An update on vaccines for tuberculosis - there is more to it than just waning of BCG efficacy with time.
ABSTRACT Introduction: Apart from better diagnostics and new anti-microbial drugs, an effective vaccine for tuberculosis is urgently needed to halt this poverty-related disease, afflicting millions of people worldwide. Areas covered: After a general introduction on the global threat of tuberculosis, the pros and cons of the existing M. bovis BCG vaccine are discussed. As the correlates of protection against tuberculosis remain largely unknown, new findings in biomarker research are described. Next, an update on the ongoing Phase I and Phase II clinical trials is given. Finally, some of the most promising novel pre-clinical developments using live attenuated vaccines, sub-unit vaccines, prime-boost strategies, and new vaccination routes are discussed. The field has made considerable progress and 12 vaccine candidates have now actually entered Phase I or Phase IIa and IIb clinical trials. Expert opinion: It is argued that the variable protection conferred by the existing BCG vaccine against reactivation of latent TB is caused not only by waning of its efficacy with time but also by its weak induction of MHC class I restricted responses. Prime-boost strategies based on the actual BCG vaccine may not be sufficient to overcome this hurdle. The use of plasmid DNA vaccination might offer a solution.
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ABSTRACT: The Ag85 complex is a 30-32 kDa family of three proteins (Ag85A, Ag85B, and Ag85C), which all three possess enzymatic mycolyl-transferase activity involved in the coupling of mycolic acids to the arabinogalactan of the cell wall and in the biogenesis of cord factor. By virtue of their strong potential to induce Th1-type immune responses, important for the control of intracellular infections, members of the Ag85 family rank among the most promising TB vaccine candidate antigens. Ag85A and Ag85B, initially purified from Mycobacterium bovis bacillus Calmette-Guérin (BCG)/Mycobacterium tuberculosis culture filtrate respectively, induce strong T-cell proliferation and IFN-γ production in most healthy individuals latently infected with M. tuberculosis and in BCG-vaccinated mice and humans but not in tuberculosis patients. Members of the Ag85 complex are highly conserved in other mycobacterial species. Mice and humans infected with Mycobacterium ulcerans or cattle infected with M. bovis or Mycobacterium avium subsp. paratuberculosis also show strong T-cell responses to this protein family. Using synthetic overlapping peptides, bio-informatic prediction programs and tetramer-binding studies, a number of immunodominant CD4(+) and CD8(+) T-cell epitopes have been identified in experimental animal models as well as in humans, using proliferation and Th1 cytokine secretion as main read-outs. The results from these studies are summarized in this review.Frontiers in Immunology 07/2014; 5:321. DOI:10.3389/fimmu.2014.00321
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ABSTRACT: Vaccination is the most effective method of preventing infectious diseases. Since the eradication of small pox in 1976, many other potentially life compromising if not threatening diseases have been dealt with subsequently. This event was a major leap not only in the scientific world already burdened with many diseases but also in the mindset of the common man who became more receptive to novel treatment options. Among the many protozoan diseases, the leishmaniases have emerged as one of the largest parasite killers of the world, second only to malaria. There are three types of leishmaniasis namely cutaneous (CL), mucocutaneous (ML), and visceral (VL), caused by a group of more than 20 species of Leishmania parasites. Visceral leishmaniasis, also known as kala-azar is the most severe form and almost fatal if untreated. Since the first attempts at leishmanization, we have killed parasite vaccines, subunit protein, or DNA vaccines, and now we have live recombinant carrier vaccines and live attenuated parasite vaccines under various stages of development. Although some research has shown promising results, many more potential genes need to be evaluated as live attenuated vaccine candidates. This mini-review attempts to summarize the success and failures of genetically modified organisms used in vaccination against some of major parasitic diseases for their application in leishmaniasis.Frontiers in Immunology 05/2014; 5:213. DOI:10.3389/fimmu.2014.00213This article is viewable in ResearchGate's enriched formatRG Format enables you to read in context with side-by-side figures, citations, and feedback from experts in your field.
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ABSTRACT: Tuberculosis (TB) is an ancient disease, but not a disease of the past. Despite the declaration of TB as a global emergency by the World Health Organization in 1993 the worldwide problem of TB has worsened. The increasing prevalence of drug-resistant strains of Mycobacterium tuberculosis, the causative agent of TB, demands new measures to combat the situation. Rapid and accurate diagnosis of the pathogen, and its drug susceptibility pattern, is essential for timely initiation of treatment, and ultimately, control of the disease. Furthermore, knowledge about which precise mutations confer drug resistance in M. tuberculosis does not only lead to a basic understanding of drug resistance mechanisms and drug actions, but is also important for the design and development of clinically sensitive and specific molecular methods aiming at detecting drug-resistant M. tuberculosis. Paper I in this thesis investigated cross-resistance between the aminoglycosides amikacin (AMK) and kanamycin (KAN), and the cyclic peptide capreomycin (CAP). The results show that tlyA is neither a sensitive nor a specific genetic marker for detection of CAP resistance in M. tuberculosis, and that it is advisable to include rrs nucleotide position 1401 in a molecular-based assay for the detection of AMK-, KAN- and CAP-resistant M. tuberculosis clinical isolates. Paper II aimed at developing a pyrosequencing method for detection of first- and second-line resistance in M. tuberculosis. Pyrosequencing assays were developed for the genes rpoB, katG, embB, rrs, gyrA and the promoter regions of inhA and eis, which are associated with resistance to rifampicin (RIF), isoniazid, ethambutol, AMK, KAN, CAP and fluoroquinolones, respectively. Pyrosequencing is a highly throughput and robust method for detection of novel and a priori known mutations. The method can be used to screen a large sample volume, which is desired if aiming at investigating the prevalence of mutations in large sample collections. In Paper III, the utility of padlock probes for detecting drug resistance in M. tuberculosis was evaluated. The assay was developed for RIF resistance due to the importance of RIF in the standard TB treatment and its potential role as a surrogate marker for multidrug-resistant TB. The method proved to be robust for detection of specific mutations in the gene rpoB, and confirmation of loss of wild type as well as detection of M. tuberculosis complex DNA. The padlock probe assay was further extended in Paper IV to detection of extensively drugresistant TB in a multiplexed fashion. Padlock probes were designed to target the most common mutations occurring in rpoB, katG, rrs, gyrA and in the promoter region of inhA. The analytical sensitivity achieved in Paper IV is comparable to that of PCR. The readout format employed in Paper IV eliminates the use of extensive equipment, but rather, signal can be detected by the naked eye. This thesis has contributed to increased knowledge of drug resistance in TB, and has successfully developed new methods for rapid detection of drug-resistant M. tuberculosis. The results can guide future research and development of molecular methods aiming at detecting drug-resistant M. tuberculosis.05/2013, Degree: PhD, Supervisor: Pontus Juréen