important diseases of humans and major public health problem worldwide. Early and accurate diagnosis of TB is necessary for the treatment, prevention, and control of TB. Therefore, it is important to identify suitable antigens that can differentiate active tuberculosis patients from BCG-vaccinated individuals. In the present study, we have used Rv0256c (PPE2) protein of Mycobacterium tuberculosis to screen the sera of infected patients belonging to different clinical TB presentations, and BCG-vaccinated clinically healthy individuals by enzyme immunoassay. Our results demonstrated that Rv0256c displayed stronger and specific immunoreactivity against the sera obtained from clinically active tuberculosis patients compared to PPD and ESAT-6 and could differentiate the TB-patients from the BCG-vaccinated controls. Importantly, Rv0256c was also found to detect even the extrapulmonary and smear-negative pulmonary cases which often are tedious and difficult to detect using conventional diagnostic methods. This study suggests that Rv0256c can be used as a potential marker for the serodiagnosis of tuberculosis patients. PMID:23827809

  1. Tuberculosis: General Information

    MedlinePlus

    TB Elimination Tuberculosis: General Information What is TB? Tuberculosis (TB) is a disease caused by germs that are spread from person ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination CS227840_A What Does a Positive Test ...

  2. Global Tuberculosis Report 2015

    MedlinePlus

    ... Feed Youtube Twitter Facebook Google + iTunes Play Store Tuberculosis (TB) Menu Tuberculosis The End TB Strategy Areas ... data News, events and features About us Global tuberculosis report 2015 This is the twentieth global report ...

  3. Tuberculosis diagnostics: Challenges and opportunities.

    PubMed

    Nema, Vijay

    2012-07-01

    Tuberculosis (TB) has been a disease affecting almost all parts of the world since ages. Lot many efforts came in the past for improving diagnosis and treatment. Also, an effective vaccine has been sought after for long. With the emergence of resistant strains of Mycobacterium tuberculosis, the causal organisms of tuberculosis, and complexities emerging due to other associated infections and disease conditions, there is a desperate need for further research input in the field. Be it the better medication and care or better resistance management, proper diagnostics holds the key to success. It has been observed that a high burden of the disease was accompanied by resource limitations and poor research set-up. The scenario remained like this for several decades. With the refreshed vision of resourceful countries and funding agencies, funding is being provided in many areas of research in tuberculosis diagnosis and treatment. This review has been written with an aim to bring forth the limitations of available methods in the field of diagnostics and making researchers aware about the changing scenario with better funding opportunities and support. The author visualizes an enthusiasm from all over the world for the development of better modalities and urges scientists to join the struggle at this very perfect time to take the challenge and come forward with innovations in this field. PMID:22919166

  4. Peritoneal tuberculosis.

    PubMed

    Guirat, A; Koubaa, M; Mzali, R; Abid, B; Ellouz, S; Affes, N; Ben Jemaa, M; Frikha, F; Ben Amar, M; Beyrouti, M I

    2011-01-01

    The peritoneum is one of the locations outside the most common pulmonary tuberculosis. Peritoneal tuberculosis poses a public health problem in endemic regions of the world. The phenomenon of migration, the increased use of immunosuppressive therapy and the epidemic of AIDS have contributed to a resurgence of this disease in regions where it was previously controlled. The aim of this review is to expose the clinical, biologic end radiologic futures of the peritoneal tuberculosis and to present the methods of diagnosis and treatment. The diagnosis of this disease is difficult and still remains a challenge because of its insidious nature, the variability of presentation and limitations of available diagnostic tests. The disease usually presents a picture of lymphocytic exudative ascites. There are many complementary tests with variable sensitivities and specificities to confirm the diagnosis of peritoneal tuberculosis. Isolation of mycobacteria by culture of ascitic fluid or histological examination of peritoneal biopsy ideally performed by laparoscopy remains the investigation of choice. The role of PCR, ascitic adenosine deaminase, interferon gamma and the radiometric BACTEC system can improve the diagnostic yield. An antituberculous treatment with group 1 of the WHO for 6 months is sufficient in most cases.

  5. Postmenopausal Tuberculosis Endometritis

    PubMed Central

    Güngördük, Kemal; Ulker, Volkan; Sahbaz, Ahmet; Ark, Cemal; Tekırdag, Alı Ismet

    2007-01-01

    Tuberculosis remains a global health problem, primarily in developing countries with inadequate health services. A significant portion of tuberculosis in these settings is extrapulmonary, including tuberculosis of the genitourinary tract. Patients with genital tuberculosis are usually young women detected during work up for infertility. After menopause, tuberculosis of the endometrium is a rare possibility probably because of the decreased vascularity of the tissues. We present a case of endometrial tuberculosis with postmenopausal vaginal bleeding. PMID:17541465

  6. Enhancement of tumor-specific T cell-mediated immunity in dendritic cell-based vaccines by Mycobacterium tuberculosis heat shock protein X.

    PubMed

    Jung, In Duk; Shin, Sung Jae; Lee, Min-Goo; Kang, Tae Heung; Han, Hee Dong; Lee, Seung Jun; Kim, Woo Sik; Kim, Hong Min; Park, Won Sun; Kim, Han Wool; Yun, Cheol-Heui; Lee, Eun Kyung; Wu, T-C; Park, Yeong-Min

    2014-08-01

    Despite the potential for stimulation of robust antitumor immunity by dendritic cells (DCs), clinical applications of DC-based immunotherapy are limited by the low potency in generating tumor Ag-specific T cell responses. Therefore, optimal conditions for generating potent immunostimulatory DCs that overcome tolerance and suppression are key factors in DC-based tumor immunotherapy. In this study, we demonstrate that use of the Mycobacterium tuberculosis heat shock protein X (HspX) as an immunoadjuvant in DC-based tumor immunotherapy has significant potential in therapeutics. In particular, the treatment aids the induction of tumor-reactive T cell responses, especially tumor-specific CTLs. The HspX protein induces DC maturation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IFN-β) through TLR4 binding partially mediated by both the MyD88 and the TRIF signaling pathways. We employed two models of tumor progression and metastasis to evaluate HspX-stimulated DCs in vivo. The administration of HspX-stimulated DCs increased the activation of naive T cells, effectively polarizing the CD4(+) and CD8(+) T cells to secrete IFN-γ, as well as enhanced the cytotoxicity of splenocytes against HPV-16 E7 (E7)-expressing TC-1 murine tumor cells in therapeutic experimental animals. Moreover, the metastatic capacity of B16-BL6 melanoma cancer cells toward the lungs was remarkably attenuated in mice that received HspX-stimulated DCs. In conclusion, the high therapeutic response rates with tumor-targeted Th1-type T cell immunity as a result of HspX-stimulated DCs in two models suggest that HspX harnesses the exquisite immunological power and specificity of DCs for the treatment of tumors.

  7. Tuberculosis 2004: Challenges and Opportunities

    PubMed Central

    Glassroth, Jeffrey

    2005-01-01

    Tuberculosis (TB) continues as a major public health challenge worldwide. HIV-TB coinfection is especially concerning as it accelerates progression of infection to active disease and amplifies spread of TB including drug resistant disease. Application of molecular biology and insights from classic microbiology to TB control have resulted in important innovations in diagnosis and treatment. Radiometric assay and, particularly, PCR, with nucleic acid probing, have reduced the time to diagnosis. Moreover, the sensitivity of these techniques is potentially log orders of magnitude more sensitive. Molecular techniques can be adapted to drug susceptibility testing. The differential activity and post-antibiotic effect of various drugs against TB have led to highly effective briefer regimens and to directly observed therapy. Insights into basic host defense against TB and description of the M. tuberculosis genome have created optimism for developing new treatments and effective vaccines in the years to come. PMID:16555622

  8. Immunology of vaccination.

    PubMed

    Beverley, P C L

    2002-01-01

    An ideal vaccine is relatively easy to define, but few real vaccines approach the ideal and no vaccines exist for many organisms, for which a vaccine is the only realistic protective strategy in the foreseeable future. Many difficulties account for the failure to produce these vaccines. All micro-organisms deploy evasion mechanisms that interfere with effective immune responses and, for many organisms, it is not clear which immune responses provide effective protection. However, recent advances in methods for studying immune response to pathogens have provided a better understanding of immune mechanisms, including immunological memory, and led to the realisation that the initiation of immune responses is a key event requiring triggering through 'danger' signals. Based on these findings, the development of novel adjuvants, vectors and vaccine formulations allowing stimulation of optimal and prolonged protective immunity should lead to the introduction of vaccines for previously resistant organisms. PMID:12176847

  9. Hypoxia: a window into Mycobacterium tuberculosis latency.

    PubMed

    Rustad, Tige R; Sherrid, Ashley M; Minch, Kyle J; Sherman, David R

    2009-08-01

    Tuberculosis is a massive public health problem on a global scale and the success of Mycobacterium tuberculosis is linked to its ability to persist within humans for long periods without causing any overt disease symptoms. Hypoxia is predicted to be a key host-induced stress limiting growth of the pathogen in vivo. However, multiple studies in vitro and in vivo indicate that M. tuberculosis adapts to oxygen limitation by entering into a metabolically altered state, while awaiting the opportunity to reactivate. Molecular signatures of bacteria adapted to hypoxia in vitro are accumulating, although correlations to human disease are only now being established. Similarly, defining the mechanisms that control this adaptation is an active area of research. In this review we discuss the historical precedents linking hypoxia and latency, and the gathering knowledge of M. tuberculosis hypoxic responses. We also examine the role of these responses in tuberculosis latency, and identify promising avenues for future studies.

  10. The Importance of First Impressions: Early Events in Mycobacterium tuberculosis Infection Influence Outcome

    PubMed Central

    Cadena, Anthony M.; Fortune, Sarah M.

    2016-01-01

    ABSTRACT Tuberculosis remains a major health threat in much of the world. New vaccines against Mycobacterium tuberculosis are essential for preventing infection, disease, and transmission. However, the host immune responses that need to be induced by an effective vaccine remain unclear. Increasingly, it has become clear that early events in infection are of major importance in the eventual outcome of the infection. Studying such events in humans is challenging, as they occur within the lung and thoracic lymph nodes, and any clinical signs of early infection are relatively nonspecific. Nonetheless, clinical studies and animal models of tuberculosis have provided new insights into the local events that occur in the first few weeks of tuberculosis. Development of an effective vaccine requires a clear understanding of the successful (and detrimental) early host responses against M. tuberculosis, with the goal to improve upon natural immune responses and prevent infection or disease. PMID:27048801

  11. The Importance of First Impressions: Early Events in Mycobacterium tuberculosis Infection Influence Outcome.

    PubMed

    Cadena, Anthony M; Flynn, JoAnne L; Fortune, Sarah M

    2016-01-01

    Tuberculosis remains a major health threat in much of the world. New vaccines against Mycobacterium tuberculosis are essential for preventing infection, disease, and transmission. However, the host immune responses that need to be induced by an effective vaccine remain unclear. Increasingly, it has become clear that early events in infection are of major importance in the eventual outcome of the infection. Studying such events in humans is challenging, as they occur within the lung and thoracic lymph nodes, and any clinical signs of early infection are relatively nonspecific. Nonetheless, clinical studies and animal models of tuberculosis have provided new insights into the local events that occur in the first few weeks of tuberculosis. Development of an effective vaccine requires a clear understanding of the successful (and detrimental) early host responses against M. tuberculosis, with the goal to improve upon natural immune responses and prevent infection or disease.

  12. Tuberculosis Prevention

    MedlinePlus

    ... Patients Procedure for Accessing Lab Services Data Package Requirements AIDS Therapies Resource Guide In Vitro Efficacy Evaluations ... Assurances to Users Application and Approval Process User Requirements Malaria Vaccine Production Services Data Sharing and Release ...

  13. Global routine vaccination coverage, 2013.

    PubMed

    Harris, Jennifer B; Gacic-Dobo, Marta; Eggers, Rudolf; Brown, David W; Sodha, Samir V

    2014-11-21

    In 1974, the World Health Organization (WHO) established the Expanded Program on Immunization to ensure that all children have access to routinely recommended vaccines. Since then, global coverage with the four core vaccines (Bacille Calmette-Guérin vaccine [for protection against tuberculosis], diphtheria-tetanus-pertussis vaccine [DTP], polio vaccine, and measles vaccine) has increased from <5% to ≥84%, and additional vaccines have been added to the recommended schedule. Coverage with the third dose of DTP vaccine (DTP3) by age 12 months is a key indicator of immunization program performance. Estimated global DTP3 coverage has remained at 83%-84% since 2009, with estimated 2013 coverage at 84%. Global coverage estimates for the second routine dose of measles-containing vaccine (MCV2) are reported for the first time in 2013; global coverage was 35% by the end of the second year of life and 53% when including older age groups. Improvements in equity of access and use of immunization services will help ensure that all children are protected from vaccine-preventable diseases. PMID:25412062

  14. [Retrospect of tuberculosis control in Brazil].

    PubMed

    Hijjar, Miguel Aiub; Gerhardt, Germano; Teixeira, Gilmário M; Procópio, Maria José

    2007-09-01

    The aim of the study was to look back on the course of action involving measures of tuberculosis control in Brazil since the end of the 19th century, covering the history of social struggles and pointing out institutions and people that have dedicated themselves to looking for solutions to these issues. The Brazilian response to tuberculosis started in society with the Ligas Contra a Tuberculose (Leagues Against Tuberculosis), promoting scientific advances, such as the BCG vaccination, which begun in 1927. From the public power, the Inspetoria de Profilaxia da TB (TB Prophylaxis Inspection Service - 1920), the Serviço Nacional de Tuberculose (National Service of Tuberculosis - 1940), and the Campanha Nacional Contra a Tuberculose (National Campaign Against Tuberculosis - 1946), coordinated national policies such as chemotherapy, beginning with the discovery of streptomycin in 1944. The emergence of bacterial resistance led to the development of several therapeutic schemes. The Scheme 1 (rifampycin, hydrazide and pyrazinamid), which was the main one in 1979 and is still used nowadays, had a great epidemiological effect. The WHO declared TB a public health emergency in 1993. In response, Brazil developed some strategies; the first one was the Plano Emergencial para Controle da Tuberculose (Emergency Plan for Tuberculosis Control - 1994), prioritizing 230 municipalities. The current prospects are an effective municipalization of actions and their greater integration with the Programas de Agentes Comunitários e Saúde da Família (Humanitarian Agents and Family Health Programs).

