WO1994006466A1 - Therapeutic agent from mycobacterium vaccae and its use against hiv infection - Google Patents

Therapeutic agent from mycobacterium vaccae and its use against hiv infection Download PDF

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Publication number
WO1994006466A1
WO1994006466A1 PCT/GB1993/000463 GB9300463W WO9406466A1 WO 1994006466 A1 WO1994006466 A1 WO 1994006466A1 GB 9300463 W GB9300463 W GB 9300463W WO 9406466 A1 WO9406466 A1 WO 9406466A1
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vaccae
aids
material derived
hiv infection
tuberculosis
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PCT/GB1993/000463
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French (fr)
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John Lawson Stanford
Graham Arthur William Rook
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University College London
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University College London
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Priority to DE69322280T priority Critical patent/DE69322280T2/en
Priority to DK93905520T priority patent/DK0661998T3/en
Priority to KR1019950701002A priority patent/KR100272743B1/en
Priority to EP93905520A priority patent/EP0661998B1/en
Priority to HK98112443.1A priority patent/HK1011289B/en
Priority to AU36420/93A priority patent/AU683835B2/en
Publication of WO1994006466A1 publication Critical patent/WO1994006466A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • This invention relates to therapeutic agents useful in the therapy of HIV infection with or without AIDS (acquired immune deficiency syndrome) .
  • the causative agent for AIDS is known to be a virus of the retrovirus family called HIV (human immunodeficiency virus) .
  • HIV human immunodeficiency virus
  • Infection with HIV does not, however, immediately give rise to overt symptoms of AIDS.
  • the only indication of exposure to the virus may be the presence of antibodies thereto in the blood of an infected subject who is then described as 'HIV positive'.
  • the infection may lie dormant, giving rise to no obvious symptoms, and the incubation period prior to development of AIDS may vary from several months to decades.
  • Development of AIDS itself may be preceded by the AIDS-related complex (ARC) which is characterised by unexplained fever, weight loss, chronic cough or diarrhoea.
  • ARC AIDS-related complex
  • the present invention accordingly provides the use of antigenic and/or immunoregulatory materials derived from Mycobacterium vaccae for the manufacture of a medicament useful in the therapy of AIDS and also in the therapy of HIV-positive asymptomatic patients, with or without associated tuberculosis.
  • Such material may be administered to a subject, for example a subject who is HIV positive and shows overt symptoms of AIDS with or without infection by Mycobacterium tuberculosis, in an amount sufficient at least to arrest the progression of the symptoms.
  • the therapeutic agent of the invention conveniently, and therefore preferably, comprises dead cells of M ⁇ _ vaccae. most preferably cells which have been killed by autoclaving.
  • the immunotherapeutic agent normally comprises more than 10 8 microorganisms per ml of diluent, and preferably from 10 8 to 10 11 killed M. vaccae microorganisms per ml of diluent.
  • the invention includes within its scope antigenic and/or immunoregulatory material from M. vaccae for use in therapy of HIV infection with or without AIDS and with or without associated tuberculosis.
  • the diluent may be pyrogen-free saline for injection alone, or a borate buffer of pH 8.0. The diluent should be sterile.
  • a suitable borate buffer is:
  • the preferred strain of M. vaccae is one denoted R877R isolated from mud samples from the Lango district of Central Kenya (J.L. Stanford and R.C. Paul, Ann. Soc. Beige Med, Trop. 1973, 53, 141-389).
  • the strain is a stable rough variant and belongs to the aurum sub-species. It can be identified as belonging to M. vaccae by biochemical and antigenic criteria (R. Bonicke, S.E. Juhasz., Zentr albl. Bakteriol. Parasitenkd. Infection skr. Hyg. Abt. 1, Orig., 1964, 192 . , 133).
