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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    • "In particular, an increase in ESAT-6 specific IFN-γ responses after challenge is generally an indicator of vaccine failure , as these responses have been shown to positively correlate with TB-associated pathology (Vordermeier et al. 2002). A possi- Table 2 Relevance of IFN-γ and delayed type hypersensitivity responses to efficacy of bovine tuberculosis vaccines A. Responses to vaccination and prior to challenge Most effective TB vaccines elicit IFN-γ and DTH responses (Black et al. 2002) Not all vaccines inducing IFN-γ and DTH responses are protective (Waters et al. 2007) Protection is not linked with maintenance of these responses (Whelan et al. 2011) The amount of IFN-γ produced in response to vaccination does not necessarily correlate with the level of protection afforded by the vaccine (Abebe 2012; Mittrücker et al. 2007; Waters et al. 2012a) B. Responses after vaccination and after challenge IFN-γ responses are generally inversely correlated with responses that predict vaccine efficacy (Vordermeier et al. 2011) A robust ESAT-6/CFP-10-specific IFN-γ response (ex vivo, effector response) after challenge is a negative prognostic indicator of vaccine efficacy, as these responses have been shown to positively correlate with TB-associated pathology (Dietrich et al. 2005; Vordermeier et al. 2002; Waters et al. 2007, 2009) The level of DTH responses detectable after M. bovis challenge does not correlate with the level of pathological changes in cattle or vaccine-elicited protection (Whelan et al. 2011); however, analysis of DTH responses is often confounded by responses evoked by attenuated live vaccines Abbreviations: BCG, Bacille Calmette Guerin; CFP, culture filtrate protein; DTH, delayed type hypersensitivity; IFN, interferon; Tb, tuberculosis. Table 3 Candidate surrogates of protection against bovine tuberculosis "
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    ABSTRACT: Tuberculosis (TB) is a premier example of a disease complex with pathogens primarily affecting humans (i.e., Mycobacterium tuberculosis) or livestock and wildlife (i.e., Mycobacterium bovis) and with a long history of inclusive collaborations between physicians and veterinarians. Advances in the study of bovine TB have been applied to human TB, and vice versa. For instance, landmark discoveries on the use of Koch's tuberculin and interferon-γ release assays for diagnostic purposes, as well as Calmette and Guérin's attenuated M. bovis strain as a vaccine, were first evaluated in cattle for control of bovine TB prior to wide-scale use in humans. Likewise, recent discoveries on the role of effector/memory T cell subsets and polyfunctional T cells in the immune response to human TB, particularly as related to vaccine efficacy, have paved the way for similar studies in cattle. Over the past 15 years, substantial funding for development of human TB vaccines has led to the emergence of multiple promising candidates now in human clinical trials. Several of these vaccines are being tested for immunogenicity and efficacy in cattle. Also, the development of population-based vaccination strategies for control of M. bovis infection in wildlife reservoirs will undoubtedly have an impact on our understanding of herd immunity with relevance to the control of both bovine and human TB in regions of the world with high prevalence of TB. Thus, the one-health approach to research on TB is mutually beneficial for our understanding and control of TB in humans, livestock, and wildlife. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 05/2015; 56(1):26-43. DOI:10.1093/ilar/ilv001 · 2.39 Impact Factor
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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 ClinicalTrial.gov 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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