Development of new vaccines and drugs for TB: Limitations and potential strategic errors

Department of Microbiology, Immunology & Pathology, Colorado State University, Colorado, CO 80523, USA.
Future Microbiology (Impact Factor: 4.28). 02/2011; 6(2):161-77. DOI: 10.2217/fmb.10.168
Source: PubMed


The concomitant HIV and TB epidemics pose an enormous threat to humanity. After invading the host Mycobacterium tuberculosis initially behaves as an intracellular pathogen, which elicits the emergence of acquired specific resistance in the form of a T-helper-1 T-cell response, and involves the secretion of a myriad of cytokines and chemokines to drive protective immunity and granuloma formation. However, after that, a second phase of the disease process involves survival of bacilli in an extracellular state that is still poorly understood. This article briefly reviews the various strategies currently being used to improve both vaccination and drug therapy of TB, and attempts to make the argument that current viewpoints that dominate [both the field and the current literature] may be seriously flawed. This includes both the choice of new vaccine and drug candidates, and also the ways these are being tested in animal models, which in the opinion of the author run the risk of driving the field backwards rather than forward.

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    • "This implies that the precise structures of these epitopes are required for survival and transmission of organism to new hosts. It has been proposed that they are conserved because they induce highly toxic hypersensitivity reactions[49,51]. However, it seems unlikely that loss of toxicity of a single epitope of hundreds could doom the organism. "
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    ABSTRACT: Lack of access to human tissues with untreated tuberculosis (TB) has forced generations of researchers to use animal models and to adopt a paradigm that granulomas are the characteristic lesion of both primary and post primary TB. An extended search of studies of human lung tissues failed to find any reports that support this paradigm. We found scores of publications from gross pathology in 1804 through high resolution CT scans in 2015 that identify obstructive lobular pneumonia, not granulomas, as the characteristic lesion of developing post-primary TB. This paper reviews this literature together with other relevant observations to formulate a new paradigm of TB with three distinct stages: a three-act play. First, primary TB, a war of attrition, begins with infection that spreads via lymphatics and blood stream before inducing systemic immunity that contains and controls the organisms within granulomas. Second, post-primary TB, a sneak attack, develops during latent TB as an asymptomatic obstructive lobular pneumonia in persons with effective systemic immunity. It is a paucibacillary process with no granulomas that spreads via bronchi and accumulates mycobacterial antigens and host lipids for 1–2 years before suddenly undergoing caseous necrosis. Third, the fallout, is responsible for nearly all clinical post primary disease. It begins with caseous necrotic pneumonia that is either retained to become the focus of fibrocaseous disease or is coughed out to leave a cavity. This three-stage paradigm suggests testable hypotheses and plausible answers to long standing questions of immunity to TB.
    Full-text · Article · Jan 2016 · Tuberculosis
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    • "We strongly suspect that neutrophils are the main cause of necrosis in both the mouse and guinea pig models of tuberculosis [3,5,34], and this is further emphasized by studies in humans [21,22]. To date we were assuming that our observations in NOS2 -/- and other murine models were due to the influx of neutrophils, based on simply measuring “Gr1-positive” cells, but clearly our current concept needs to be significantly modified based on the observations here that Gr1hi and Gr1int cells represent two distinct granulocyte subsets. "
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    ABSTRACT: Tuberculosis is one of the world’s leading killers, stealing 1.4 million lives and causing 8.7 million new and relapsed infections in 2011. The only vaccine against tuberculosis is BCG which demonstrates variable efficacy in adults worldwide. Human infection with Mycobacterium tuberculosis results in the influx of inflammatory cells to the lung in an attempt to wall off bacilli by forming a granuloma. Gr1intCD11b+ cells are called myeloid-derived suppressor cells (MDSC) and play a major role in regulation of inflammation in many pathological conditions. Although MDSC have been described primarily in cancer their function in tuberculosis remains unknown. During M. tuberculosis infection it is crucial to understand the function of cells involved in the regulation of inflammation during granuloma formation. Understanding their relative impact on the bacilli and other cellular phenotypes is necessary for future vaccine and drug design.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Thus, the development of a more effective TB vaccine is required to combat the global threat of TB (Hawkridge and Mahomed, 2011). Several alternative TB vaccine candidates are currently being tested experimentally as pre-exposure or post-exposure or booster preparations, including subunit, live attenuated, recombinant BCG, and DNA vaccines (Hawkridge and Mahomed, 2011; Orme, 2011; Walzl et al., 2011; Yuan et al., 2011). DNA vaccines represent novel vaccine approach for TB, and are currently under rigorous investigation (Liu et al., 2008; Ly and McMurray, 2008; Lowrie, 2006; Saha et al., 2011; Yuan et al., 2011). "
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    ABSTRACT: Tuberculosis remains one of the major causes of global public health problems. There is no effective vaccine for the disease until now. Many reports show that DNA vaccines are promising to induce protection against Mycobacterium tuberculosis (M. tb); however, the efficiency of DNA vaccine is limited due to inadequate delivery systems. Among others, live attenuated bacterial vectors such as Salmonella enterica typhimurium (S. typhimurium) have significant promise as efficient mucosal delivery vehicles for DNA vaccines. In this study, we constructed recombinant attenuated S. typhimurium DNA vaccines carrying genes encoding resuscitation promoting factor (Rpf)-like proteins of M. tb on eukaryotic expression plasmid agianst latent tuberculosis and evaluated the plasmid stability and growth curve assays of the recombinant Salmonella vaccine constructs in vitro. Four Rpf gene fragments (RpfB, RpfC, RpfD, RpfE) associated with latency were amplified from genomic DNA of the H37Rv strain of M. tb, cloned into eukaryotic expression plasmid (pVR1020) and verified by sequencing. In later studies, we will demonstrate the potential use of the Salmonella-mediated DNA constructs as candidate post-exposure vaccines against tuberculosis through testing their immunogenicity and effectiveness for oral delivery in eukaryotic systems.
    Full-text · Article · Jul 2012 · AFRICAN JOURNAL OF BIOTECHNOLOGY
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