Recombinant early secreted antigen target 6 protein as a skin test antigen for the specific detection of <i>Mycobacterium tuberculosis</i> infection

Wu, Xueqiong; Zhang, L; Zhang, J; Zhang, C; Zhu, Lin; Shi, Yujie

doi:10.1111/j.1365-2249.2008.03605.x

Cited by 26 publications

(19 citation statements)

References 16 publications

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“…Animal experiments showed that the PPD skin test was positive in BCG- and M. tuberculosis -sensitized guinea pigs, and the rESAT6 skin test was negative in BCG-sensitized guinea pigs and positive in M. tuberculosis -sensitized guinea pigs. The experiments indicated that the rESAT6 skin test was able to be used to make the differential diagnosis between BCG vaccination and M. tuberculosis infection, which was consistent with findings of other studies [22–25]. …”

Section: Discussionsupporting

confidence: 90%

“…M. marinum (ATCC927 strain) was used in our study, whereas the TMC1218 strain was used in the Wu study. In our study, the negative skin test result of rESAT6 protein might be the reason that the ESAT6 gene was incompletely expressed in the M. marinum strains [14,25]. Wu also demonstrated that the rESAT6 skin test was negative in the guinea pigs sensitized by M. smegmatis , M. fortuitum and M. phlei , as seen in our study.…”

Section: Discussionsupporting

confidence: 77%

“…In animal experiments, we demonstrated that the ESAT6 gene distribution, which exhibited similar results in that the rESAT6 skin test was positive in the M. bovine- , M. africanum - and M. kansasii -sensitized guinea pigs, whereas the skin test was negative in other NTM-sensitized guinea pigs, including M. marinum . However, Wu reported that the rESAT6 skin test was positive in M. marinum -sensitized guinea pigs [25]. We inferred that this difference in outcomes might have resulted from different strains used in the test.…”

Section: Discussionmentioning

confidence: 95%

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Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein

Chen

et al. 2013

Med Sci Monit Basic Res

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BackgroundTo investigate the ability of rESAT6 to identify different mycobacteria-sensitized guinea pigs and its safety in preclinical and phase I clinical study.Material/MethodsGuinea pigs were sensitized with different Mycobacteria. After sensitization, all animals were intradermally injected with rESAT6 and either PPD or PPD-B. At 24 h after the injection, the erythema of the injection sites were measured using a double-blind method. For the preclinical safety study, different doses of rESAT6 and BSA were given 3 times intramuscularly to guinea pigs. On day 14 after the final immunization, the guinea pigs were intravenously injected with the same reagents in the hind legs and the allergic reactions were observed. A single-center, randomized, open phase I clinical trial was employed. The skin test was conducted in 32 healthy volunteers aged 19–65 years with 0.1 μg, 0.5 μg, and 1 μg rESAT6. Physical examination and laboratory tests were performed before and after the skin test and adverse reactions were monitored. The volunteers’ local and systemic adverse reactions and adverse events were recorded for 7 days.ResultsPositive PPD or PPD-B skin tests were observed in all Mycobacteria-sensitized guinea pigs; the diameters of erythema were all >10 mm. The rESAT6 protein induced a positive skin test result in the guinea pigs sensitized with MTB, M. bovis, M. africanum and M. kansasii; the diameters of erythema were 14.7±2.0, 9.3±3.8, 18.7±2.4, and 14.8±4.2 mm, respectively. A negative skin test result was detected in BCG-vaccinated and other NTM-sensitized guinea pigs. The rESAT6 caused no allergic symptoms, but many allergic reactions, such as cough, dyspnea, and even death, were observed in the guinea pigs who were administered BSA. During the phase I clinical trial, no adverse reactions were found in the 0.1 μg rESAT6 group, but in the 0.5 μg rESAT6 group 2 volunteers reported pain and 1 reported itching, and in the 1 μg rESAT6 group there was 1 case of pain, 1 case of itching, and 1 case of blister. No other local or systemic adverse reactions or events were reported.ConclusionsThe rESAT6 can differentiate effectively among MTB infection, BCG vaccination, and NTM infection and is safe in healthy volunteers.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 95%