  • the strain denoted R877R has been deposited at the
  • the microorganism M. vaccae may be grown on a suitable solid medium.
  • a modified Sauton's liquid medium is preferred (S.V. Boyden and E. Sorkin. , J. Immunol, 1955, 7_5, 15) solidified with agar.
  • the solid medium contains 1.3% agar.
  • the medium inoculated with the microorganisms is incubated aerobically to enable growth of the microorganisms to take place, generally at 32"C for 10 days.
  • the organisms are harvested, then weighed and suspended in a diluent.
  • the diluent may be unbuffered saline but is preferably borate- buffered and contains a surfactant such as Tween 80 as described above.
  • the suspension is diluted to give 100 mg of microorganism/ml.
  • borate buffered saline is preferably used so that the suspension contains 10 mg wet weight of microorganisms/ml of diluent.
  • the suspension may then be dispensed into 5 ml multidose vials.
  • the microorganisms in the vials may be killed using irradiation e.g. from °°Cobalt at a dose of 2.5 megarads, or by any other means, for example chemically, it is preferred to kill the microorganisms by autoclaving, for example at 10 psi for 10 minutes (115°-125°C) . It has been discovered that autoclaving yields a more effective preparation than irradiation.
  • the immunotherapeutic agent is in general administered by injection in a volume in the range 0.1-0.2 ml, preferably 0.1 ml, given intradermally.
  • a single dosage will generally contain from 10 7 to 10 10 killed M. vaccae microorganisms. It is preferred to administer to patients a single dose containing 10 8 to 10 9 killed M. vaccae. However, the dose may be repeated depending on the condition of the patient.
  • the i munotherapeutic agent will generally be administered by intradermal injection, other routes, e.g. oral administration, can also be used.
  • the invention includes within its scope a method for the treatment of HIV infection with or without AIDS, including AIDS associated with tuberculosis, which comprises administering to a subject suffering from HIV infection with or without AIDS, and with or without associated tuberculosis, antigenic and/or immunoregulatory material derived from Mycobacterium vaccae in an amount sufficient to provoke an immune response effective against the AIDS symptoms.
  • AIDS associated with tuberculosis For 20 to 50% of African patients with HIV infection tuberculosis is the first symptom in development of AIDS.
  • a group of patients being treated for tuberculosis were seventeen who were seropositive by the Wellcome ELISA for HIV1.
  • the therapeutic agent may also contain BCG
  • the therapeutic agent can contain further ingredients such as adjuvants, preservatives, stabilisers etc. It may be supplied in sterile injectable liquid form or in sterile freeze-dried form which is reconstituted prior to use.
  • M. vaccae may be used as such or as an extract or fractionated portion of the organism to prepare therapeutic agents according to the invention.
  • EXAMPLE M. vaccae is grown on a solid medium comprising modified Sauton's medium solidified with 1.3% agar.
  • the medium is inoculated with the microorganism and incubated for 10 days at 32°C to enable growth of the microorganism to take place.
  • the microorganisms are then harvested and weighed and suspended in diluent to give 100 mg of microorganisms/ml of diluent.
  • the suspension is then further diluted with buffered saline to give a suspension containing 10 mg wet weight of microorganisms/ml of diluent and dispensed into 5 ml multidose vials.
  • the vials containing the live microorganism are then autoclaved for 10 minutes at 10 psi to kill the microorganisms and give the immunotherapeutic agent of the invention, which may (if desired) be further diluted for use.
  • This immunotherapeutic agent may be administered by intradermal injection in the manner already described.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Virology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

