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Diagnostic reagents for improved in vivo or in vitro cell-mediated immunological diagnosis of tuberculosis

A technology for tuberculosis and reagent kits, applied in the field of immunodiagnostic compositions for tuberculosis, which can solve the problems of difficulty and difficulty in increasing the sensitivity of non-specific responses

Active Publication Date: 2016-08-03
STATENS SERUM INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] a) Most (>99%) antigens of the TB genome are non-specific and shared among multiple mycobacterial species, thus identifying strongly recognized antigens specific for M. tuberculosis is very difficult;
[0027] b) Sensitivity of the diagnostic combination of CFP10 / RV3615c and CFP10 / ESAT6 is already very high, so it becomes even more difficult to further increase sensitivity due to non-specific responses

Method used

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  • Diagnostic reagents for improved in vivo or in vitro cell-mediated immunological diagnosis of tuberculosis
  • Diagnostic reagents for improved in vivo or in vitro cell-mediated immunological diagnosis of tuberculosis
  • Diagnostic reagents for improved in vivo or in vitro cell-mediated immunological diagnosis of tuberculosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Example 1: Preliminary Selection of Antigens

[0129] The T-cell antigens chosen for immunodiagnosis of TB should be specific for M. tuberculosis infection to avoid interference from BCG vaccination and most prevalent atypical mycobacteria. At the same time, avoiding ESAT-6 is important given that it is present in many novel vaccines against TB. As described above in the Background of the Invention, through an extensive and rigorous down-selection approach based on theoretical considerations, practical testing and literature searches of hundreds of selected potential antigens, we have no more than 9 Mycobacterium tuberculosis antigens were used for further testing. They are:

[0130] CFP10(Rv3874). The 10-kDa culture filtrate antigen together with ESAT-6 is the basis of the current cell-based diagnostic blood test for M. tuberculosis infection by the IFN-γ release assay (IGRA). CFP10 is an immunodominant Mycobacterium tuberculosis antigen, and the diagnostic specific...

Embodiment 2

[0140] Example 2. Selection of antigens

[0141] Recognition of the seven antigens listed above in TB patients or latently infected individuals was tested in two separate studies in Egypt and Greenland. In both studies ESAT-6 (Rv3875) was also included as a comparator and reference antigen. In addition, PPD was included in Egypt as an example of non-specific antigenic stimulation.

[0142] Freshly sampled diluted whole blood was restimulated with peptides selected from the listed antigens, and responses to the peptide pool of ESAT-6 and CFP10 were included as benchmarks.

[0143] In the Egyptian study, 34 volunteer donors (8 female and 26 male) were included as positive controls. 32 of these were diagnosed with TB disease with documented positive sputum cultures (subjects 3-34). Two had latent TB (subjects 1 and 2). In addition, 30 endemic negative control donors (5 female and 26 male) were included. They were all presumptively BCG vaccinated, had no history of TB disease...

Embodiment 3

[0146] Example 3. CFP10 and 3615c are comparable to CFP10 and ESAT-6

[0147] The diagnostic performance of combining CFP10 and Rv3615c was then compared with that of combining CFP10 and ESAT-6. We included whole blood samples from 35 individuals from Greenland, 18 of the 35 individuals had latent M. tuberculosis infection, defined as a positive Quantiferon test and / or demonstrated exposure to M. tuberculosis and tuberculosis The plain skin test was converted, and 17 patients were microbiologically confirmed as TB. A single aliquot of 200 μl undiluted whole blood was treated with overlapping peptides representing CFP10 (SEQID1) or Rv3615 (SEQID15-18) or ESAT-6 (SEQID51) at a final concentration of 5 μg / ml in a humidified 37°C incubator Stimulate for 7 days. Negative control samples (nil) were prepared in parallel. After incubation, plasma supernatants were isolated and ELISA was used to determine the levels of IFN-γ.

[0148] By summing the measured levels of antigen-speci...

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Abstract

The invention discloses diagnostic reagents for improved in vivo or in vitro cell-mediated immunological diagnosis of tuberculosis. The present invention discloses in vitro and in vivo diagnostic methods with enhanced specificity and sensitivity for the detection of tuberculosis. The diagnostic re agents of the present invention can replace former mixtures / cocktails / pools of antigens comprising ESAT-6 but including ESAT6 improves the diagnosis even further.

Description

[0001] The present invention discloses compositions for improved in vivo or in vitro cell-mediated immunodiagnosis of tuberculosis in humans or animals as drugs or diagnostic reagents. The present invention relates to antigen combinations that increase sensitivity (produce fewer false negatives) without sacrificing specificity (amount of false positives) compared to existing antigen combinations. In particular, the present invention relates to antigenic compositions that do not comprise the antigen designated Early Secreted Antigen Target 6 kDa (ESAT-6) currently used in registered products for the detection of Mycobacterium tuberculosis infection. Optionally, the novel diagnostic or immunogenic composition can be used in combination with ESAT-6 to further enhance the sensitivity of cell-mediated diagnosis. Background of the invention [0002] Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. It is estimated that every 4 seconds someone develops TB and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/569
CPCG01N33/5695G01N33/6893G01N2333/522G01N2333/57G01N2469/20
Inventor 克劳斯·埃格德索伦·特滕斯·霍夫艾达·罗森克兰达斯艾尔沙·玛丽·阿格尔彼得·拉瓦茨·安德森
Owner STATENS SERUM INST
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