Exchanging ESAT6 with TB10.4 in an Ag85B Fusion Molecule-Based Tuberculosis Subunit Vaccine: Efficient Protection and ESAT6-Based Sensitive Monitoring of Vaccine Efficacy

Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark.
The Journal of Immunology (Impact Factor: 4.92). 06/2005; 174(10):6332-9. DOI: 10.4049/jimmunol.174.10.6332
Source: PubMed


Previously we have shown that Ag85B-ESAT-6 is a highly efficient vaccine against tuberculosis. However, because the ESAT-6 Ag is also an extremely valuable diagnostic reagent, finding a vaccine as effective as Ag85B-ESAT-6 that does not contain ESAT-6 is a high priority. Recently, we identified a novel protein expressed by Mycobacterium tuberculosis designated TB10.4. In most infected humans, TB10.4 is strongly recognized, raising interest in TB10.4 as a potential vaccine candidate and substitute for ESAT-6. We have now examined the vaccine potential of this protein and found that vaccination with TB10.4 induced a significant protection against tuberculosis. Fusing Ag85B to TB10.4 produced an even more effective vaccine, which induced protection against tuberculosis comparable to bacillus Calmette-Guerin vaccination and superior to the individual Ag components. Thus, Ag85B-TB10 represents a new promising vaccine candidate against tuberculosis. Furthermore, having now exchanged ESAT-6 for TB10.4, we show that ESAT-6, apart from being an excellent diagnostic reagent, can also be used as a reagent for monitoring vaccine efficacy. This may open a new way for monitoring vaccine efficacy in clinical trials.

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Available from: Timothy Mark Doherty, Oct 04, 2015
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    • "Several previous studies have investigated the role of Ag85-BESAT-6 (early secreted antigenic target of 6 kDa) as a highly efficient vaccine against TB [102,103,104]. The TB subunit vaccine containing Ag85B-ESAT-6/CAF01 induced sustained protective vaccine effects by inducing the proliferation of memory CD4+ T cells with TNF-α(+)IL-2(+) and IFN-γ(+) TNF-α(+)IL-2(+) multifunctional profiles [116]. Additionally, a novel TB protein, designated TB10.4, "
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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.
    07/2014; 3(2):155-67. DOI:10.7774/cevr.2014.3.2.155
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    • "Dietrich et al. demonstrated that the fusion protein Ag85B-TB10.4 (HyVac4) combined with the adjuvant protein dimethyl dioctadecyl ammonium/monophosphoryl lipid A (DDA/MPL) was highly immunogenic and induced strong protection against TB in mice model [53]. "
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    ABSTRACT: one of the World Health Organization Millennium Development Goal is to reduce tuberculosis incidence by 2015. However, more of 8.5 million tuberculosis cases have been reported in 2011, with an increase of multidrug-resistant strains. Therefore, the World Health Organization target cannot be reach without the help of a vaccine able to limit the spread of tuberculosis. Nowadays, bacille Calmette-Guérin is the only vaccine available against tuberculosis. It prevents against meningeal and disseminated tuberculosis in children, but its effectiveness against pulmonary form in adolescents and adults is argued. a systematic review was performed by searches of Pubmed, references of the relevant articles and Aeras and websites. 100 articles were included in this review. Three viral vectored booster vaccines, five protein adjuvant booster vaccines, two priming vaccines and two therapeutic vaccines have been analyzed. Several vaccines are in the pipeline, but further studies on basic research, clinical trial and mass vaccination campaigns are needed to achieve the TB eradication target by 2050.
    BMC Infectious Diseases 01/2014; 14 Suppl 1(Suppl 1):S2. DOI:10.1186/1471-2334-14-S1-S2 · 2.61 Impact Factor
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    • "The ESX family members ESAT-6 and TB10.4 have previously been demonstrated to share very similar characteristics regarding immune recognition during infection and protective activity in preventive TB vaccines [26]. To further study the role of these antigens in TB vaccines for preventive and post-exposure administration we compared vaccines that differ only in these two components. "
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    ABSTRACT: The ESX systems from Mycobacterium tuberculosis are responsible for the secretion of highly immunogenic proteins of key importance for bacterial survival and growth. The two prototypic proteins, ESAT-6 (EsxA from ESX-1) and TB10.4 (EsxH from ESX-3) share a lot of characteristics regarding genome organization, size, antigenic properties, and vaccine potential but the two molecules clearly have very different roles in bacterial physiology. To further investigate the role of ESAT-6 and TB10.4 as preventive and post-exposure tuberculosis vaccines, we evaluated four different fusion-protein vaccines; H1, H4, H56 and H28, that differ only in these two components. We found that all of these vaccines give rise to protection in a conventional prophylactic vaccination model. In contrast, only the ESAT-6-containing vaccines resulted in significant protection against reactivation, when administered post-exposure. This difference in post-exposure activity did not correlate with a difference in gene expression during infection or a differential magnitude or quality of the vaccine-specific CD4 T cells induced by ESAT-6 versus TB10.4-containing vaccines. The post-exposure effect of the ESAT-6 based vaccines was found to be influenced by the infectious load at the time-point of vaccination and was abolished in chronically infected animals with high bacterial loads at the onset of vaccination. Our data demonstrate that there are specific requirements for the immune system to target an already established tuberculosis infection and that ESAT-6 has a unique potential in post-exposure vaccination strategies.
    PLoS ONE 12/2013; 8(12):e80579. DOI:10.1371/journal.pone.0080579 · 3.23 Impact Factor
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