  15. Veterinary and human vaccine evaluation methods.

    PubMed

    Knight-Jones, T J D; Edmond, K; Gubbins, S; Paton, D J

    2014-06-01

    Despite the universal importance of vaccines, approaches to human and veterinary vaccine evaluation differ markedly. For human vaccines, vaccine efficacy is the proportion of vaccinated individuals protected by the vaccine against a defined outcome under ideal conditions, whereas for veterinary vaccines the term is used for a range of measures of vaccine protection. The evaluation of vaccine effectiveness, vaccine protection assessed under routine programme conditions, is largely limited to human vaccines. Challenge studies under controlled conditions and sero-conversion studies are widely used when evaluating veterinary vaccines, whereas human vaccines are generally evaluated in terms of protection against natural challenge assessed in trials or post-marketing observational studies. Although challenge studies provide a standardized platform on which to compare different vaccines, they do not capture the variation that occurs under field conditions. Field studies of vaccine effectiveness are needed to assess the performance of a vaccination programme. However, if vaccination is performed without central co-ordination, as is often the case for veterinary vaccines, evaluation will be limited. This paper reviews approaches to veterinary vaccine evaluation in comparison to evaluation methods used for human vaccines. Foot-and-mouth disease has been used to illustrate the veterinary approach. Recommendations are made for standardization of terminology and for rigorous evaluation of veterinary vaccines.

  16. Tuberculosis (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Tuberculosis KidsHealth > For Parents > Tuberculosis Print A A A Text Size What's in ... When to You Call the Doctor en español Tuberculosis Tuberculosis (popularly known as "TB") is a disease ...

  17. Polio Vaccination

    MedlinePlus

    ... inactive polio vaccine OPV=oral polio vaccine Polio Vaccination Pronounced [PO-lee-oh] Recommend on Facebook Tweet ... handling and storage Related Pages Global Vaccines and Immunization Global Polio Also Known As & Abbreviations Polio=poliomyelitis ...

  18. The Human Antibody Response to the Surface of Mycobacterium tuberculosis

    PubMed Central

    Perley, Casey C.; Frahm, Marc; Click, Eva M.; Dobos, Karen M.; Ferrari, Guido; Stout, Jason E.; Frothingham, Richard

    2014-01-01

    Background Vaccine-induced human antibodies to surface components of Haemophilus influenzae and Streptococcus pneumonia are correlated with protection. Monoclonal antibodies to surface components of Mycobacterium tuberculosis are also protective in animal models. We have characterized human antibodies that bind to the surface of live M. tuberculosis. Methods Plasma from humans with latent tuberculosis (TB) infection (n = 23), active TB disease (n = 40), and uninfected controls (n = 9) were assayed by ELISA for reactivity to the live M. tuberculosis surface and to inactivated M. tuberculosis fractions (whole cell lysate, lipoarabinomannan, cell wall, and secreted proteins). Results When compared to uninfected controls, patients with active TB disease had higher antibody titers to the surface of live M. tuberculosis (Δ = 0.72 log10), whole cell lysate (Δ = 0.82 log10), and secreted proteins (Δ = 0.62 log10), though there was substantial overlap between the two groups. Individuals with active disease had higher relative IgG avidity (Δ = 1.4 to 2.6) to all inactivated fractions. Surprisingly, the relative IgG avidity to the live M. tuberculosis surface was lower in the active disease group than in uninfected controls (Δ = –1.53, p = 0.004). Patients with active disease had higher IgG than IgM titers for all inactivated fractions (ratios, 2.8 to 10.1), but equal IgG and IgM titers to the live M. tuberculosis surface (ratio, 1.1). Higher antibody titers to the M. tuberculosis surface were observed in active disease patients who were BCG-vaccinated (Δ = 0.55 log10, p = 0.008), foreign-born (Δ = 0.61 log10, p = 0.004), or HIV-seronegative (Δ = 0.60 log10, p = 0.04). Higher relative IgG avidity scores to the M. tuberculosis surface were also observed in active disease patients who were BCG-vaccinated (Δ = 1.12, p<0.001) and foreign-born (Δ = 0.87, p = 0.01). Conclusions/Significance Humans

  19. Drug-resistant tuberculosis: emerging treatment options

    PubMed Central

    Adhvaryu, Meghna; Vakharia, Bhasker

    2011-01-01

    Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug–drug interactions in patients coinfected with human immunodeficiency virus (HIV), inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drugsusceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO) has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and markers for adequacy of treatment and an integrative approach to fulfill WHO goals. However, regulatory control over the drug market, as well as public-private partnership to use health program facilities to track patients and ensure

  20. [Vaccines in the year 2000].

    PubMed

    Lambert, P H

    1997-01-01

    Vaccinology nowadays is going through an explosive "evolution". This development, which is due to progress in molecular biology and immunology, is accompanied by a world-wide change of how we view vaccination strategies. Thus, the vaccination of travellers and migrants should be increasingly included in the global control of the infectious diseases. The risks linked to travelling, which thanks to extensive vaccination are now better controlled globally, should decrease as the success of these programs grows. However, risks connected to those diseases, which do not yet lend themselves to preventive mass vaccination carried out systematically, will no doubt prevail for a long time. This is the case, for example, for diarrhetic diseases, typhoid fever, malaria, severe respiratory diseases, AIDS, tuberculosis or more regional diseases such as dengue or leishmaniasis. As far as vaccination is concerned, the best approach must take into account industrial feasibility and immunological considerations, as to the nature of the "target" of these new vaccines and the desired time of protection. It is also necessary to simplify immunization protocols in order to improve conditions for those who are vaccinated. Priority is given to the search for new vaccinal formulas compatible with these objectives. Significant changes in the domain of vaccination should therefore be expected in a future near enough to have an impact on our upcoming preventive programs ... from the year 2000 onwards.

  1. Tuberculosis: a new vision for the 21st century.

    PubMed

    Small, Peter M

    2009-11-01

    Tuberculosis is a global problem that we can't afford to keep ignoring. In 2006, tuberculosis killed 1.7 million people--almost twice as many people as malaria--and it is the leading cause of death among people living with HIV/AIDS. This is all the more tragic because these deaths are preventable. For a long time the world thought that we had defeated tuberculosis, but just because tuberculosis doesn't make headlines doesn't mean it has gone away. The fact is that tuberculosis is getting worse, as complacency and lack of adequate tools and funding fuel the disease and the spread of drug resistance. Drug resistant tuberculosis is the wake-up call, it is an airborne epidemic of increasingly untreatable disease. Drug resistant tuberculosis develops when tuberculosis patients take low-quality drugs, do not finish their full course of treatment, or pass drug resistant tuberculosis from one person to another. In 2007, there were approximately 500,000 cases of drug resistant tuberculosis globally. MDR-TB is resistant to the two most commonly used first-line TB drugs, and requires long, complex and expensive treatment. XDR-TB is resistant to first- and second-line drugs, severely limiting treatment options. While progress is being made, much more is needed. Basic tuberculosis control is one of the most cost-effective interventions in global health. Appropriate treatment can save a life and stop the spread of disease for US$14. It is essential that countries implement the World Health Organization's (WHO) internationally recommended Stop TB strategy, which includes DOTS. But due to outdated tools and methods, DOTS alone is not enough. The remarkable fact is that global control of tuberculosis, a disease that kills someone every 20 seconds, depends upon a 125-year-old test, an 85-year-old vaccine and drugs that take six months to cure and haven't changed in four decades. To successfully treat tuberculosis and prevent resistance, we need to use current tools better and

  2. Tip of nose tuberculosis: A rare presentation of extra pulmonary tuberculosis

    PubMed Central

    Bajaj, Darshan K.; Verma, Ajay K.; Jaiswal, Riddhi; Kant, Surya; Patel, Anand; Asnani, Mona

    2016-01-01

    Summary Tuberculosis is notorious that it affects various sites of the human body and presents in different ways. One of the uncommon or rather rare presentation of extra pulmonary tuberculosis is nasal tuberculosis. The nose apart from its physiological functions also contributes to facial aesthetics and gives a defined appearance and its deformity imparts cosmetic disfigurement and unsightly appearance. Both primary and secondary forms of nasal tuberculosis are rare but should be considered in the differential diagnosis of ulcerative or crusting lesions of the nose. Here we report such a case of nasal tuberculosis, which presented as an ulcerative and crusting lesion over the tip of the nose in a female child. The patient was given antituberculous chemotherapy after establishing the diagnosis and responded well to treatment. PMID:27195200

  3. Abdominal tuberculosis.

    PubMed Central

    Ahmed, M. E.; Hassan, M. A.

    1994-01-01

    The abdomen is involved in 10% to 30% of patients with pulmonary tuberculosis. The diagnosis is not difficult in societies where the disease is common and clinicians are aware of it. While previously rare in Western countries, the incidence is now rising among immigrants, and patients with AIDS. In HIV-infected patients, the disease is of a rapidly progressive nature, often fatal through usually treatable, but the diagnosis is difficult and often delayed. Treatment is essentially medical but occasionally surgical operation is necessary. PMID:8154817

  4. Vaccine hesitancy

    PubMed Central

    Dubé, Eve; Laberge, Caroline; Guay, Maryse; Bramadat, Paul; Roy, Réal; Bettinger, Julie A.

    2013-01-01

    Despite being recognized as one of the most successful public health measures, vaccination is perceived as unsafe and unnecessary by a growing number of individuals. Lack of confidence in vaccines is now considered a threat to the success of vaccination programs. Vaccine hesitancy is believed to be responsible for decreasing vaccine coverage and an increasing risk of vaccine-preventable disease outbreaks and epidemics. This review provides an overview of the phenomenon of vaccine hesitancy. First, we will characterize vaccine hesitancy and suggest the possible causes of the apparent increase in vaccine hesitancy in the developed world. Then we will look at determinants of individual decision-making about vaccination. PMID:23584253

  5. Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints

    PubMed Central

    McEvoy, Christopher R. E.; Cloete, Ruben; Müller, Borna; Schürch, Anita C.; van Helden, Paul D.; Gagneux, Sebastien; Warren, Robin M.; Gey van Pittius, Nicolaas C.

    2012-01-01

    Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of “classical” antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design. PMID:22496726

  6. New vaccines: challenges of discovery.

    PubMed

    Mahmoud, Adel

    2016-09-01

    Vaccines have been a major component of preventing and controlling infectious diseases. The basis for discovery of what protects is reviewed as well as new attempts in utilizing Reverse Vaccinology, RNA-RNA methods and proteome analysis are adding significantly to our knowledge. The challenge of how to define protective and defined components of microbes is still hampering efforts to discover new vaccines. Recent excitement about immunotherapy of cancer opens the way to develop vaccines against multiple malignancies. PMID:27534704

  7. Genetic diversity and dynamic distribution of Mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in Thailand.

    PubMed

    Srilohasin, Prapaporn; Chaiprasert, Angkana; Tokunaga, Katsushi; Nishida, Nao; Prammananan, Therdsak; Smittipat, Nat; Mahasirimongkol, Surakameth; Chaiyasirinroje, Boonchai; Yanai, Hideki; Palittapongarnpim, Prasit

    2014-12-01

    This study examined the genetic diversity and dynamicity of circulating Mycobacterium tuberculosis strains in Thailand using nearly neutral molecular markers. The single nucleotide polymorphism (SNP)-based genotypes of 1,414 culture-positive M. tuberculosis isolates from 1,282 pulmonary tuberculosis (PTB) and 132 extrapulmonary TB (EPTB) patients collected from 1995 to 2011 were characterized. Among the eight SNP cluster groups (SCG), SCG2 (44.1%), which included the Beijing (BJ) genotype, and SCG1 (39.4%), an East African Indian genotype, were dominant. Comparisons between the genotypes of M. tuberculosis isolates causing PTB and EPTB in HIV-negative cases revealed similar prevalence trends although genetic diversity was higher in the PTB patients. The identification of 10 reported sequence types (STs) and three novel STs was hypothesized to indicate preferential expansion of the SCG2 genotype, especially the modern BJ ST10 (15.6%) and ancestral BJ ST19 (13.1%). An association between SCG2 and SCG1 genotypes and particular patient age groups implies the existence of different genetic advantages among the bacterial populations. The results revealed that increasing numbers of young patients were infected with M. tuberculosis SCGs 2 and 5, which contrasts with the reduction of the SCG1 genotype. Our results indicate the selection and dissemination of potent M. tuberculosis genotypes in this population. The determination of heterogeneity and dynamic population changes of circulating M. tuberculosis strains in countries using the Mycobacterium bovis BCG (bacillus Calmette-Guérin) vaccine are beneficial for vaccine development and control strategies.

  8. Vikings against tuberculosis: the International Tuberculosis Campaign in India, 1948-1951.

    PubMed

    Brimnes, Niels

    2007-01-01

    Between 1947 and 1951 the Scandinavian-led International Tuberculosis Campaign tested more than 37 million children and adolescents for tuberculosis, and vaccinated more than 16 million with BCG vaccine. The campaign was an early example of an international health program, and it was generally seen as the largest medical campaign to date. It was born, however, as a Danish effort to create goodwill in war-ravaged Europe, and was extended outside Europe only because UNICEF in 1948 unexpectedly donated US $2 million specifically for BCG vaccination in areas outside Europe. As the campaign transformed from postwar relief to an international health program it was forced to make adaptations to different demographic, social, and cultural contexts. This created a tension between a scientific ideal of uniformity, on the one hand, and pragmatic flexibility on the other. Looking at the campaign in India, which was the most important non-European country in the campaign, this article analyzes three issues in more detail: the development of a simplified vaccination technique; the employment of lay-vaccinators; and whether the campaign in India was conceived as a short-term demonstration or a more extensive mass-vaccination effort.