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Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein

Chen

et al. 2013

Med Sci Monit Basic Res

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“…ESAT-6 (Rv3875) and CFP10 (Rv3874), highly studied T-cell antigens that are absent in BCG, are currently used as reagents for the diagnosis of TB via an Interferon-gamma release assay (Mazurek, 2005;Chang & Leung, 2010). Recombinant ESAT-6 elicits a positive skin response in Mtb-infected guinea pigs and humans (Wu et al, 2008). Compared to the maximal DTH response at 72 h induced by PPD, the DTH response to ESAT-6 peaked 24 h later (Pollock et al, 2003).…”

Section: Pitfalls Of Ppdmentioning

confidence: 99%

Purified protein derivatives of tuberculin — past, present, and future

Yang

Kruh-Garcia

Dobos

2012

FEMS Immunol Med Microbiol

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The tuberculin skin test, which involves monitoring the immune reaction to an injection of purified protein derivative (PPD), has been the most widely used method for detecting infection with Mycobacterium tuberculosis since its development in 1930s. Until recently, the molecular composition of PPD was unknown. This thwarted the discovery of improved skin testing reagents and drastically hindered efforts to define the mechanism of action. Proteomic evaluation of PPD combined with a detailed analysis in the guinea pig model of tuberculosis led to further definition of the molecular composition of PPD. This communication reviews the history and current status of PPD, in addition to describing candidate next‐generation PPD reagents, based on the use of an individual protein or protein cocktails.

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“…This might especially be the case where the logistics of access to laboratorybased resources are problematic. It is also notable that in recent years, there has also been renewed interest in a skin test-based test for DIVA for human TB, with several reports demonstrating the skin test potential of ESAT-6 (1,3,28).…”

mentioning

confidence: 99%

Development of a Skin Test for Bovine Tuberculosis for Differentiating Infected from Vaccinated Animals

Whelan¹,

Clifford²,

Upadhyay³

et al. 2010

J Clin Microbiol

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The tuberculin skin test has been used for the diagnosis of bovine and human tuberculosis (TB) for over a hundred years. However, the specificity of the test is compromised by vaccination with the Mycobacterium bovis-derived vaccine strain bacille Calmette-Guérin (BCG). Since current promising vaccines against bovine TB are based on heterologous prime-boost combinations that include BCG, there is a need for diagnostic tests for differentiating infected from vaccinated animals (DIVA). The application of antigens such as ESAT-6 and CFP-10 for DIVA has so far been realized largely through their application in the blood-based gamma interferon release assay. In the current study, we have reassessed the potential of such antigens as skin test reagents for DIVA in cattle. A cocktail of the Mycobacterium tuberculosis complex recombinant protein antigens ESAT-6, CFP-10, MPB70, and MPB83 elicited delayed-type hypersensitivity (DTH) skin test responses in 78% of naturally infected tuberculin-positive cattle. Importantly, this cocktail induced no skin responses in BCGvaccinated cattle despite them being sensitized for strong tuberculin responses. Further optimization of skin test antigen combinations identified that the inclusion of Rv3615c (Mb3645c) enhanced skin test sensitivity in naturally infected cattle without compromising specificity. In addition, we demonstrate for the first time the utility of synthetic peptides as promising skin test antigens for bovine TB for DIVA. Our data provide a promising basis for the future development of skin tests for DIVA with practical relevance for TB diagnosis in both veterinary and clinical settings.

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Recombinant early secreted antigen target 6 protein as a skin test antigen for the specific detection of Mycobacterium tuberculosis infection

Cited by 26 publications

References 16 publications

Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein

Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein

Purified protein derivatives of tuberculin — past, present, and future

Development of a Skin Test for Bovine Tuberculosis for Differentiating Infected from Vaccinated Animals

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