Recombinant live vaccine candidates against tuberculosis

Max Planck Institute for Infection Biology, Department of Immunology, Charitéplatz 1, 10117 Berlin, Germany.
Current Opinion in Biotechnology (Impact Factor: 7.12). 04/2012; 23(6). DOI: 10.1016/j.copbio.2012.03.007
Source: PubMed


Tuberculosis (TB) remains among the most deadly health threats to humankind despite availability of several potent antibiotics and a vaccine, bacille Calmette-Guérin (BCG). BCG partially protects children but not adults from the disease. Growing knowledge of the molecular basis of infection, immunity, and pathology in TB has driven various approaches, which strive to complement or replace BCG with more effective vaccines. Three recombinant live TB vaccine candidates have entered clinical trials. These candidates have been genetically engineered to be attenuated, to overexpress TB antigens and/or to secrete bacterial perforins, ultimately seeking to trigger a robust immune response thereby providing long-lasting protection against TB.

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    • "Candidates include recombinant BCG [6], attenuated strains of M. tuberculosis [7], recombinant Mycobacterium smegmatis [8], subunit vaccines [9] and recombinant viruses [10]. Many more candidate vaccines have been explored, however, the attrition rate proved to be high [11] [12]. A few advanced candidates are currently tested for safety in clinical trials. "
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    ABSTRACT: Having demonstrated previously that deletion of zinc metalloprotease zmp1 in Mycobacterium bovis BCG increased immunogenicity of BCG vaccines, we here investigated the protective efficacy of BCG zmp1 deletion mutants in a guinea pig model of tuberculosis infection. zmp1 deletion mutants of BCG provided enhanced protection by reducing the bacterial load of tubercle bacilli in the lungs of infected guinea pigs. The increased efficacy of BCG due to zmp1 deletion was demonstrated in both BCG Pasteur and BCG Denmark indicating that the improved protection by zmp1 deletion is independent from the BCG sub-strain. In addition, unmarked BCG Δzmp1 mutant strains showed a better safety profile in a CB-17 SCID mouse survival model than the parental BCG strains. Together, these results support the further development of BCG Δzmp1 for use in clinical trials. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · Vaccine
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    • "The only licensed vaccine is the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine, a live attenuated strain of M. bovis, which has been used since 1921. Although the BCG vaccine gives consistent protection against TB infection in children, it is highly variable in protecting against adult pulmonary TB disease [3,4,5,6]. There is therefore an urgent need to develop a more effective vaccine to combat this notorious pathogen. "
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    ABSTRACT: Tuberculosis (TB) remains a worldwide health problem, causing around 2 million deaths per year. Despite the bacillus Calmette Guérin vaccine being available for more than 80 years, it has limited effectiveness in preventing TB, with inconsistent results in trials. This highlights the urgent need to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection. Recent studies have revealed a potential role for autophagy, an intracellular homeostatic process, in vaccine development against TB, through enhanced immune activation. This review attempts to understand the host innate immune responses induced by a variety of protein antigens from Mycobacterium tuberculosis, and to identify future vaccine candidates against TB. We focus on recent advances in vaccine development strategies, through identification of new TB antigens using a variety of innovative tools. A new understanding of the host-pathogen relationship, and the usefulness of mycobacterial antigens as novel vaccine candidates, will contribute to the design of the next generation of vaccines, and to improving the host protective immune responses while limiting immunopathology during M. tuberculosis infection.
    Full-text · Article · Jul 2014
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    • "Among the most promising TB live vaccine candidates (Ottenhoff and Kaufmann, 2012; Kaufmann and Gengenbacher, 2012), the prototype vaccine SO2 was attenuated by insertion of a kanamycin-resistance cassette in the phoP gene of a Mtb clinical isolate (Perez et al., 2001). The transcriptional regulator PhoP controls approximately 2% of Mtb coding capacity, including the synthesis of the trehalose-derived lipids, diacyl-and polyacyl-trehaloses, and the secretion of the virulence factor ESAT-6 (Frigui et al., 2008; Walters et al., 2006; Gonzalo Asensio et al., 2006, 2008). "
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    ABSTRACT: 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.
    Full-text · Article · May 2014 · Archivos de Medicina Veterinaria
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