  9. Vikings against tuberculosis: the International Tuberculosis Campaign in India, 1948-1951.

    PubMed

    Brimnes, Niels

    2007-01-01

    Between 1947 and 1951 the Scandinavian-led International Tuberculosis Campaign tested more than 37 million children and adolescents for tuberculosis, and vaccinated more than 16 million with BCG vaccine. The campaign was an early example of an international health program, and it was generally seen as the largest medical campaign to date. It was born, however, as a Danish effort to create goodwill in war-ravaged Europe, and was extended outside Europe only because UNICEF in 1948 unexpectedly donated US $2 million specifically for BCG vaccination in areas outside Europe. As the campaign transformed from postwar relief to an international health program it was forced to make adaptations to different demographic, social, and cultural contexts. This created a tension between a scientific ideal of uniformity, on the one hand, and pragmatic flexibility on the other. Looking at the campaign in India, which was the most important non-European country in the campaign, this article analyzes three issues in more detail: the development of a simplified vaccination technique; the employment of lay-vaccinators; and whether the campaign in India was conceived as a short-term demonstration or a more extensive mass-vaccination effort. PMID:17844722

  10. Parental knowledge of paediatric vaccination

    PubMed Central

    Borràs, Eva; Domínguez, Àngela; Fuentes, Miriam; Batalla, Joan; Cardeñosa, Neus; Plasencia, Antoni

    2009-01-01

    Background Although routine vaccination is a major tool in the primary prevention of some infectious diseases, there is some reluctance in a proportion of the population. Negative parental perceptions of vaccination are an important barrier to paediatric vaccination. The aim of this study was to investigate parental knowledge of paediatric vaccines and vaccination in Catalonia. Methods A retrospective, cross-sectional study was carried out in children aged < 3 years recruited by random sampling from municipal districts of all health regions of Catalonia. The total sample was 630 children. Parents completed a standard questionnaire for each child, which included vaccination coverage and knowledge about vaccination. The level of knowledge of vaccination was scored according to parental answers. Results An association was observed between greater vaccination coverage of the 4:4:4:3:1 schedule (defined as: 4 DTPa/w doses, 4 Hib doses, 4 OPV doses, 3 MenC doses and 1 MMR dose) and maternal age >30 years (OR: 2.30; 95% CI: 1.20–4.43) and with a knowledge of vaccination score greater than the mean (OR: 0.45; 95% CI: 0.28–0.72). The score increased with maternal educational level and in parents of vaccinated children. A total of 20.47% of parents stated that vaccines could have undesirable consequences for their children. Of these, 23.26% had no specific information and 17.83% stated that vaccines can cause adverse reactions and the same percentage stated that vaccines cause allergies and asthma. Conclusion Higher vaccination coverage is associated with older maternal age and greater knowledge of vaccination. Vaccination coverage could be raised by improving information on vaccines and vaccination. PMID:19473498

  11. A novel tuberculosis antigen identified from human tuberculosis granulomas.

    PubMed

    Yu, Yang; Jin, Dongdong; Hu, Shizong; Zhang, Yan; Zheng, Xiaojing; Zheng, Jianhua; Liao, Mingfeng; Chen, Xinchun; Graner, Michael; Liu, Haiying; Jin, Qi

    2015-04-01

    Tuberculosis is a global infectious disease caused by Mycobacterium tuberculosis (Mtb). Although novel Mtb biomarkers from both the pathogen and host have been studied, more breakthroughs are still needed to meet different clinic requirements. In an effort to identify Mtb antigens, chaperone-peptide complexes were purified from TB infected lungs using free-solution isoelectric focusing combined with high resolution LTQ Orbitrap Velos mass spectrometry. Antigen specific cellular immune responses in vitro were then examined. Those efforts led to the identification of six Mtb peptides only identified in Tuberculosis lung samples and that were not found in the control samples. Additionally, antigen-specific IFN-γ secretion, T-cell proliferation, cytokine expression, and a cytotoxic assay were also evaluated. Among the peptides isolated, we identified a 34 amino acid peptide named PKAp belonging to a serine/threonine-protein kinase, as being able to generate Mtb-specific cellular immune responses as noted by elevated antigen-specific cytokine secretion levels, increased CD8(+) T-cell proliferation and a strong cytotoxic lymphocyte (CTL) response. Moreover, the immune stimulating abilities of PKAp were further validated in vivo, with target peptide immunized mice showing an increased cellular IFN-γ in both the lungs and spleen without causing immunopathogenesis. In conclusion, we identified novel functional Mtb antigens directly from the granulomatous lesions of Tuberculosis patients, inducing not only significant antigen-specific IFN-γ secretion but also a marked cytotoxic lymphocyte functional response. These findings indicated that PKAp has potential as a novel antigen biomarker for vaccine development. PMID:25605460

  12. IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

    PubMed Central

    Marín, Nancy D.; Marín, Diana M.; López, Lucelly; Henao, Hanna M.; Martínez, Teresita; Villa, Liliana; Barrera, Luis F.; Ortiz, Blanca L.; Ramírez, María E.; Montes, Carlos J.; Oquendo, María C.; Arango, Lisandra M.; Riaño, Felipe; Aguirre, Carlos; Bustamante, Alberto; Belisle, John T.; Dobos, Karen; Mejía, Gloria I.; Giraldo, Margarita R.; Brennan, Patrick J.; Robledo, Jaime; Arbeláez, María P.; Rojas, Carlos A.; García, Luis F.

    2009-01-01

    Objectives Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNγ produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNγ levels in HHCs correlate with tuberculosis development. Methods A cohort of 2060 HHCs was followed for 2–3 years after exposure to a tuberculosis case. Besides TST, IFNγ responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. Results Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNγ response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNγ responders to CFP-10 (HR 1.82 95% CI 0.79–4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNγ producers was observed (trend Log rank p = 0.007). Discussion CFP-10-induced IFNγ production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high

  13. [Update on the radiological study of pulmonary tuberculosis].

    PubMed

    Navarro Ballester, A; Marco Domenech, S F

    2015-01-01

    Tuberculosis has made a comeback in recent years. This upsurge has been attributed to factors such as increased immigration and the human immunodeficiency virus epidemic. Primary pulmonary tuberculosis manifests radiologically with parenchymal involvement, lymph node involvement, pleural effusion, and/or miliary disease. In post-primary tuberculosis, the earliest radiological sign is small nodules and branching centrilobular lesions that increase in size and coalesce to form ill-defined patchy consolidations; cavitations are very characteristic of active disease. The aim of this article is to describe the radiologic findings for pulmonary tuberculosis and its complications. PMID:26074301

  14. [Update on the radiological study of pulmonary tuberculosis].

    PubMed

    Navarro Ballester, A; Marco Domenech, S F

    2015-01-01

    Tuberculosis has made a comeback in recent years. This upsurge has been attributed to factors such as increased immigration and the human immunodeficiency virus epidemic. Primary pulmonary tuberculosis manifests radiologically with parenchymal involvement, lymph node involvement, pleural effusion, and/or miliary disease. In post-primary tuberculosis, the earliest radiological sign is small nodules and branching centrilobular lesions that increase in size and coalesce to form ill-defined patchy consolidations; cavitations are very characteristic of active disease. The aim of this article is to describe the radiologic findings for pulmonary tuberculosis and its complications.

  15. [Fight against tuberculosis in the world].

    PubMed

    El Kamel, A; Joobeur, S; Skhiri, N; Cheikh Mhamed, S; Mribah, H; Rouatbi, N

    2015-01-01

    Tuberculosis (TB) in a major health problem in the world. WHO and its partners especially, the stop TB partnership launched numerous strategies against TB especially in the 1990. Strategy DOTS (directly observed therapy short course) was launched in 1995. One main key was the direct supervision of drug intake by patients. Progress was achieved but it was insufficient. A new strategy called "Stop TB Strategy 2006-2015" was launched in 2006 in the context of Millennium Development Goals (MDG) elaborated by United Nations. The common goals were to halt and start to reverse the incidence of TB, reduce the prevalence and death rate by 50% compared to their level in 1990 by 2015 to eliminate TB as a public health problem by 2050. The end of 2010 marks the mid-point of the Global Plan and is an obvious time to update it and take into account actual progress with a focus on the 2015 to reach goals. So an updated Global Plan to stop TB 2011-2015, was launched. Expected progress and targets were defined for 2015, in diagnosis and treatment, in co-infection TB/HIV, in drug-resistant TB and achievements expected in new tests for diagnosis, new medications, new vaccines and new regimens with shorter duration of treatment. WHO and partners have started discussions to define the new post 2015 strategy to TB control and elimination. Risk factors (diabetes, malnutrition, tobacco smoke…) and socioeconomic factors, which are associated with TB, should be included in the new strategy to eliminate TB in 2050.

  16. Defining "Development".

    PubMed

    Pradeu, Thomas; Laplane, Lucie; Prévot, Karine; Hoquet, Thierry; Reynaud, Valentine; Fusco, Giuseppe; Minelli, Alessandro; Orgogozo, Virginie; Vervoort, Michel

    2016-01-01

    Is it possible, and in the first place is it even desirable, to define what "development" means and to determine the scope of the field called "developmental biology"? Though these questions appeared crucial for the founders of "developmental biology" in the 1950s, there seems to be no consensus today about the need to address them. Here, in a combined biological, philosophical, and historical approach, we ask whether it is possible and useful to define biological development, and, if such a definition is indeed possible and useful, which definition(s) can be considered as the most satisfactory.

  17. Advocacy, partnership and political commitment for TB vaccine research.

    PubMed

    Olesen, Ole F; Chan, Sharon; Chappell, Janice; Guo, Yan; Leite, Luciana C C

    2016-08-01

    The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Advancing the Pipeline: A Vision for the Next Decade, Engaging the BRICS: Basic Research to Manufacturing, and Regulatory and Access Issues for New TB Vaccines. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30]. PMID:27402313

  18. Advocacy, partnership and political commitment for TB vaccine research.

    PubMed

    Olesen, Ole F; Chan, Sharon; Chappell, Janice; Guo, Yan; Leite, Luciana C C

    2016-08-01

    The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Advancing the Pipeline: A Vision for the Next Decade, Engaging the BRICS: Basic Research to Manufacturing, and Regulatory and Access Issues for New TB Vaccines. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30].

  19. Defining Infertility

    MedlinePlus

    ... of the American Society for Reproductive Medicine Defining infertility What is infertility? Infertility is “the inability to conceive after 12 months ... to conceive after 6 months is generally considered infertility. How common is it? Infertility affects 10%-15% ...

  20. The analysis of optimal singular controls for SEIR model of tuberculosis

    NASA Astrophysics Data System (ADS)

    Marpaung, Faridawaty; Rangkuti, Yulita M.; Sinaga, Marlina S.

    2014-12-01

    The optimally of singular control for SEIR model of Tuberculosis is analyzed. There are controls that correspond to time of the vaccination and treatment schedule. The optimally of singular control is obtained by differentiate a switching function of the model. The result shows that vaccination and treatment control are singular.

  1. Gene Transfer in Mycobacterium tuberculosis: Shuttle Phasmids to Enlightenment.

    PubMed

    Jacobs, William R

    2014-04-01

    Infectious diseases have plagued humankind throughout history and have posed serious public health problems. Yet vaccines have eradicated smallpox and antibiotics have drastically decreased the mortality rate of many infectious agents. These remarkable successes in the control of infections came from knowing the causative agents of the diseases, followed by serendipitous discoveries of attenuated viruses and antibiotics. The discovery of DNA as genetic material and the understanding of how this information translates into specific phenotypes have changed the paradigm for developing new vaccines, drugs, and diagnostic tests. Knowledge of the mechanisms of immunity and mechanisms of action of drugs has led to new vaccines and new antimicrobial agents. The key to the acquisition of the knowledge of these mechanisms has been identifying the elemental causes (i.e., genes and their products) that mediate immunity and drug resistance. The identification of these genes is made possible by being able to transfer the genes or mutated forms of the genes into causative agents or surrogate hosts. Such an approach was limited in Mycobacterium tuberculosis by the difficulty of transferring genes or alleles into M. tuberculosis or a suitable surrogate mycobacterial host. The construction of shuttle phasmids-chimeric molecules that replicate in Escherichia coli as plasmids and in mycobacteria as mycobacteriophages-was instrumental in developing gene transfer systems for M. tuberculosis. This review will discuss M. tuberculosis genetic systems and their impact on tuberculosis research.

  2. Gene Transfer in Mycobacterium tuberculosis: Shuttle Phasmids to Enlightenment

    PubMed Central

    JACOBS, WILLIAM R.

    2016-01-01

    Infectious diseases have plagued humankind throughout history and have posed serious public health problems. Yet vaccines have eradicated smallpox and antibiotics have drastically decreased the mortality rate of many infectious agents. These remarkable successes in the control of infections came from knowing the causative agents of the diseases, followed by serendipitous discoveries of attenuated viruses and antibiotics. The discovery of DNA as genetic material and the understanding of how this information translates into specific phenotypes have changed the paradigm for developing new vaccines, drugs, and diagnostic tests. Knowledge of the mechanisms of immunity and mechanisms of action of drugs has led to new vaccines and new antimicrobial agents. The key to the acquisition of the knowledge of these mechanisms has been identifying the elemental causes (i.e., genes and their products) that mediate immunity and drug resistance. The identification of these genes is made possible by being able to transfer the genes or mutated forms of the genes into causative agents or surrogate hosts. Such an approach was limited in Mycobacterium tuberculosis by the difficulty of transferring genes or alleles into M. tuberculosis or a suitable surrogate mycobacterial host. The construction of shuttle phasmids—chimeric molecules that replicate in Escherichia coli as plasmids and in mycobacteria as mycobacteriophages—was instrumental in developing gene transfer systems for M. tuberculosis. This review will discuss M. tuberculosis genetic systems and their impact on tuberculosis research. “I had to know my enemy in order to prevail against him.”Nelson Mandela PMID:26105819

  3. Therapeutic vaccination to treat chronic infectious diseases: current clinical developments using MVA-based vaccines.

    PubMed

    Boukhebza, Houda; Bellon, Nadine; Limacher, Jean Marc; Inchauspé, Geneviève

    2012-12-01

    A famous milestone in the vaccine field has been the first successful vaccination against smallpox, in 1798, by Edward Jenner. Using the vaccinia cowpox virus, Jenner was able to protect vaccinees from variola or smallpox. The Modified Virus Ankara (MVA) poxvirus strain has been one of the vaccines subsequently developed to prevent smallpox infection and was selected by the US government in their Biodefense strategy. Progress in molecular biology and immunology associated with MVA infection has led to the development of MVA as vaccine platform, both in the field of preventive and therapeutic vaccines. This later class of therapeutics has witnessed growing interest that has translated into an increasing number of vaccine candidates reaching the clinics. Among those, MVA-based therapeutic vaccines have addressed four major chronic infections including viral hepatitis, AIDS, human papillomavirus-linked pathologies and tuberculosis. Clinical trials encompass phase 1 and 2 and have started to show significant results and promises. PMID:22894957

