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Hawn T.R.,University of Washington | Day T.A.,Fred Hutchinson Cancer Research Center | Scriba T.J.,University of Cape Town | Hatherill M.,University of Cape Town | And 9 more authors.
Microbiology and Molecular Biology Reviews | Year: 2014

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. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Fletcher H.A.,London School of Hygiene and Tropical Medicine | Schrager L.,Aeras
Transactions of the Royal Society of Tropical Medicine and Hygiene | Year: 2016

TB is now the leading, global cause of death due to a single infectiousmicrobe. To achieve the End TB vision of reducing TB by 90% by 2035 we will need new interventions. The objectives of this manuscript are to summarize the status of the clinical TB vaccine pipeline; to assess the challenges facing the TB development field; and to discuss some of the key strategies being embraced by the field to overcome these challenges. Currently, 8 of the 13 vaccines in clinical development are subunit vaccines; 6 of these contain or express either Ag85A or Ag85B proteins. Amajor challenge to TB vaccine development is the lack of diversity in both the antigens included in TB vaccines, and the immune responses elicited by TB vaccine candidates. Both will need to be expanded to maximise the potential for developing a successful candidate by 2025. Current research efforts are focused on broadening both antigen selection and the range of vaccine-mediated immune responses. Previous and ongoing TB vaccine efficacy trials have built capacity, generated high quality data on TB incidence and prevalence, and provided insight into immune correlates of risk of TB disease. These gains will enable the design of better TB vaccines and, importantly,move these vaccines into efficacy trials more rapidly and at a lower cost than was possible for previous TB vaccine candidates. © The Author 2016.

Delogu G.,Catholic University of the Sacred Heart | Manganelli R.,University of Padua | Brennan M.J.,Aeras
Clinical Microbiology and Infection | Year: 2014

A new and improved vaccine against tuberculosis (TB) would provide a powerful tool to conquer one of the most insidious infectious diseases of mankind. Protection afforded by bacillus Calmette-Guérin (BCG) has been shown to be limited and inconsistent, especially in adults that are known to transmit TB disease. In the last two decades, several new vaccines have been developed and tested with the aim to elicit robust and long-lived T-cell responses against Mycobacterium tuberculosis antigens. Although much progress has been made in the TB vaccine field, there is an urgent need to address critical research questions about TB immunity with a special focus on designing vaccines aimed at preventing infection and transmission of TB. Here, we discuss the rationale behind the current immunization strategies being implemented for TB vaccines and provide some suggestions for hypothesis driven research to encourage the development of novel TB vaccines. © 2013 The Authors Clinical Microbiology and Infection. © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Villarreal D.O.,University of Pennsylvania | Walters J.,University of Pennsylvania | Laddy D.J.,Aeras | Yan J.,Inovio Pharmaceuticals, Inc. | Weiner D.B.,University of Pennsylvania
Human Vaccines and Immunotherapeutics | Year: 2014

Development of a broad-spectrum synthetic vaccine against TB would represent an important advance to the limited vaccine armamentarium against TB. It is believed that the esx family of TB antigens may represent important vaccine candidates. However, only 4 esx antigens have been studied as potential vaccine antigens. The challenge remains to develop a vaccine that simultaneously targets all 23 members of the esx family to induce enhanced broad-spectrum cell-mediated immunity. We sought to investigate if broader cellular immune responses could be induced using a multivalent DNA vaccine representing the esx family protein members delivered via electroporation. In this study, 15 designed esx antigens were created to cross target al. members of the esx family. They were distributed into groups of 3 self-processing antigens each, resulting in 5 trivalent highly optimized DNA plasmids. Vaccination with all 5 constructs elicited robust antigen-specific IFN-γ responses to all encoded esx antigens and induced multifunctional CD4 Th1 and CD8 T cell responses. Importantly, we show that when all constructs are combined into a cocktail, the RSQ-15 vaccine, elicited substantial broad Ag-specific T cell responses to all esx antigens as compared with vaccination with BCG. Moreover, these vaccine-induced responses were highly cross-reactive with BCG encoded esx family members and were highly immune effective in a BCG DNA prime-boost format. Furthermore, we demonstrate the vaccine potential and immunopotent profile of several novel esx antigens never previously studied. These data highlight the likely importance of these novel immunogens for study as preventative or therapeutic synthetic TB vaccines in combination or as stand alone antigens. © 2014 Landes Bioscience.

News Article | April 12, 2016
Site: www.biosciencetechnology.com

A team of scientists led by Oxford University have made a discovery that could improve our chances of developing an effective vaccine against Tuberculosis. The researchers have identified new biomarkers for Tuberculosis (TB) which have shown for the first time why immunity from the widely used Bacillus Calmette-Guérin (BCG) vaccine is so variable. The biomarkers will also provide valuable clues to assess whether potential new vaccines could be effective. TB remains one of the world's major killer diseases, causing TB disease in 9.6 million people and 1.5 million deaths in 2014. The only available vaccine, Bacillus Calmette-Guérin (BCG), works well (estimated 50 percent effective) to prevent severe disease in children but is very variable (0 percent to 80 percent effective) in how well it protects against lung disease, particularly in countries where TB is most common. While BCG is one of the safest and most widely used vaccines worldwide, there is one key issue: It is currently very difficult to determine whether it will work or not. This also makes it really hard to determine if any new vaccines might work. For many vaccines, medics and scientists can use what are called immune correlates or biomarkers, typically in the blood, which can be measured to determine whether a vaccine has successfully induced immunity. Not only are these correlates useful in measuring the success of existing vaccination programmes, they are also invaluable in assessing whether potential new vaccines could be effective. With a pressing need for a TB vaccine that is more effective than BCG, a research team drawn from a number of groups at Oxford University, working with colleagues from the South African Tuberculosis Vaccine Initiative at the University of Cape Town and the London School of Hygiene & Tropical Medicine, set out to identify immune correlates that could facilitate TB vaccine development. The team, funded by the Wellcome Trust and Aeras, and led by Professor Helen McShane and Dr. Helen Fletcher, studied immune responses in infants in South Africa who were taking part in a TB vaccine trial. Professor McShane said: "We looked at a number of factors that could be used as immune correlates, to try and find biomarkers that will help us develop a better vaccine." The team carried out tests for twenty-two possible factors. One - levels of activated HLA-DR+CD4+ T-cells - was linked to higher TB disease risk. Meanwhile, BCG-specific Interferon-gamma secreting T-cells indicated lower TB risk, with higher levels of these cells directly linked to greater reduction of the risk of TB. Antibodies to a TB protein, Ag85A, were also identified as a possible correlate. Higher levels of Ag85A antibody were associated with lower TB risk. However, the team cautions that other environmental and disease factors could also cause Ag85A antibody levels to rise and so there may not be a direct link between the antibody and TB risk. Professor McShane said: "These are useful results which ideally would now be confirmed in further trials. They show that antigen-specific T cells are important in protection against TB, but that activated T cells increase the risk". Dr. Helen Fletcher from the London School of Hygiene & Tropical Medicine, said: "For the first time we have some evidence of how BCG might work, and also what could block it from working. Although there is still much work to do, these findings may bring us a step closer to developing a more effective vaccine for TB." Dr. Tom Scriba from the South African Tuberculosis Vaccine Initiative said: "TB is still a major international killer, and rates of TB disease in some areas of South Africa are among the highest in the world. These findings provide important clues about the type of immunity TB vaccines should elicit, and bring us closer to our vision, a world without TB." The team is continuing its work to develop a TB vaccine, aiming to protect more people from the disease. The paper was published in the jounral Nature Communications.

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