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Mycobacterium tuberculosis vaccine

一种结核分枝杆菌、分枝杆菌的技术，应用在抗细菌药、抗体医疗成分、细菌抗原成分等方向，能够解决免疫有限等问题，达到其他医学或兽医学应用改善、预防改善的效果

Inactive Publication Date: 2011-09-14
UNIV ZURICH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the failure of natural disease to protect against reinfection with disease at subsequent time points suggests that immunity due to natural infection is limited, explaining in part the relative ineffectiveness of vaccination with BCG

Method used

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  • Mycobacterium tuberculosis vaccine
  • Mycobacterium tuberculosis vaccine
  • Mycobacterium tuberculosis vaccine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 - Materials and methods

[0050] Mycobacterial strains and growth conditions

[0051] M. bovis BCG was grown on Middlebrook 7H10 agar plates supplemented with oleic acid albumin dextrose catalase (OADC) (Becton Dickinson), on Dubos agar, supplemented in the presence of Tween 80 (0.05%) in liquid 7H9 medium with OADC or in Dubos broth and incubated at 37°C.

[0052] BCG zmp1 The construction of knockout mutants has been described previously (Master et al., supra). Briefly, Rv165 was cloned from BAC (Brosch et al. Infect. Immun. 66, 2221-2229 1998) contained Mycobacterium tuberculosis zmp1 (Rv0198c) and 4.4 kbp of its flanking region not I Fragment, via Nhe I digestion and removal zmp1 part (770 bp) and replaced by the kanamycin resistance cassette. The resulting suicide vector was transformed into BCG strain 1721 and selection was done on 7H10 agar supplemented with OADC in the presence of appropriate antibiotics (Sander et al., rpsL+: a domina...

Embodiment 2

[0063] Example 2 - zmp deletion increases the immunogenicity of BCG

[0064] To analyze the role of Zmp1 in BCG immunogenicity, titrated doses of wild-type and zmp1 Deficient strains were used to immunize mice. DTH responses were measured after challenge with PPD footpads and different thresholds for induction were observed for the 2 vaccine strains. Although it takes 10 3 CFU inoculum of the wild-type strain produced significant footpad swelling, but with the mutant this dose one-tenth was sufficient to induce an equivalent response, at 10 4 and 10 5 Maximal footpad swelling was observed between CFUs (data not shown). We further analyze the 10 2 -10 4 Degree of footpad swelling upon inoculation. Such as figure 1 shown in the 10 3 (P=0.0006; Mann Whitney) and 10 4 (P=0.0262) CFU, zmp1 The mutant induced a significantly stronger DTH response than the BCG wild type. Experiments were repeated, and univariate ANOVA of the combined data showed no dependence on inoc...

Embodiment 3

[0067] Example 3 - zmp1 deletion increases the protective efficacy of BCG

[0068] Testing Mycobacterium bovis BCG in a mouse model of tuberculosis zmp1 Protective efficacy of mutants. Mouse (C57BL / 6) group passed BCG, BCG zmp1 Mutants were immunized by subcutaneous injection, or left untreated. After 6 weeks, a low dose (10 2 CFU) M. tuberculosis H37Rv challenged mice and monitored CFU, lung pathology and mortality. Three weeks after aerosol challenge, the lungs of control mice contained high numbers of M. tuberculosis. Vaccination reduced the bacterial load in the lungs and spleen by approximately 1-2 logs in the 3 weeks prior to infection. Mice were able to control the infection and CFU counts stabilized between 3 and 23 weeks post-challenge.

[0069] 22 weeks post-infection, from all 3 groups of animals (unvaccinated control, BCG vaccinated, BCG zmp1 Lung sections from vaccinated) showed areas of lung parenchyma with reduced open alveolar spaces, variable wideni...

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Abstract

The present invention relates to the use of live mycobacterium of the M. tuberculosis complex for preparing a medicament, wherein the function of the zmp1-gene is inactivated, pharmaceutical compositions prepared from such mycobacteria as well as a method for the treatment and / or prophylaxis of a disease or medical condition using said pharmaceutical composition.

Description

technical field [0001] The present invention relates to Mycobacterium tuberculosis ( M. tuberculosis ) complex of live mycobacteria for the preparation of a medicament in which the function of the zmp1 gene is inactivated, pharmaceutical compositions prepared from such mycobacteria and the use of said pharmaceutical compositions for the treatment and / or prophylaxis of diseases or Approach to medical conditions. Background technique [0002] Mycobacterium tuberculosis( Mycobacterium tuberculosis ) is one of the most serious pathogens known today, killing millions of individuals worldwide each year. A hallmark of M. tuberculosis infection is that after phagocytosis the microorganism resists lysosomal delivery and instead resides in phagosomes that do not fuse with lysosomes. Phagolysosomes are equipped with machinery to generate peptide-MHC II complexes. Inhibition of phagolysosome fusion has been proposed to represent a mechanism by which M. tuberculosis evades efficient...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/04A61P31/06A61P31/04A61P31/12A61P35/00A61K39/00
CPCA61K2039/522A61K2039/523A61K39/04A61P31/00A61P31/04A61P31/06A61P31/12A61P33/02A61P35/00A61P37/04
Inventor E·博特格P·桑德
Owner UNIV ZURICH
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