  4. Defining an emerging disease.

    PubMed

    Moutou, F; Pastoret, P-P

    2015-04-01

    Defining an emerging disease is not straightforward, as there are several different types of disease emergence. For example, there can be a 'real' emergence of a brand new disease, such as the emergence of bovine spongiform encephalopathy in the 1980s, or a geographic emergence in an area not previously affected, such as the emergence of bluetongue in northern Europe in 2006. In addition, disease can emerge in species formerly not considered affected, e.g. the emergence of bovine tuberculosis in wildlife species since 2000 in France. There can also be an unexpected increase of disease incidence in a known area and a known species, or there may simply be an increase in our knowledge or awareness of a particular disease. What all these emerging diseases have in common is that human activity frequently has a role to play in their emergence. For example, bovine spongiform encephalopathy very probably emerged as a result of changes in the manufacturing of meat-and-bone meal, bluetongue was able to spread to cooler climes as a result of uncontrolled trade in animals, and a relaxation of screening and surveillance for bovine tuberculosis enabled the disease to re-emerge in areas that had been able to drastically reduce the number of cases. Globalisation and population growth will continue to affect the epidemiology of diseases in years to come and ecosystems will continue to evolve. Furthermore, new technologies such as metagenomics and high-throughput sequencing are identifying new microorganisms all the time. Change is the one constant, and diseases will continue to emerge, and we must consider the causes and different types of emergence as we deal with these diseases in the future. PMID:26470448

  5. Defining an emerging disease.

    PubMed

    Moutou, F; Pastoret, P-P

    2015-04-01

    Defining an emerging disease is not straightforward, as there are several different types of disease emergence. For example, there can be a 'real' emergence of a brand new disease, such as the emergence of bovine spongiform encephalopathy in the 1980s, or a geographic emergence in an area not previously affected, such as the emergence of bluetongue in northern Europe in 2006. In addition, disease can emerge in species formerly not considered affected, e.g. the emergence of bovine tuberculosis in wildlife species since 2000 in France. There can also be an unexpected increase of disease incidence in a known area and a known species, or there may simply be an increase in our knowledge or awareness of a particular disease. What all these emerging diseases have in common is that human activity frequently has a role to play in their emergence. For example, bovine spongiform encephalopathy very probably emerged as a result of changes in the manufacturing of meat-and-bone meal, bluetongue was able to spread to cooler climes as a result of uncontrolled trade in animals, and a relaxation of screening and surveillance for bovine tuberculosis enabled the disease to re-emerge in areas that had been able to drastically reduce the number of cases. Globalisation and population growth will continue to affect the epidemiology of diseases in years to come and ecosystems will continue to evolve. Furthermore, new technologies such as metagenomics and high-throughput sequencing are identifying new microorganisms all the time. Change is the one constant, and diseases will continue to emerge, and we must consider the causes and different types of emergence as we deal with these diseases in the future.

  6. Clinical value of the measurement of Mycobacterium tuberculosis specific antibody in pulmonary tuberculosis.

    PubMed Central

    Bothamley, G H; Rudd, R; Festenstein, F; Ivanyi, J

    1992-01-01

    BACKGROUND: A serological test that could help to diagnose tuberculosis, especially smear negative disease, would contribute to patient management. METHODS: Levels of antibody to distinct antigens of Mycobacterium tuberculosis were assessed for their value in the diagnosis and management of pulmonary tuberculosis. Serum was taken from 52 patients who were smear positive, from 27 patients who were smear negative but with evidence of active tuberculosis (sputum culture positive in 16, response to antituberculosis chemotherapy in 11), from 11 patients with old healed tuberculosis (pre-antibiotic era), and from 39 healthy subjects vaccinated with BCG. RESULTS: In smear positive tuberculosis an enzyme linked immunosorbent assay using a single 38 kDa antigen gave a diagnostic sensitivity of 80% with a 100% specificity. In smear negative pulmonary tuberculosis, however, combination of the 19 kDa antigen, lipoarabinomannan (ML 34 epitope), and hsp 65 (TB 78 epitope) was needed to achieve a sensitivity of 64% with a specificity of 95%. Recurrent and extensive radiographic disease with a poor prognosis was associated with high anti-38 kDa and low anti-14 kDa antibody levels in patients with active disease. Patients with less pulmonary cavitation had high anti-19 kDa titres. Bacteriological relapse during treatment was indicated by a rise in anti-14 kDa (TB68 epitope) antibodies. Four patients with non-tuberculous mycobacterial infection showed no anti-38 kDa antibody. CONCLUSION: Antigen or epitope specific serology may help in the diagnosis, assessment of prognosis, and monitoring of chemotherapy in patients with pulmonary tuberculosis. PMID:1585290

  7. Tuberculosis and Pregnancy

    MedlinePlus

    ... Contacts of Persons with Infectious TB Epidemiology of Pediatric Tuberculosis in the United States Targeted Tuberculosis Testing ... and unknown risks of second-line antituberculosis drugs. Breastfeeding Breastfeeding should not be discouraged for women being ...

  8. Isolated perianal tuberculosis.

    PubMed

    Akgun, E; Tekin, F; Ersin, S; Osmanoglu, H

    2005-03-01

    Perianal tuberculosis, without the presence of any previous or active pulmonary infection, is extremely rare. A case of isolated perianal tuberculosis without gastrointestinal or pulmonary spread will be discussed here with an evaluation of the clinical features. PMID:15813425

  9. Tuberculosis and Diabetes

    MedlinePlus

    TUBERCULOSIS www.who.int/tb & DIABETES THE DUAL EPIDEMIC OF TB AND DIABETES DEADLY LINKAGES  People with ... higher risk of progressing from latent to active tuberculosis.  Diabetes triples a person’s risk of developing TB. ...

  10. Vaccine Failures in Patients Properly Vaccinated with 13-Valent Pneumococcal Conjugate Vaccine in Catalonia, a Region with Low Vaccination Coverage.

    PubMed

    Moraga-Llop, Fernando; Garcia-Garcia, Juan-Jose; Díaz-Conradi, Alvaro; Ciruela, Pilar; Martínez-Osorio, Johanna; González-Peris, Sebastià; Hernández, Sergi; de Sevilla, Mariona Fernández; Uriona, Sonia; Izquierdo, Conchita; Selva, Laura; Campins, Magda; Codina, Gemma; Batalla, Joan; Esteva, Cristina; Domínguez, Àngela; Muñoz-Almagro, Carmen

    2016-04-01

    Vaccine failures occurring with 13-valent pneumococcal conjugate vaccine (PCV13) in 3 pediatric hospitals in Barcelona (2012-2013) are described. PCV13 vaccine failure was defined as the occurrence of an invasive pneumococcal infection in children properly vaccinated by PCV13. Among 84 patients with invasive pneumococcal infection, 32 had received at least one dose of PCV13. Seventeen of them had invasive pneumococcal infection produced by a PCV13 serotype. Among those, 9 patients were considered to have a PCV13 vaccine failure. Serotype 3 was isolated in 6 patients, serotype 19A in 2 and serotype 6B in 1. PMID:26658626

  11. Defining cure.

    PubMed

    Hilton, Paul; Robinson, Dudley

    2011-06-01

    This paper is a summary of the presentations made as Proposal 2-"Defining cure" to the 2nd Annual meeting of the ICI-Research Society, in Bristol, 16th June 2010. It reviews definitions of 'cure' and 'outcome', and considers the impact that varying definition may have on prevalence studies and cure rates. The difference between subjective and objective outcomes is considered, and the significance that these different outcomes may have for different stakeholders (e.g. clinicians, patients, carers, industry etc.) is discussed. The development of patient reported outcome measures and patient defined goals is reviewed, and consideration given to the use of composite end-points. A series of proposals are made by authors and discussants as to how currently validated outcomes should be applied, and where our future research activity in this area might be directed.

  12. Biomarkers of CD4+ CTL cell Mediated Immunity to Tuberculosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The immune responses mediated by interactions between T-lymphocyte subsets and mycobacteria-infected macrophages are critical for control of tuberculosis. In these studies, the bovine model was used to characterize the cytolytic and mycobactericidal CD4+ T cell response induced by BCG vaccination. ...

  13. Vaccine Safety

    MedlinePlus

    ... During Pregnancy Frequently Asked Questions about Vaccine Recalls Historical Vaccine Safety Concerns FAQs about GBS and Menactra ... CISA Resources for Healthcare Professionals Evaluation Current Studies Historical Background 2001-12 Publications Technical Reports Vaccine Safety ...

  14. Smallpox Vaccination

    MedlinePlus

    ... Newsletters Events Also Known As Smallpox = Vaccinia Smallpox Vaccination Recommend on Facebook Tweet Share Compartir The smallpox ... like many other vaccines. For that reason, the vaccination site must be cared for carefully to prevent ...

  15. Peptide/protein vaccine delivery system based on PLGA particles

    PubMed Central

    Allahyari, Mojgan; Mohit, Elham

    2016-01-01

    abstract Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co-delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DC-based vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to M-cells will be highlighted. PMID:26513024

  16. Tuberculosis incidence among contacts of active pulmonary tuberculosis

    PubMed Central

    Cailleaux-Cezar, M.; de A. Melo, D.; Xavier, G. M.; de Salles, C. L. G.; de Mello, F. C. Q.; Ruffino-Netto, A.; Golub, J. E.; Efron, A.; Chaisson, R. E.; Conde, M. B.

    2013-01-01

    SUMMARY BACKGROUND Treatment of latent tuberculosis (TB) infection (LTBI) in Brazil is recommended only in the case of contacts of pulmonary smear-positive TB patients aged ≤15 years with a tuberculin skin test (TST) ≥10 mm and no previous bacille Calmette-Guérin (BCG) vaccination or with a TST ≥15 mm regardless of previous BCG vaccination. OBJECTIVE To evaluate the 2-year incidence and predictors of TB among contacts who did not meet the Brazilian criteria for LTBI treatment. DESIGN Retrospective cohort study. Contacts aged between 12 and 15 years and those aged >15 years who did not meet the Brazilian criteria for LTBI treatment were enrolled in the study. RESULTS TB incidence was 3.2% (22/667), with an estimated TB rate of 1649 per 100 000 population. Risk of TB was greater among the 349 contacts with TST ≥5 mm (5.4%) compared to the 318 contacts with TST < 5 mm (0.9%; RR 6.04, 95%CI 1.7–20.6). CONCLUSION The high incidence of TB among contacts who did not meet the Brazilian criteria for LTBI treatment strongly suggests that these criteria should be reviewed. Furthermore, even among BCG-vaccinated contacts, TST induration ≥5 mm was the only variable that predicted the development of TB disease within 2 years. PMID:19146746

  17. Systems-based approaches to probing metabolic variation within the Mycobacterium tuberculosis complex.

    PubMed

    Lofthouse, Emma K; Wheeler, Paul R; Beste, Dany J V; Khatri, Bhagwati L; Wu, Huihai; Mendum, Tom A; Kierzek, Andrzej M; McFadden, Johnjoe

    2013-01-01

    The Mycobacterium tuberculosis complex includes bovine and human strains of the tuberculosis bacillus, including Mycobacterium tuberculosis, Mycobacterium bovis and the Mycobacterium bovis BCG vaccine strain. M. bovis has evolved from a M. tuberculosis-like ancestor and is the ancestor of the BCG vaccine. The pathogens demonstrate distinct differences in virulence, host range and metabolism, but the role of metabolic differences in pathogenicity is poorly understood. Systems biology approaches have been used to investigate the metabolism of M. tuberculosis, but not to probe differences between tuberculosis strains. In this study genome scale metabolic networks of M. bovis and M. bovis BCG were constructed and interrogated, along with a M. tuberculosis network, to predict substrate utilisation, gene essentiality and growth rates. The models correctly predicted 87-88% of high-throughput phenotype data, 75-76% of gene essentiality data and in silico-predicted growth rates matched measured rates. However, analysis of the metabolic networks identified discrepancies between in silico predictions and in vitro data, highlighting areas of incomplete metabolic knowledge. Additional experimental studies carried out to probe these inconsistencies revealed novel insights into the metabolism of these strains. For instance, that the reduction in metabolic capability observed in bovine tuberculosis strains, as compared to M. tuberculosis, is not reflected by current genetic or enzymatic knowledge. Hence, the in silico networks not only successfully simulate many aspects of the growth and physiology of these mycobacteria, but also provide an invaluable tool for future metabolic studies.

