Novel tuberculosis vaccines on the horizon

Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.
Current opinion in immunology (Impact Factor: 7.48). 06/2010; 22(3):374-84. DOI: 10.1016/j.coi.2010.04.006
Source: PubMed


Eleven new tuberculosis (TB) vaccines are in various phases of clinical trials. These include subunit vaccines to improve the current vaccine BCG, and recombinant BCG to substitute for BCG, both given pre-exposure to prevent active disease. A plethora of potential candidates have reached various stages of the pre-clinical development pipeline, some ready to enter Phase I clinical trial soon. A boost vaccine to top up the immunity of existing BCG is on the horizon and will have to suffice until a better candidate to replace BCG is ready. The live mutants of Mycobacterium tuberculosis show great promise, but face a myriad of regulatory challenges.

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    • "Protective Th1 immune response against TB depends on CD4 T cells secreting IFN-γ, IL-2 and TNF-α, and CD8 T cells secreting similar cytokines and producing perforin and granulysin [33], [34], [35]. CD4 and CD8 T cells are in turn, primed through MHC-II and MHC-I dependent pathways of peptide presentation by mycobacteria infected APCs. "
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    ABSTRACT: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death due to bacterial infections in mankind, and BCG, an attenuated strain of Mycobacterium bovis, is an approved vaccine. BCG sequesters in immature phagosomes of antigen presenting cells (APCs), which do not fuse with lysosomes, leading to decreased antigen processing and reduced Th1 responses. However, an Mtb derived ΔfbpA attenuated mutant underwent limited phagosome maturation, enhanced immunogenicity and was as effective as BCG in protecting mice against TB. To facilitate phagosome maturation of ΔfbpA, we disrupted an additional gene sapM, which encodes for an acid phosphatase. Compared to the wild type Mtb, the ΔfbpAΔsapM (double knock out; DKO) strain was attenuated for growth in mouse macrophages and PMA activated human THP1 macrophages. Attenuation correlated with increased oxidants in macrophages in response to DKO infection and enhanced labeling of lysosomal markers (CD63 and rab7) on DKO phagosomes. An in vitro Antigen 85B peptide presentation assay was used to determine antigen presentation to T cells by APCs infected with DKO or other mycobacterial strains. This revealed that DKO infected APCs showed the strongest ability to present Ag85B to T cells (>2500 pgs/mL in 4 hrs) as compared to APCs infected with wild type Mtb or ΔfbpA or ΔsapM strain (<1000 pgs/mL in 4 hrs), indicating that DKO strain has enhanced immunogenicity than other strains. The ability of DKO to undergo lysosomal fusion and vacuolar acidification correlated with antigen presentation since bafilomycin, that inhibits acidification in APCs, reduced antigen presentation. Finally, the DKO vaccine elicited a better Th1 response in mice after subcutaneous vaccination than either ΔfbpA or ΔsapM. Since ΔfbpA has been used in mice as a candidate vaccine and the DKO (ΔfbpAΔsapM) mutant is more immunogenic than ΔfbpA, we propose the DKO is a potential anti-tuberculosis vaccine.
    PLoS ONE 05/2012; 7(5):e36198. DOI:10.1371/journal.pone.0036198 · 3.23 Impact Factor
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    • "One of the focuses of vaccine development is to combine multiple epitopes in the same construct, with the aim of achieving a broader and more potent response than whole-protein vaccines (Parida and Kaufmann, 2010). To streamline the selection of epitopes for this purpose, microarray and immuno-informatics have been used. "
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    ABSTRACT: Since its publication in 1998, the genome sequence of the Mycobacterium tuberculosis H37Rv laboratory strain has acted as the cornerstone for the study of tuberculosis. In this review we address some of the practical aspects that have come to light relating to the use of H37Rv throughout the past decade which are of relevance for the ongoing genomic and laboratory studies of this pathogen. These include errors in the genome reference sequence and its annotation, as well as the recently detected variation amongst isolates of H37Rv from different laboratories.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 06/2011; 12(4):807-10. DOI:10.1016/j.meegid.2011.06.011 · 3.02 Impact Factor
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    • "Perhaps the unstable structure feature is one of possible reasons for ESAT-6 low inherent immunogenicity that is not sufficient to elicit specific protective immunity against M. tb infection by itself. Many studies have tried to fuse ESAT-6 with other TB antigens or carrier proteins to enhance its immunogenicity [4] [5] [6] [7] [8] [9] [10] [11]. For the instance, in the new promising TB vaccine H56, ESAT-6 was fused with two other TB antigens Ag85B and Rv2660c [7]. "
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    ABSTRACT: Early secreted antigenic target-6 (ESAT-6), an important Mycobacterium tuberculosis T-cell antigen, is an attractive candidate antigen for tuberculosis subunit vaccine development. Because ESAT-6 has a low inherent immunogenicity, we used Hepatitis B virus core (HBc) protein as an immune carrier to enhance ESAT-6 immunogenicity. The ESAT-6 gene was inserted into the major immunodominant region of the HBc molecule by fusion PCR. The recombinant protein, HBc-ESAT-6 (HE6), was expressed in Escherichia coli, and electron microscopy confirmed the formation of virus-like particles. The immunogenicity of the chimeric particles was assessed in mice. Serological assays and in vitro Th1-biased cytokine assays found that immunization with HE6 particles elicited significantly higher ESAT-6-specific antibodies and CD4⁺/CD8⁺ T cell responses in mice compared to immunization with recombinant ESAT-6 protein. These data demonstrate the feasibility of HBc particles serving as an efficient immune carrier for ESAT-6 and suggest that HE6 has potential for use in a tuberculosis subunit vaccine.
    Vaccine 06/2011; 29(34):5645-51. DOI:10.1016/j.vaccine.2011.06.012 · 3.62 Impact Factor
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