  18. Pattern recognition and cellular immune responses to novel Mycobacterium tuberculosis-antigens in individuals from Belarus

    PubMed Central

    2012-01-01

    Background Tuberculosis (TB) is an enduring health problem worldwide and the emerging threat of multidrug resistant (MDR) TB and extensively drug resistant (XDR) TB is of particular concern. A better understanding of biomarkers associated with TB will aid to guide the development of better targets for TB diagnosis and for the development of improved TB vaccines. Methods Recombinant proteins (n = 7) and peptide pools (n = 14) from M. tuberculosis (M.tb) antigens associated with M.tb pathogenicity, modification of cell lipids or cellular metabolism, were used to compare T cell immune responses defined by IFN-γ production using a whole blood assay (WBA) from i) patients with TB, ii) individuals recovered from TB and iii) individuals exposed to TB without evidence of clinical TB infection from Minsk, Belarus. Results We identified differences in M.tb target peptide recognition between the test groups, i.e. a frequent recognition of antigens associated with lipid metabolism, e.g. cyclopropane fatty acyl phospholipid synthase. The pattern of peptide recognition was broader in blood from healthy individuals and those recovered from TB as compared to individuals suffering from pulmonary TB. Detection of biologically relevant M.tb targets was confirmed by staining for intracellular cytokines (IL-2, TNF-α and IFN-γ) in T cells from non-human primates (NHPs) after BCG vaccination. Conclusions PBMCs from healthy individuals and those recovered from TB recognized a broader spectrum of M.tb antigens as compared to patients with TB. The nature of the pattern recognition of a broad panel of M.tb antigens will devise better strategies to identify improved diagnostics gauging previous exposure to M.tb; it may also guide the development of improved TB-vaccines. PMID:22336002

  19. Vaccine Hesitancy.

    PubMed

    Jacobson, Robert M; St Sauver, Jennifer L; Finney Rutten, Lila J

    2015-11-01

    Vaccine refusal received a lot of press with the 2015 Disneyland measles outbreak, but vaccine refusal is only a fraction of a much larger problem of vaccine delay and hesitancy. Opposition to vaccination dates back to the 1800 s, Edward Jenner, and the first vaccine ever. It has never gone away despite the public's growing scientific sophistication. A variety of factors contribute to modern vaccine hesitancy, including the layperson's heuristic thinking when it comes to balancing risks and benefits as well as a number of other features of vaccination, including falling victim to its own success. Vaccine hesitancy is pervasive, affecting a quarter to a third of US parents. Clinicians report that they routinely receive requests to delay vaccines and that they routinely acquiesce. Vaccine rates vary by state and locale and by specific vaccine, and vaccine hesitancy results in personal risk and in the failure to achieve or sustain herd immunity to protect others who have contraindications to the vaccine or fail to generate immunity to the vaccine. Clinicians should adopt a variety of practices to combat vaccine hesitancy, including a variety of population health management approaches that go beyond the usual call to educate patients, clinicians, and the public. Strategies include using every visit to vaccinate, the creation of standing orders or nursing protocols to provide vaccination without clinical encounters, and adopting the practice of stating clear recommendations. Up-to-date, trusted resources exist to support clinicians' efforts in adopting these approaches to reduce vaccine hesitancy and its impact. PMID:26541249

  20. Vaccine Hesitancy.

    PubMed

    Jacobson, Robert M; St Sauver, Jennifer L; Finney Rutten, Lila J

    2015-11-01

    Vaccine refusal received a lot of press with the 2015 Disneyland measles outbreak, but vaccine refusal is only a fraction of a much larger problem of vaccine delay and hesitancy. Opposition to vaccination dates back to the 1800 s, Edward Jenner, and the first vaccine ever. It has never gone away despite the public's growing scientific sophistication. A variety of factors contribute to modern vaccine hesitancy, including the layperson's heuristic thinking when it comes to balancing risks and benefits as well as a number of other features of vaccination, including falling victim to its own success. Vaccine hesitancy is pervasive, affecting a quarter to a third of US parents. Clinicians report that they routinely receive requests to delay vaccines and that they routinely acquiesce. Vaccine rates vary by state and locale and by specific vaccine, and vaccine hesitancy results in personal risk and in the failure to achieve or sustain herd immunity to protect others who have contraindications to the vaccine or fail to generate immunity to the vaccine. Clinicians should adopt a variety of practices to combat vaccine hesitancy, including a variety of population health management approaches that go beyond the usual call to educate patients, clinicians, and the public. Strategies include using every visit to vaccinate, the creation of standing orders or nursing protocols to provide vaccination without clinical encounters, and adopting the practice of stating clear recommendations. Up-to-date, trusted resources exist to support clinicians' efforts in adopting these approaches to reduce vaccine hesitancy and its impact.

  1. Scientific challenges and opportunities in developing novel vaccines for the emerging and developing markets: New Technologies in Emerging Markets, October 16th-18th 2012, World Vaccine Congress, Lyon.

    PubMed

    Kochhar, Sonali

    2013-04-01

    Vaccines have had a major role in enhancing the quality of life and increasing life expectancy. Despite these successes and the development of new vaccine technologies, there remain multiple infectious diseases including AIDS, malaria and tuberculosis that require effective prophylactic vaccines. New and traditional technologies have a role in the development and delivery of the new vaccine candidates. The scientific challenges, opportunities and funding models for developing vaccines for low resource settings are highlighted here.

  2. Factors associated with the development of tuberculosis in BCG immunized children.

    PubMed

    Tipayamongkholgul, Mathuros; Podhipak, Amornrath; Chearskul, Sanay; Sunakorn, Pramuan

    2005-01-01

    In this hospital-based case-control study, children attending Siriraj Hospital and Queen Sirikit National Institute of Child Health from 1 December 2002 to 30 June 2003 were studied to define factors associated with TB in BCG immunized children (n = 260). Subjects of the same age and sex were divided into case and control groups by tuberculosis status. Caregivers were interviewed with a structured questionnaire. Data were analyzed by univariate analysis and multivariate analysis for biological factors (birth weight, health status, nutritional status), socioeconomic factors (parental education, education of caregiver, parental occupation, household incomes, and stability of household incomes), and environmental factors (history of contact with a tuberculosis patient, housing ventilation, child's bedroom ventilation, biomass smoke, passive smoking, crowded family and crowded in child's bedroom). Our findings show that children who had contact with TB patients had a very high risk of tuberculosis, even though they were vaccinated at birth. The risks vary according to the closeness level: very close (OR 85.67, 95%CI = 11.33-647.79), close (OR 31.11, 95%CI = 3.93-246.22) and not close (OR 32.70, 95%CI = 4.18-255.94). In order to identify the effect of others variables, the data was reanalyzed only in the group with no history of TB patient contacts (n = 192). Living in a crowded family, which was reflected by an average of 5 or more persons per room, also increased the risk (OR 11.18, 95%CI = 2.35-53.20). The other factor that increased the risk for tuberculosis was passive smoking. Children who were exposed to passive smoking had a 9.31 times increased risk of getting tuberculosis (95%CI = 3.14-27.58). These findings suggest that the public health department must develop a TB surveillance system in high TB prevalence areas, and in high density communities, and encourage smokers in every family to avoid smoking near children. Latent tuberculosis treatment

  3. A Multi-scale Approach to Designing Therapeutics for Tuberculosis

    PubMed Central

    Linderman, Jennifer J.; Cilfone, Nicholas A.; Pienaar, Elsje; Gong, Chang; Kirschner, Denise E.

    2015-01-01

    Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi-compartment view of the in vivo immune response to M. tuberculosis. We describe computational models that can be used to study (a) immunomodulation with the cytokines tumor necrosis factor and interleukin 10, (b) oral and inhaled antibiotics, and (c) the effect of vaccination. PMID:25924949

  4. Cutaneous tuberculosis in children.

    PubMed

    Sethuraman, Gomathy; Ramesh, Venkatesh

    2013-01-01

    Cutaneous tuberculosis is a rare form of extrapulmonary tuberculosis that accounts for 1% to 2% of cases. Childhood skin tuberculosis represents 18% to 82% of all cutaneous tuberculosis cases. Scrofuloderma and lupus vulgaris are the two most common clinical forms in children. An increase in the number of tuberculids, especially lichen scrofulosorum, has been observed in the last several years. Cutaneous tuberculosis in children can be severe and have a protracted course. Multiplicity of lesions and multifocal disseminated involvement in scrofuloderma and lupus vulgaris is common. Scrofuloderma progressing to gummatous lesions (scrofulous gumma) is mostly described in children. Morbidities and deformities are more severe in children.

  5. A brief history of tuberculosis in Iran during the 19th and 20th centuries.

    PubMed

    Azizi, Mohammad Hossein; Bahadori, Moslem

    2011-05-01

    The history of tuberculosis as a worldwide fatal illness traces back to antiquity, a well-known disease in ancient civilizations. However, its causative agent remained unidentified until the last decades of the 19th century, when discovered by Robert Koch. In due course, preparation of the BCG vaccine, application of the Mantoux intradermal diagnostic tuberculosis test and administration of proper antituberculosis medications eventually controlled tuberculosis. However, despite these significant advancements tuberculosis remained uneradicated, particularly in developing countries after the emergence of both multidrug-resistant tuberculosis and HIV co-infection. Presented here, is a brief review of the history of tuberculosis in the world as well as its historical background in Iran, mainly during the 19th and 20th centuries.

  6. Bacterial pathogen genomics and vaccines.

    PubMed

    Moxon, Richard; Rappuoli, Rino

    2002-01-01

    Infectious diseases remain a major cause of deaths and disabilities in the world, the majority of which are caused by bacteria. Although immunisation is the most cost effective and efficient means to control microbial diseases, vaccines are not yet available to prevent many major bacterial infections. Examples include dysentery (shigellosis), gonorrhoea, trachoma, gastric ulcers and cancer (Helicobacter pylori). Improved vaccines are needed to combat some diseases for which current vaccines are inadequate. Tuberculosis, for example, remains rampant throughout most countries in the world and represents a global emergency heightened by the pandemic of HIV. The availability of complete genome sequences has dramatically changed the opportunities for developing novel and improved vaccines and facilitated the efficiency and rapidity of their development. Complete genomic databases provide an inclusive catalogue of all potential candidate vaccines for any bacterial pathogen. In conjunction with adjunct technologies, including bioinformatics, random mutagenesis, microarrays, and proteomics, a systematic and comprehensive approach to identifying vaccine discovery can be undertaken. Genomics must be used in conjunction with population biology to ensure that the vaccine can target all pathogenic strains of a species. A proof in principle of the utility of genomics is provided by the recent exploitation of the complete genome sequence of Neisseria meningitidis group B.

  7. The onset of adaptive immunity in the mouse model of tuberculosis and the factors that compromise its expression.

    PubMed

    Robinson, Richard T; Orme, Ian M; Cooper, Andrea M

    2015-03-01

    Mycobacterium tuberculosis (Mtb) has been evolving with its human host for over 50 000 years and is an exquisite manipulator of the human immune response. It induces both a strong inflammatory and a strong acquired immune response, and Mtb then actively regulates these responses to create an infectious lesion in the lung while maintaining a relatively ambulatory host. The CD4(+) T cell plays a critical yet contradictory role in this process by both controlling disseminated disease while promoting the development of the lesion in the lung that mediates transmission. In light of this manipulative relationship between Mtb and the human immune response, it is not surprising that our ability to vaccinate against tuberculosis (TB) has not been totally successful. To overcome the current impasse in vaccine development, we need to define the phenotype of CD4(+) T cells that mediate protection and to determine those bacterial and host factors that regulate the effective function of these cells. In this review, we describe the initiation and expression of T cells during TB as well as the fulminant inflammatory response that can compromise T-cell function and survival.

  8. [Childhood tuberculosis].

    PubMed

    Hamzaoui, A

    2015-01-01

    Childhood TB is an indication of failing TB control in the community. It allows disease persistence in the population. Mortality and morbidity due to TB is high in children. Moreover, HIV co-infection and multidrug-resistant diseases are as frequent in children as in adults. Infection is more frequent in younger children. Disease risk after primary infection is greatest in infants younger than 2 years. In case of exposure, evidence of infection can be obtained using the tuberculin skin test (TST) or an interferon-gamma assay (IGRA). There is no evidence to support the use of IGRA over TST in young children. TB suspicion should be confirmed whenever possible, using new available tools, particularly in case of pulmonary and lymph node TB. Induced sputum, nasopharyngeal aspiration and fine needle aspiration biopsy provide a rapid and definitive diagnosis of mycobacterial infection in a large proportion of patients. Analysis of paediatric samples revealed higher sensitivity and specificity values of molecular techniques in comparison with the ones originated from adults. Children require higher drugs dosages than adults. Short courses of steroids are associated with TB treatment in case of respiratory distress, bronchoscopic desobstruction is proposed for severe airways involvement and antiretroviral therapy is mandatory in case of HIV infection. Post-exposure prophylaxis in children is a highly effective strategy to reduce the risk of TB disease. The optimal therapy for treatment of latent infection with a presumably multidrug-resistant Mycobacterium tuberculosis strain is currently not known.

  9. Defining chaos

    SciTech Connect

    Hunt, Brian R.; Ott, Edward

    2015-09-15

    In this paper, we propose, discuss, and illustrate a computationally feasible definition of chaos which can be applied very generally to situations that are commonly encountered, including attractors, repellers, and non-periodically forced systems. This definition is based on an entropy-like quantity, which we call “expansion entropy,” and we define chaos as occurring when this quantity is positive. We relate and compare expansion entropy to the well-known concept of topological entropy to which it is equivalent under appropriate conditions. We also present example illustrations, discuss computational implementations, and point out issues arising from attempts at giving definitions of chaos that are not entropy-based.

  10. [Semeiotics of abdominal tuberculosis].

    PubMed

    Guseĭnov, G K; Ramazanova, A M; Guseĭnov, A G

    1984-01-01

    Examination of 119 patients with abdominal tuberculosis permitted the description of the characteristic semiotics of the illness. Today the patients with abdominal tuberculosis are mainly women of child-bearing age with a long-term tuberculosis catamnesis and intoxication, with a history of tuberculosis of different sites, those suffering from tuberculosis or its sequels at present (64%), those with pains (94%), discomfort or swelling of the abdomen (79%), malfunction of the gastrointestinal tract (65%), weight loss (86%), malnutrition (72%), anemia (63%), not infrequently with inflammatory induration (43%) or ascites in the abdominal cavity (39%). In addition to this characteristic semiotics, the patients with abdominal tuberculosis may demonstrate the most different and unexpected symptoms up to acute abdomen (23%). To make differential diagnosis of abdominal tuberculosis, one has often to resort to diagnostic laparotomy, laparoscopy, Koch's test and to trial therapy.

  11. [Public laboratories for vaccine production: a new paradigm].

    PubMed

    Homma, A; di Fabio, J L; de Quadros, C

    1998-10-01

    In Latin America and the Caribbean, public laboratories that produce vaccines have contributed in varying degrees to the control and eradication of vaccine-preventable diseases, and several of them are manufacturing vaccines that are routinely applied in national immunization programs, such as the vaccine against tuberculosis (made with the bacillus of Calmette-Guérin, BCG), the triple vaccine against diphtheriatetanus-pertussis (DTP), tetanus toxoid (TT), the vaccine against measles and the oral vaccine against polio. Thanks to recent scientific strides, one can foresee an important increase in the number of safe and effective vaccines that will be available in the near future for use in routine vaccination programs. However, there are high costs involved in developing such vaccines and in protecting the intellectual property rights involved, and few laboratories in Latin America have the technical capacity to research and develop these vaccines. Such factors will affect the speed with which they are assimilated into vaccination programs in countries of the Region. Currently, public laboratories that manufacture vaccines in the Region are not equipped to compete in this new scenario and run the risk of being completely outmarketed. Thus, they must radically change their style of management and their scientific and technical capabilities, backed by a commitment from governments to improve and strengthen those political and financial aspects that can assure that national laboratories participate in the sustainable supply of vaccines to immunization programs, as well as in researching, developing, and producing new vaccines.

  12. Profiling the host response to malaria vaccination and malaria challenge

    PubMed Central

    Dunachie, Susanna; Hill, Adrian V.S.; Fletcher, Helen A.

    2015-01-01

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research. PMID:26256528

  13. Profiling the host response to malaria vaccination and malaria challenge.

    PubMed

    Dunachie, Susanna; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research.

  14. [Vaccinations 1979].

    PubMed

    Herzog, C; Just, M

    1980-05-17

    On the basis of the Federal Health Department's "Swiss Vaccination Scheme" of 1976, some up to data additions and alterations are proposed mainly with regard to combined measles-mumps-rubella vaccination during the second year of life together with the first tetanus, diphtheria and poliomyelitis booster. Oral vaccination against poliomyelitis is not contraindicated during pregnancy. Among the inoculations not considered in the official vaccination scheme, regular influenza vaccination is only indicated for certain chronically ill people. Whether this is also true of the pneumococcal vaccine newly licensed in Switzerland remains uncertain. The (likewise new) meningococcal vaccine is only effective against type A and C and not against the type B meningococci prevalent in Switzerland. In view of its safety, only HDC vaccine produced with human tissue cultures should be used for anti-rabies vaccination. For counselling prior to travel abroad, a simple vaccination scheme is provided and the importance of other prophylactic measures is emphasized. PMID:7394495

  15. Fistula Formation between Right Upper Bronchus and Bronchus Intermedius Caused by Endobronchial Tuberculosis: A Case Report.

    PubMed

    Kim, Mikyoung; Kang, Eun Seok; Park, Jin Yong; Kang, Hwa Rim; Kim, Jee Hyun; Chang, YouJin; Choi, Kang Hyeon; Lee, Ki Man; Kim, Yook; An, Jin Young

    2015-07-01

    Endobronchial tuberculosis is defined as a tuberculous infection of the tracheobronchial tree and has a prevalence of up to 50% in active pulmonary tuberculosis cases. The most common complication of endobronchial tuberculosis is bronchial stenosis; benign fistula formation by endobronchial tuberculosis is rare, especially inter-bronchial fistula formation. We reported a rare case of a 73-year-old woman with a fistula between the right upper bronchus and bronchus intermedius. A diagnosis of inter-bronchial fistula caused by endobronchial tuberculosis was based on the results of chest computed tomography scans, bronchoscopy, and microbiological and pathological tests. The patient was treated with anti-tuberculous medication, and her symptoms gradually improved.

  16. Workshop report: Schistosomiasis vaccine clinical development and product characteristics.

    PubMed

    Mo, Annie X; Colley, Daniel G

    2016-02-17

    A schistosomiasis vaccine meeting was organized to evaluate the utility of a vaccine in public health programs, to discuss clinical development paths, and to define basic product characteristics for desirable vaccines to be used in the context of schistosomiasis control and elimination programs. It was concluded that clinical evaluation of a schistosomiasis vaccine is feasible with appropriate trial design and tools. Some basic Preferred Product Characteristics (PPC) for a human schistosomiasis vaccine and for a veterinary vaccine for bovine use were also proposed.

  17. Tuberculosis in the lung (image)

    MedlinePlus

    Tuberculosis is caused by a group of organisms: Mycobacterium tuberculosis, M bovis , M africanum and a few other rarer subtypes. Tuberculosis usually appears as a lung (pulmonary) infection. However, ...

  18. Tuberculosis Facts - Testing for TB

    MedlinePlus

    Tuberculosis (TB) Facts Testing for TB What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  19. Tuberculosis Facts - Exposure to TB

    MedlinePlus

    Tuberculosis (TB) Facts Exposure to TB What is TB? “TB” is short for a disease called tuberculosis. TB is spread through the air from one ... Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

  20. Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens, Providing Sterile Immunity to Challenge Infection

    PubMed Central

    Hewitson, James P.; Filbey, Kara J.; Esser-von Bieren, Julia; Camberis, Mali; Schwartz, Christian; Murray, Janice; Reynolds, Lisa A.; Blair, Natalie; Robertson, Elaine; Harcus, Yvonne; Boon, Louis; Huang, Stanley Ching-Cheng; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Voehringer, David; Le Gros, Graham; Harris, Nicola; Maizels, Rick M.

    2015-01-01

    Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations. PMID:25816012

  1. Vaccines for Canine Leishmaniasis

    PubMed Central

    Palatnik-de-Sousa, Clarisa B.

    2012-01-01

    Leishmaniasis is the third most important vector-borne disease worldwide. Visceral leishmaniasis (VL) is a severe and frequently lethal protozoan disease of increasing incidence and severity due to infected human and dog migration, new geographical distribution of the insect due to global warming, coinfection with immunosuppressive diseases, and poverty. The disease is an anthroponosis in India and Central Africa and a canid zoonosis (ZVL) in the Americas, the Middle East, Central Asia, China, and the Mediterranean. The ZVL epidemic has been controlled by one or more measures including the culling of infected dogs, treatment of human cases, and insecticidal treatment of homes and dogs. However, the use of vaccines is considered the most cost–effective control tool for human and canine disease. Since the severity of the disease is related to the generation of T-cell immunosuppression, effective vaccines should be capable of sustaining or enhancing the T-cell immunity. In this review we summarize the clinical and parasitological characteristics of ZVL with special focus on the cellular and humoral canine immune response and review state-of-the-art vaccine development against human and canine VL. Experimental vaccination against leishmaniasis has evolved from the practice of leishmanization with living parasites to vaccination with crude lysates, native parasite extracts to recombinant and DNA vaccination. Although more than 30 defined vaccines have been studied in laboratory models no human formulation has been licensed so far; however three second-generation canine vaccines have already been registered. As expected for a zoonotic disease, the recent preventive vaccination of dogs in Brazil has led to a reduction in the incidence of canine and human disease. The recent identification of several Leishmania proteins with T-cell epitopes anticipates development of a multiprotein vaccine that will be capable of protecting both humans and dogs against VL. PMID:22566950

  2. West Nile virus vaccine.

    PubMed

    Monath, T P; Arroyo, J; Miller, C; Guirakhoo, F

    2001-05-01

    Within the past 5 years, West Nile encephalitis has emerged as an important disease of humans and horses in Europe. In 1999, the disease appeared for the first time in the northeastern United States. West Nile virus (a mosquito-borne flavivirus) has flourished in the North American ecosystem and is expected to expand its geographic range. In this review, the rationale for a human and veterinary vaccine is presented and a novel approach for rapid development of a molecularly-defined, live, attenuated vaccine is described. The technology (ChimeriVax) is applicable to the development of vaccines against all flaviviruses, and products against Japanese encephalitis (a close relative of West Nile) and dengue are in or are nearing clinical trials, respectively. ChimeriVax vaccines utilize the safe and effective vaccine against the prototype flavivirus -yellow fever 17D- as a live vector. Infectious clone technology is used to replace the genes encoding the pre-membrane (prM) and envelope (E) protein of yellow fever 17D vaccine with the corresponding genes of the target virus (e.g., West Nile). The resulting chimeric virus contains the antigens responsible for protection against West Nile but retains the replication efficiency of yellow fever 17D. The ChimeriVax technology is well-suited to the rapid development of a West Nile vaccine, and clinical trials could begin as early as mid-2002. Other approaches to vaccine development are briefly reviewed. The aim of this brief review is to describe the features of West Nile encephalitis, a newly introduced infectious disease affecting humans, horses and wildlife in the United States; the rationale for rapid development of vaccines; and approaches to the development of vaccines against the disease.

  3. Evaluation of Xpert® MTB/RIF Assay in Induced Sputum and Gastric Lavage Samples from Young Children with Suspected Tuberculosis from the MVA85A TB Vaccine Trial

    PubMed Central

    Geldenhuys, Hennie; Schmidt, Bey-Marrie; Luabeya, Angelique Kany Kany; Mulenga, Humphrey; Scriba, Thomas J.; Hanekom, Willem A.; Mahomed, Hassan; McShane, Helen; Hatherill, Mark

    2015-01-01

    Objective Diagnosis of childhood tuberculosis is limited by the paucibacillary respiratory samples obtained from young children with pulmonary disease. We aimed to compare accuracy of the Xpert® MTB/RIF assay, an automated nucleic acid amplification test, between induced sputum and gastric lavage samples from young children in a tuberculosis endemic setting. Methods We analyzed standardized diagnostic data from HIV negative children younger than four years of age who were investigated for tuberculosis disease near Cape Town, South Africa [2009–2012]. Two paired, consecutive induced sputa and early morning gastric lavage samples were obtained from children with suspected tuberculosis. Samples underwent Mycobacterial Growth Indicator Tube [MGIT] culture and Xpert MTB/RIF assay. We compared diagnostic yield across samples using the two-sample test of proportions and McNemar’s χ2 test; and Wilson’s score method to calculate sensitivity and specificity. Results 1,020 children were evaluated for tuberculosis during 1,214 admission episodes. Not all children had 4 samples collected. 57 of 4,463[1.3%] and 26 of 4,606[0.6%] samples tested positive for Mycobacterium tuberculosis on MGIT culture and Xpert MTB/RIF assay respectively. 27 of 2,198[1.2%] and 40 of 2,183[1.8%] samples tested positive [on either Xpert MTB/RIF assay or MGIT culture] on induced sputum and gastric lavage samples, respectively. 19/1,028[1.8%] and 33/1,017[3.2%] admission episodes yielded a positive MGIT culture or Xpert MTB/RIF assay from induced sputum and gastric lavage, respectively. Sensitivity of Xpert MTB/RIF assay was 8/30[26.7%; 95% CI: 14.2–44.4] for two induced sputum samples and 7/31[22.6%; 11.4–39.8] [p = 0.711] for two gastric lavage samples. Corresponding specificity was 893/893[100%;99.6–100] and 885/890[99.4%;98.7–99.8] respectively [p = 0.025]. Conclusion Sensitivity of Xpert MTB/RIF assay was low, compared to MGIT culture, but diagnostic performance of Xpert MTB

  4. [Pharyngeal tuberculosis: Case report].

    PubMed

    Spini, Roxana Gabriela; Bordino, Lucas; Cohen, Daniela; Martins, Andrea; Ramírez, Zaida; González, Norma E

    2015-08-01

    Pharyngeal tuberculosis is a rare extrapulmonary manifestation. In Argentina, the number of cases of tuberculosis reported in children under 19 years in 2012 was 1752. Only 12.15% had extrapulmonary manifestation. A case of a 17 year old girl with pharyngeal tuberculosis is reported. The patient presented intermittent fever and swallowing pain for 6 months, without response to conventional antibiotic treatment. Chest X-ray showedbilateral micronodular infiltrate, so hospitalization was decided to study and treat. The sputum examination for acid-fast resistant bacilli was positive and treatment with four antituberculous drugs was started, with good evolution and disappearance of symptoms. Diagnostic confirmation with the isolation of Mycobacterium tuberculosis in sputum culture was obtained. The main symptoms of pharyngeal tuberculosis are sore throat and difficulty in swallowing of long evolution. It is important to consider tuberculosis as differential diagnosis in patients with chronic pharyngitis unresponsive to conventional treatment. PMID:26172025

  5. Tuberculosis and poverty.

    PubMed Central

    Spence, D P; Hotchkiss, J; Williams, C S; Davies, P D

    1993-01-01

    OBJECTIVE--To examine whether the historical link between tuberculosis and poverty still exists. DESIGN--Retrospective study examining the notifications of all forms of tuberculosis by council ward over a six year period and correlating this with four indices of poverty; council housing, free school meals, the Townsend overall deprivation index, and the Jarman index. SETTING--The 33 electoral wards of the city of Liverpool. SUBJECTS--344 residents of Liverpool with tuberculosis. RESULTS--The rate of tuberculosis was correlated with all measures of poverty, the strongest correlation being with the Jarman index (r = 0.73, p < 0.0001). This link was independent of the high rates of tuberculosis seen in ethnic minorities. CONCLUSION--Tuberculosis remains strongly associated with poverty. PMID:8219945

  6. [Vaccination status of children in the Vienna area (author's transl)].

    PubMed

    Kessler, T

    1978-12-01

    The vaccination status was investigated in 1482 patients between the ages of 1 and 14 years admitted to hospital with scarlet fever. Most of the patients were vaccinated against tuberculosis (97.7%), diphtheria, tetanus and whooping-cough (95.3%) and poliomyelitis (94.1%), relatively few against measles (21.1%) and very few indeed against mumps (0.7%) and tick-borne encephalitis (1.9%). The booster vaccination against tetanus and diphtheria had been omitted in more than 40%. Although the beneficial results of vaccination against tuberculosis, diphtheria-pertussis-tetanus and poliomyelitis remained more or less the same, the tendency towards vaccination did not spread as might have been anticipated. On the contrary, the extent of vaccination decreased, especially during the past years. In the same way the tendency towards vaccination against measles showed a sudden slowing down after a period of rapid increase. This implies that vaccination of children does not tend towards perfection. The vaccination rates differ widely between foreign children living in Vienna and natives. Although the foreigners show a similar vaccination distribution pattern as the natives, the numbers of unvaccinated children are much higher.

  7. Computer-assisted prediction of HLA-DR binding and experimental analysis for human promiscuous Th1-cell peptides in the 24 kDa secreted lipoprotein (LppX) of Mycobacterium tuberculosis.

    PubMed

    Al-Attiyah, R; Mustafa, A S

    2004-01-01

    The secreted 24 kDa lipoprotein (LppX) is an antigen that is specific for Mycobacterium tuberculosis complex and M. leprae. The present study was carried out to identify the promiscuous T helper 1 (Th1)-cell epitopes of the M. tuberculosis LppX (MT24, Rv2945c) antigen by using 15 overlapping synthetic peptides (25 mers overlapping by 10 residues) covering the sequence of the complete protein. The analysis of Rv2945c sequence for binding to 51 alleles of nine serologically defined HLA-DR molecules, by using a virtual matrix-based prediction program (propred), showed that eight of the 15 peptides of Rv2945c were predicted to bind promiscuously to >/=10 alleles from more than or equal to three serologically defined HLA-DR molecules. The Th1-cell reactivity of all the peptides was assessed in antigen-induced proliferation and interferon-gamma (IFN-gamma)-secretion assays with peripheral blood mononuclear cells (PBMCs) from 37 bacille Calmette-Guérin (BCG)-vaccinated healthy subjects. The results showed that 17 of the 37 donors, which represented an HLA-DR-heterogeneous group, responded to one or more peptides of Rv2945c in the Th1-cell assays. Although each peptide stimulated PBMCs from one or more donors in the above assays, the best positive responses (12/17 (71%) responders) were observed with the peptide p14 (aa 196-220). This suggested a highly promiscuous presentation of p14 to Th1 cells. In addition, the sequence of p14 is completely identical among the LppX of M. tuberculosis, M. bovis and M. leprae, which further supports the usefulness of Rv2945c and p14 in the subunit vaccine design against both tuberculosis and leprosy.

  8. Vaccines against typhoid fever.

    PubMed

    Guzman, Carlos A; Borsutzky, Stefan; Griot-Wenk, Monika; Metcalfe, Ian C; Pearman, Jon; Collioud, Andre; Favre, Didier; Dietrich, Guido

    2006-05-01

    Because of high infectivity and significant disease burden, typhoid fever constitutes a major global health problem. Implementation of adequate food handling practices and establishment of safe water supplies are the cornerstone for the development of an effective prevention program. However, vaccination against typhoid fever remains an essential tool for the effective management of this disease. Currently, there are two well tolerated and effective licensed vaccines. One is based on defined subunit virulence (Vi) polysaccharide antigen and can be administered either intramuscularly or subcutaneously and the other is based on the use of live attenuated bacteria for oral administration. The advantages and disadvantages of the various approaches taken in the development of a vaccine against typhoid fever are discussed, along with the potential for future vaccine candidates.

  9. [Dengue vaccines].

    PubMed

    Morita, Kouichi

    2008-10-01

    Dengue is the most important mosquito borne virus infection in the tropics. Based on the effects of global warming, it is expected that dengue epidemic areas will further expand in the next decades unless effective and affordable vaccines are made available soon. At the moment, several vaccine developers have utilized live-attenuated live tetravalent vaccines and two of them have already completed phase two trials. However, the risk of antibody-dependent enhancement infection is not well elucidated and thus further and careful evaluation of the safety on proposed candidate vaccines are essential. At the moment, Bill and Melinda Gates Foundation strongly support the vaccine development through the Pediatric Dengue Vaccine Initiative.

  10. TUBERCULOSIS COMO ENFERMEDAD OCUPACIONAL

    PubMed Central

    Mendoza-Ticona, Alberto

    2014-01-01

    Existe evidencia suficiente para declarar a la tuberculosis como enfermedad ocupacional en diversos profesionales especialmente entre los trabajadores de salud. En el Perú están normados y reglamentados los derechos laborales inherentes a la tuberculosis como enfermedad ocupacional, como la cobertura por discapacidad temporal o permanente. Sin embargo, estos derechos aún no han sido suficientemente socializados. En este trabajo se presenta información sobre el riesgo de adquirir tuberculosis en el lugar de trabajo, se revisan las evidencias para declarar a la tuberculosis como enfermedad ocupacional en trabajadores de salud y se presenta la legislación peruana vigente al respecto. PMID:22858771

  11. Isolated Optic Disc Tuberculosis

    PubMed Central

    Mansour, Ahmad M.; Tabbara, Khalid F.; Tabbarah, Zuhair

    2015-01-01

    We present a healthy male subject who developed progressive visual loss in the left eye initially diagnosed as optic neuritis. Upon suspicion of infectious etiology, testing was positive for tuberculosis. There were no signs or symptoms of active systemic tuberculosis infection. The patient responded swiftly to antimycobacterial therapy with return of vision and resolution of disc swelling. Positive purified protein derivative skin test, negative chest radiograph, negative systemic workup, negative workup for other causes of unilateral optic neuritis and quick response to mycobacterial therapy reaffirm the entity of isolated optic disc tuberculosis similar to isolated choroidal tuberculosis without systemic manifestation. PMID:26483675

  12. Autophagy in Tuberculosis

    PubMed Central

    Deretic, Vojo

    2014-01-01

    Autophagy as an immune mechanism controls inflammation and acts as a cell-autonomous defense against intracellular microbes including Mycobacterium tuberculosis. An equally significant role of autophagy is its anti-inflammatory and tissue-sparing function. This combination of antimicrobial and anti-inflammatory actions prevents active disease in animal models. In human populations, genetic links between autophagy, inflammatory bowel disease, and susceptibility to tuberculosis provide further support to these combined roles of autophagy. The autophagic control of M. tuberculosis and prevention of progressive disease provide novel insights into physiological and immune control of tuberculosis. It also offers host-based therapeutic opportunities because autophagy can be pharmacologically modulated. PMID:25167980

  13. Epidemiological basis of tuberculosis eradication in an advanced country

    PubMed Central

    Groth-Petersen, E.; Knudsen, Jørgen; Wilbek, Erik

    1959-01-01

    The first section of the report provides a background for the long-range epidemiological studies being conducted by the Danish Tuberculosis Index. An outline is given of the main indices of tuberculosis and the changing tuberculosis situation in Denmark during the past several decades with respect to prevalence of infection, morbidity and mortality. Difficulties encountered in international comparisons are briefly discussed. The prevalence of tuberculous infection in children and the prevalence of bacillary cases of pulmonary tuberculosis in adults are suggested as the most valuable indices of eradication. The second section describes the nation-wide mass campaign of 1950-52, which was planned and conducted as a combined service and research programme under the direction of the Danish Tuberculosis Index. With a view to the follow-up studies, details are given of the results of tuberculin tests of the unvaccinated, the documented vaccinated and mixed groups in the population examined. A survey is made of the results of X-ray examination and of the relation between vaccination status, tuberculin reaction and X-ray findings. The results of the first follow-up period are analysed in the final section of the report in terms of new cases of pulmonary tuberculosis appearing in the adult population. Seventy-five per cent of the new cases appeared among the unvaccinated tuberculin-positive population, and among this population groups of persons with widely different risks of developing tuberculosis could be identified on the basis of X-ray findings and reactions to the intradermal 10 TU tuberculin test. A proposal is made to reduce the number of routine repetitive examinations for adults and to concentrate efforts on preventive measures for the high-risk groups. PMID:13829735

  14. Purine Salvage Pathway in Mycobacterium tuberculosis.

    PubMed

    Ducati, R G; Breda, A; Basso, L A; Santos, D S

    2011-01-01

    Millions of deaths worldwide are caused by the aetiological agent of tuberculosis, Mycobacterium tuberculosis. The increasing prevalence of this disease, the emergence of drug-resistant strains, and the devastating effect of human immunodeficiency virus coinfection have led to an urgent need for the development of new and more efficient antimycobacterial drugs. The modern approach to the development of new chemical compounds against complex diseases, especially the neglected endemic ones, such as tuberculosis, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a specific target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, and (iii) the development of compounds with selective toxicity. The present review describes the enzymes of the purine salvage pathway in M. tuberculosis as attractive targets for the development of new antimycobacterial agents. Enzyme kinetics and structural data have been included to provide a thorough knowledge on which to base the search for compounds with biological activity. We have focused on the mycobacterial homologues of this pathway as potential targets for the development of new antitubercular agents.

  15. [Actual problems of vaccine prophylaxis in the Russian Federation].

    PubMed

    Onishchenko, G G; Ezhlova, E B; Mel'nikova, A A

    2014-01-01

    The WHO within the framework of extended immunization program assumes a significant increase of the number of vaccine controlled infections by 2020 - 2025 to 27 - 37 including protection from diseases of parasitic etiology. Russia contributes to the international efforts of the WHO to control infections with vaccine prophylaxis. The national calendar of prophylaxis vaccinations currently provides vaccination against 11 infections--tuberculosis, hepatitis B, poliomyelitis, pertussis, diphtheria, tetanus, measles, rubella, epidemic parotitis, influenza, haemophilus type B infection. Significant progress in reduction of infectious morbidity controlled by means of specific prophylaxis has been made in the country. PMID:24738288

  16. [Actual problems of vaccine prophylaxis in the Russian Federation].

    PubMed

    Onishchenko, G G; Ezhlova, E B; Mel'nikova, A A

    2014-01-01

    The WHO within the framework of extended immunization program assumes a significant increase of the number of vaccine controlled infections by 2020 - 2025 to 27 - 37 including protection from diseases of parasitic etiology. Russia contributes to the international efforts of the WHO to control infections with vaccine prophylaxis. The national calendar of prophylaxis vaccinations currently provides vaccination against 11 infections--tuberculosis, hepatitis B, poliomyelitis, pertussis, diphtheria, tetanus, measles, rubella, epidemic parotitis, influenza, haemophilus type B infection. Significant progress in reduction of infectious morbidity controlled by means of specific prophylaxis has been made in the country.

  17. Innate resistance to tuberculosis in man, cattle and laboratory animal models: nipping disease in the bud?

    PubMed

    Cassidy, J P; Martineau, A R

    2014-11-01

    Tuberculosis (TB) does not always develop in people or cattle exposed to the disease and some exposed individuals may not exhibit evidence of infection. Such variability in susceptibility may be mediated through host innate immunity, non-specific inflammatory responses that may successfully eliminate infection or at least reduce the infectious load, thus modulating and easing the burden on the subsequent acquired immune response. Assessing evidence from research in man, cattle and laboratory animal models, this review appraises the role of innate immunity in TB including the role of particular leucocytes (i.e. macrophages, neutrophils, γδ-T lymphocytes and natural killer cells), endogenous host defence compounds (i.e. cathelicidin, human neutrophil peptide, lipocalin and natural resistance-associated membrane protein-1) and, in particular, vitamin D. Innate responses may be particularly important in neonatal animals and people where adaptive responses have not yet established and their success in preventing the establishment of infection may be predicated on dose and/or route of infection as well as on characteristics of the infecting isolate. Innate defences could potentially be exploited in novel vaccination and immunotherapeutic approaches to disease control, modulating their effectiveness through the use of defined mycobacterial peptides as adjuvants or therapeutics. Such novel immunomodulatory compounds may be particularly relevant in countering emerging multi- and extremely drug-resistant strains of Mycobacterium tuberculosis (Mtb).

  18. Mycobacterial antigen-induced T helper type 1 (Th1) and Th2 reactivity of peripheral blood mononuclear cells from diabetic and non-diabetic tuberculosis patients and Mycobacterium bovis bacilli Calmette–Guérin (BCG)-vaccinated healthy subjects

    PubMed Central

    Al-Attiyah, R J; Mustafa, A S

    2009-01-01

    Patients with diabetes mellitus are more susceptible to tuberculosis (TB), and the clinical conditions of diabetic TB patients deteriorate faster than non-diabetic TB patients, but the immunological basis for this phenomenon is not understood clearly. Given the role of cell-mediated immunity (CMI) in providing protection against TB, we investigated whether CMI responses in diabetic TB patients are compromised. Peripheral blood mononuclear cells (PBMC) obtained from diabetic TB patients, non-diabetic TB patients and Mycobacterium bovis bacilli Calmette–Guérin (BCG)-vaccinated healthy subjects were cultured in the presence of complex mycobacterial antigens and pools of M. tuberculosis regions of difference (RD)1, RD4, RD6 and RD10 peptides. The PBMC were assessed for antigen-induced cell proliferation and secretion of T helper 1 (Th1) [interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-β], and Th2 (IL-4, IL-5, IL-10) cytokines as CMI parameters. All the complex mycobacterial antigens and RD1pool stimulated strong proliferation of PBMC of all groups, except moderate responses to RD1pool in healthy subjects. In response to complex mycobacterial antigens, both IFN-γ and TNF-β were secreted by PBMC of all groups whereas diabetic TB patients secreted IL-10 with concentrations higher than the other two groups. Furthermore, in response to RD peptides, IFN-γ and IL-10 were secreted by PBMC of diabetic TB patients only. The analyses of data in relation to relative cytokine concentrations showed that diabetic TB patients had lower Th1 : Th2 cytokines ratios, and a higher Th2 bias. The results demonstrate a shift towards Th2 bias in diabetic TB patients which may explain, at least in part, a faster deterioration in their clinical conditions. PMID:19737232

  19. Acquired Drug Resistance in Mycobacterium tuberculosis and Poor Outcomes among Patients with Multidrug-Resistant Tuberculosis

    PubMed Central

    Kipiani, Maia; Mirtskhulava, Veriko; Tukvadze, Nestani; Magee, Matthew J.; Blumberg, Henry M.

    2015-01-01

    Rates and risk factors for acquired drug resistance and association with outcomes among patients with multidrug-resistant tuberculosis (MDR TB) are not well defined. In an MDR TB cohort from the country of Georgia, drug susceptibility testing for second-line drugs (SLDs) was performed at baseline and every third month. Acquired resistance was defined as any SLD whose status changed from susceptible at baseline to resistant at follow-up. Among 141 patients, acquired resistance in Mycobacterium tuberculosis was observed in 19 (14%); prevalence was 9.1% for ofloxacin and 9.8% for capreomycin or kanamycin. Baseline cavitary disease and resistance to >6 drugs were associated with acquired resistance. Patients with M. tuberculosis that had acquired resistance were at significantly increased risk for poor treatment outcome compared with patients without these isolates (89% vs. 36%; p<0.01). Acquired resistance occurs commonly among patients with MDR TB and impedes successful treatment outcomes. PMID:25993036

  20. Vaccines (immunizations) - overview

    MedlinePlus

    ... mumps, and rubella (MMR) vaccine and the varicella (chickenpox) vaccine are examples. Killed (inactivated) vaccines are made from ... countries. Some countries require this record. COMMON VACCINES ... DTaP immunization (vaccine) Hepatitis A vaccine Hepatitis B ...

  1. Australia's role in promoting and supporting tuberculosis control in the Western Pacific Region.

    PubMed

    Shaw, Kerrie A

    2013-07-01

    Twenty-one percent of the world's tuberculosis cases are found in the Western Pacific Region. The region has demonstrated a lower rate of decline in incidence than the regions of Africa, the Americas and Europe. Issues around drug resistance, human immunodeficiency virus and diabetes impact on the burden of tuberculosis disease in the Western Pacific Region. Australia has exhibited a low and relatively stable tuberculosis incidence rate but has not progressed toward the desired international goal for tuberculosis elimination (<1 case per million population). The pathogenesis and transmission of tuberculosis make it difficult to achieve elimination within a geographically defined area. These aspects of disease control are amplified by globalisation and Australia's increasing economic and strategic engagement within the Western Pacific Region and South-East Asia. Promoting and supporting tuberculosis control within the Western Pacific Region provides an opportunity for Australia to maintain its low tuberculosis incidence rate and progress toward elimination. PMID:23849030

  2. Australia's role in promoting and supporting tuberculosis control in the Western Pacific Region.

    PubMed

    Shaw, Kerrie A

    2013-07-01

    Twenty-one percent of the world's tuberculosis cases are found in the Western Pacific Region. The region has demonstrated a lower rate of decline in incidence than the regions of Africa, the Americas and Europe. Issues around drug resistance, human immunodeficiency virus and diabetes impact on the burden of tuberculosis disease in the Western Pacific Region. Australia has exhibited a low and relatively stable tuberculosis incidence rate but has not progressed toward the desired international goal for tuberculosis elimination (<1 case per million population). The pathogenesis and transmission of tuberculosis make it difficult to achieve elimination within a geographically defined area. These aspects of disease control are amplified by globalisation and Australia's increasing economic and strategic engagement within the Western Pacific Region and South-East Asia. Promoting and supporting tuberculosis control within the Western Pacific Region provides an opportunity for Australia to maintain its low tuberculosis incidence rate and progress toward elimination.

  3. Diagnosis and management of miliary tuberculosis: current state and future perspectives

    PubMed Central

    Ray, Sayantan; Talukdar, Arunansu; Kundu, Supratip; Khanra, Dibbendhu; Sonthalia, Nikhil

    2013-01-01

    -induced hepatotoxicity and drug–drug interactions in HIV/TB coinfected patients create significant problems during treatment. Data available from randomized controlled trials are insufficient to define the optimum regimen and duration of treatment in patients with drug-sensitive as well as drug-resistant miliary TB, including those with HIV/AIDS, and the role of adjunctive corticosteroid treatment has not been properly studied. Research is going on worldwide in an attempt to provide a more effective vaccine than bacille Calmette–Guérin. This review highlights the epidemiology and clinical manifestation of miliary TB, challenges, recent advances, needs, and opportunities related to TB diagnostics and treatment. PMID:23326198

  4. Diphtheria Vaccination

    MedlinePlus

    ... and adults - Tetanus-diphtheria-acellular Pertussis vaccine Diphtheria Vaccination Pronounced (dif-THEER-ee-a) Recommend on Facebook ... Related Pages Pertussis Tetanus Feature Story: Adults Need Immunizations, Too Abbreviations DTaP=Pediatric - Diphtheria-Tetanus-acellular Pertussis ...

  5. [Tuberculosis and exposed personnel: prevention and surveillance].

    PubMed

    2004-01-01

    Tuberculosis is defined as an occupational disease for healthcare and laboratory personnel for the Social security (table no 40). This table was modified in 1998 in order to deal with, not only pulmonary and extra-pulmonary tuberculosis-disease, but also with primary infections. Coverage is specific for hospital personnel; the disease is imputable to the service, imputability acknowledged by the departmental reform commissions, after expertise. For private institutions, the total number of cases for healthcare personnel is reported to the CNAM (national insurance system), that is to say 30 to 50 cases per year including 90% of pleuro-pulmonary cases (1989-2000). Tuberculosis-infection (primary infections) has been reported since 1998 (1998: 2 cases; 1999: 10 cases; 2000: 23 case). There is no centralized collection of cases for public hospitals. In the Assistance Publique-Hôpitaux de Paris (approximately 60,000 paramedics), 30 cases of pleuropulmonary tuberculosis and four primary infections were reported as occupational diseases from 1997 to 2001, that is to say approximately six cases per year among hospital personnel, not including physicians. A census made at the time of the previous report in 1995 showed higher figures: 94 reported cases of tuberculosis declared from 1987 to 1992 (an average of slightly more than 15 cases per year).

  6. Mycobacterium tuberculosis Zinc Metalloprotease-1 Elicits Tuberculosis-Specific Humoral Immune Response Independent of Mycobacterial Load in Pulmonary and Extra-Pulmonary Tuberculosis Patients

    PubMed Central

    Vemula, Mani H.; Ganji, Rakesh; Sivangala, Ramya; Jakkala, Kiran; Gaddam, Sumanlatha; Penmetsa, Sitaramaraju; Banerjee, Sharmistha

    2016-01-01

    Conventionally, facultative intracellular pathogen, Mycobacterium tuberculosis, the tuberculosis (TB) causing bacilli in human is cleared by cell-mediated immunity (CMI) with CD4+ T cells playing instrumental role in protective immunity, while antibody-mediated immunity (AMI) is considered non-protective. This longstanding convention has been challenged with recent evidences of increased susceptibility of hosts with compromised AMI and monoclonal antibodies conferring passive protection against TB and other intracellular pathogens. Therefore, novel approaches toward vaccine development include strategies aiming at induction of humoral response along with CMI. This necessitates the identification of mycobacterial proteins with properties of immunomodulation and strong immunogenicity. In this study, we determined the immunogenic potential of M. tuberculosis Zinc metalloprotease-1 (Zmp1), a secretory protein essential for intracellular survival and pathogenesis of M. tuberculosis. We observed that Zmp1 was secreted by in vitro grown M. tuberculosis under granuloma-like stress conditions (acidic, oxidative, iron deficiency, and nutrient deprivation) and generated Th2 cytokine microenvironment upon exogenous treatment of peripheral blood mononulear cells PBMCs with recombinant Zmp1 (rZmp1). This was supported by recording specific and robust humoral response in TB patients in a cohort of 295. The anti-Zmp1 titers were significantly higher in TB patients (n = 121) as against healthy control (n = 62), household contacts (n = 89) and non-specific infection controls (n = 23). A significant observation of the study is the presence of equally high titers of anti-Zmp1 antibodies in a range of patients with high bacilli load (sputum bacilli load of 300+ per mL) to paucibacillary smear-negative pulmonary tuberculosis (PTB) cases. This clearly indicated the potential of Zmp1 to evoke an effective humoral response independent of mycobacterial load. Such mycobacterial proteins can

  7. Who Needs Chickenpox Vaccine

    MedlinePlus

    ... Not Get Chickenpox Vaccine Types of Chickenpox Vaccine Child and Adult Immunization Schedules Possible Side Effects of Chickenpox Vaccine Childcare and School Vaccine Requirements Also Known As & Abbreviations ...

  8. "Tuberculosis Case Management" Training.

    ERIC Educational Resources Information Center

    Knebel, Elisa; Kolodner, Jennifer

    2001-01-01

    The need to isolated health providers with critical knowledge in tuberculosis (TB) case management prompted the development of "Tuberculosis Case Management" CD-ROM. Features include "Learning Center,""Examination Room," and "Library." The combination of audio, video, and graphics allows participants to practice acquired skills in a simulated…

  9. Tuberculosis in Somalia.

    PubMed

    Turpie, I D

    2008-05-01

    This is a description of a tuberculosis treatment programme in a country at war where security and the absence of order pose problems to health care delivery. It is also a description of an epidemic of tuberculosis where treatment and diagnosis are difficult and the methods used have changed little in many years. More international pressure is needed.

  10. Pulmonary Paragonimiasis Mimicking Tuberculosis.

    PubMed

    Prasad, Kj; Basu, Arup; Khana, Shilpi; Wattal, Chand

    2015-08-01

    Paragonimiasis is a disease which is frequently misdiagnosed as pulmonary tuberculosis. In the areas where people eat crab/crayfish this disease should be considered in the differential diagnosis to avoid antituberculosis treatment for a non-tubercular condition. We are reporting a case of pulmonary paragonimiasis who had been treated for tuberculosis. PMID:27604443

  11. Seasonality of Tuberculosis

    PubMed Central

    Fares, Auda

    2011-01-01

    Objectives: This study was designed to review previous studies and analyse the current knowledge and controversies related to seasonal variability of tuberculosis (TB) to examine whether TB has an annual seasonal pattern. Study Design and Methods: Systematic review of peer reviewed studies identified through literature searches using online databases belonging to PubMed and the Cochrane library with key words “Tuberculosis, Seasonal influence” and “Tuberculosis, Seasonal variation”. The search was restricted to articles published in English. The references of the identified papers for further relevant publications were also reviewed. Results: Twelve studies conducted between the period 1971 and 2006 from 11 countries/regions around the world (South Western Cameroon, South Africa, India, Hong Kong, Japan, Kuwait, Spain, UK, Ireland, Russia, and Mongolia) were reviewed. A seasonal pattern of tuberculosis with a mostly predominant peak is seen during the spring and summer seasons in all of the countries (except South Western Cameroon and Russia). Conclusions: The observation of seasonality leads to assume that the risk of transmission of M. tuberculosis does appear to be the greatest during winter months. Vitamin D level variability, indoor activities, seasonal change in immune function, and delays in the diagnosis and treatment of tuberculosis are potential stimuli of seasonal tuberculosis disease. Additionally, seasonal variation in food availability and food intake, age, and sex are important factors which can play a role in the tuberculosis notification variability. Prospective studies regarding this topic and other related subjects are highly recommended. PMID:21572609

  12. Antibodies to diverse lipids in the serum of patients with clinically cured leprosy and tuberculosis.

    PubMed

    Rojas-Espinosa, O; Arenas, R; Arce-Parades, P; Miranda-Contreras, G

    2003-01-01

    In this study we looked for the presence of antibodies to cardiolipin, cerebrosides, and whole lipids extracted from M. leprae, M. tuberculosis and M. habana, in the serum of patients with clinically cured lepromatous leprosy (sixteen) or tuberculosis (sixteen), 8 to 12 months after arresting the corresponding multi-drug therapy (MDT). Compared to healthy controls (sixteen), both leprosy and tuberculosis ex-patients had still significant levels of antibodies to the three mycobacterial lipids but no detectable levels of antibodies to cardiolipin or cerebroside lipids. Although leprosy and tuberculosis sera recognized the homologous mycobacterial lipids in a preferential fashion, all of them, on the average, reacted more strongly with the lipids of M. habana. This observation backs up, in a certain way, the proposition of using M. habana as a prospective vaccine for leprosy and tuberculosis.

  13. Translating the Tuberculosis Research Agenda: Much Accomplished, but Much More to Be Done.

    PubMed

    Schito, Marco; Maeurer, Markus; Kim, Peter; Hanna, Debra; Zumla, Alimuddin

    2015-10-15

    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.

  14. A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.

    PubMed

    Carpenter, Stephen M; Nunes-Alves, Cláudio; Booty, Matthew G; Way, Sing Sing; Behar, Samuel M

    2016-01-01

    T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.

  15. A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis

    PubMed Central

    Carpenter, Stephen M.; Nunes-Alves, Cláudio; Booty, Matthew G.; Way, Sing Sing; Behar, Samuel M.

    2016-01-01

    T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection. PMID:26745507

  16. Peritoneal tuberculosis: diagnostic options.

    PubMed Central

    Lal, N; Soto-Wright, V

    1999-01-01

    BACKGROUND: Extrapulmonary tuberculosis has vague symptoms and few signs. It is essential to recognize and diagnose this curable disease prior to performing definitive surgery. Newer tests such as DNA or RNA amplification allow for early diagnosis but have limitations. CASE: We report a case of peritoneal tuberculosis in an immigrant woman. She had vague symptoms of low-grade fever, mild abdominal pain, obstipation, and bloating. Diagnostic laparoscopy was performed to establish the diagnosis. Tuberculosis was confirmed by DNA extraction from the frozen section specimen with subsequent analysis using polymerase chain reaction. CONCLUSION: Peritoneal tuberculosis is a disease that often simulates malignancies. With the increasing prevalence of human immunodeficiency virus in developed countries, tuberculosis is also on the rise and should be considered in the differential diagnosis of a patient with an abdominal/pelvic mass and ascites. PMID:10524670

  17. Stability evaluation of vaccines: WHO approach.

    PubMed

    Knezevic, Ivana

    2009-11-01

    The stability of vaccines has a major impact on the success of immunization programmes worldwide. In line with this, clear definition of the stability characteristics of a vaccine is of critical importance. One of the concerns at country level is whether vaccines will remain potent on its way from the manufacturer, through the distribution channels, to the final users and vaccine recipients. In response to the requests for assistance in defining stability profile of vaccines, the Expert Committee on Biological Standardization (ECBS) in October 2006 agreed that new WHO guidelines be established on stability evaluation of vaccines (http://www.who.int/biologicals/publications/trs/areas/vaccines/stability/en/index.html). This document applies to all vaccines against infectious diseases. The aim of this guideline is to provide the scientific basis and guiding principles for evaluation of vaccine stability for the purpose of clinical trial approval, licensing, and post-licensure monitoring. As part of its initiative to promote use of vaccines of assured quality, WHO emphasizes the role of National Regulatory Authorities (NRAs) and National Control Laboratories (NCLs) in overall vaccine evaluation, including stability assessment. While recognizing that manufacturers are responsible for the quality of the vaccines they produce, compliance with vaccine quality specifications is part of regulatory oversight. This article provides basic information about WHO international standards as well as key definitions and principles for stability evaluation of vaccines that are elaborated in detail in the above mentioned guidance document.

  18. Heterologous vaccine effects.

    PubMed

    Saadatian-Elahi, Mitra; Aaby, Peter; Shann, Frank; Netea, Mihai G; Levy, Ofer; Louis, Jacques; Picot, Valentina; Greenberg, Michael; Warren, William

    2016-07-25

    The heterologous or non-specific effects (NSEs) of vaccines, at times defined as "off-target effects" suggest that they can affect the immune response to organisms other than their pathogen-specific intended purpose. These NSEs have been the subject of clinical, immunological and epidemiological studies and are increasingly recognized as an important biological process by a growing group of immunologists and epidemiologists. Much remain to be learned about the extent and underlying mechanisms for these effects. The conference "Off-target effects of vaccination" held in Annecy-France (June 8-10 2015) intended to take a holistic approach drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science to address fundamental questions of immunological mechanisms, as well as translational questions about vaccines NSEs. NSE observations were examined using case-studies on live attenuated vaccines and non-live vaccines followed by discussion of studies of possible biological mechanisms. Some possible pathways forward in the study of vaccines NSE were identified and discussed by the expert group. PMID:27312214

  19. DNA vaccines