The invention relates to the use of antigenic and/or immunoregulatory material derived from Mycobacterium vaccae for therapy of HIV infection with or without AIDS and with or without associated tuberculosis.

Description

THERAPEUTIC AGENT FROM MYCOBACTERIUM VACCAE AND ITS USE AGAINST HIV INFECTION
This invention relates to therapeutic agents useful in the therapy of HIV infection with or without AIDS (acquired immune deficiency syndrome) . The causative agent for AIDS is known to be a virus of the retrovirus family called HIV (human immunodeficiency virus) . Infection with HIV does not, however, immediately give rise to overt symptoms of AIDS. The only indication of exposure to the virus may be the presence of antibodies thereto in the blood of an infected subject who is then described as 'HIV positive'. The infection may lie dormant, giving rise to no obvious symptoms, and the incubation period prior to development of AIDS may vary from several months to decades. Development of AIDS itself may be preceded by the AIDS-related complex (ARC) which is characterised by unexplained fever, weight loss, chronic cough or diarrhoea.
The reasons for the variable period between infection with the virus and breakdown of the immune system in an infected individual are poorly understood. Factors at present unknown may trigger proliferation of the virus with consequential disruption of -Che immune system. The victims of the disease are then subject to various infections and malignancies which, unchecked by the disabled immune system, lead to death.
The association between HIV infection and tuberculosis is well known. An early effect of HIV infection is the reactivation of previously dormant tubercule bacilli. The maintenance of resistance to ycobacteria is an active immunological process which is compromised by HIV infection. In dually infected persons, there is a high reactivation rate of dormant tubercule bacilli and this reactivation usually occurs well before the appearance of other HIV/AIDS-related infections which strongly suggests that an important effect of HIV infection is to destroy precisely those immune functions, presumably T-cell mediated, that maintain mycobacterial dormancy. There is also evidence that where active tuberculosis is superimposed on HIV infection, there is a dramatic loss of CD4 T-cells which results in very rapid development of overt symptoms of AIDS. It appears in fact that immune mediators released in tuberculosis accelerate transactivation of the HIV provirus.
We have previously described the use of antigenic and/or immuno regulatory material derived from Mycobacterium vaccae in the treatment of tuberculosis (see, for example, British Patent No. 2156673 and United States Patent No. 4724144) . In our International Patent Application No. PCT/GB90/01169 (publication No. WO91/01751) , we have described the use of the same material for immuno- prophylactic treatment against AIDS, i.e. for increasing the period between infection by HIV and development of AIDS. We have now discovered that the same therapeutic agent not only delays development of AIDS in patients infected by HIV, but also is capable of causing regression, or even removal, of overt symptoms of AIDS even in patients where the disease is far advanced. These effects have been found in patients suffering also from tuberculosis, but are expected to occur also in patients who are suffering from HIV infection with or without AIDS and without associated tuberculosis.
The present invention accordingly provides the use of antigenic and/or immunoregulatory materials derived from Mycobacterium vaccae for the manufacture of a medicament useful in the therapy of AIDS and also in the therapy of HIV-positive asymptomatic patients, with or without associated tuberculosis. Such material may be administered to a subject, for example a subject who is HIV positive and shows overt symptoms of AIDS with or without infection by Mycobacterium tuberculosis, in an amount sufficient at least to arrest the progression of the symptoms.
The therapeutic agent of the invention conveniently, and therefore preferably, comprises dead cells of M^_ vaccae. most preferably cells which have been killed by autoclaving. The immunotherapeutic agent normally comprises more than 108 microorganisms per ml of diluent, and preferably from 108 to 1011 killed M. vaccae microorganisms per ml of diluent. The invention includes within its scope antigenic and/or immunoregulatory material from M. vaccae for use in therapy of HIV infection with or without AIDS and with or without associated tuberculosis. The diluent may be pyrogen-free saline for injection alone, or a borate buffer of pH 8.0. The diluent should be sterile. A suitable borate buffer is:
Na2B407.10H20 3.63 g
H3BO3 5.25 g
NaCl 6.19 g
Tween 0.0005%
Distilled Water to 1 litre
The preferred strain of M. vaccae is one denoted R877R isolated from mud samples from the Lango district of Central Uganda (J.L. Stanford and R.C. Paul, Ann. Soc. Beige Med, Trop. 1973, 53, 141-389). The strain is a stable rough variant and belongs to the aurum sub-species. It can be identified as belonging to M. vaccae by biochemical and antigenic criteria (R. Bonicke, S.E. Juhasz., Zentr albl. Bakteriol. Parasitenkd. Infection skr. Hyg. Abt. 1, Orig., 1964, 192., 133). The strain denoted R877R has been deposited at the
National Collection of Type Cultures (NCTC) Central Public Health Laboratory, Colindale Avenue, London NW9 5HT, United Kingdom on February 13th, 1984 under the number NCTC 11659. For the preparation of the immunotherapeutic agent, the microorganism M. vaccae may be grown on a suitable solid medium. A modified Sauton's liquid medium is preferred (S.V. Boyden and E. Sorkin. , J. Immunol, 1955, 7_5, 15) solidified with agar.
Preferably the solid medium contains 1.3% agar. The medium inoculated with the microorganisms is incubated aerobically to enable growth of the microorganisms to take place, generally at 32"C for 10 days. The organisms are harvested, then weighed and suspended in a diluent. The diluent may be unbuffered saline but is preferably borate- buffered and contains a surfactant such as Tween 80 as described above. The suspension is diluted to give 100 mg of microorganism/ml. For further dilution, borate buffered saline is preferably used so that the suspension contains 10 mg wet weight of microorganisms/ml of diluent. The suspension may then be dispensed into 5 ml multidose vials. Although the microorganisms in the vials may be killed using irradiation e.g. from °°Cobalt at a dose of 2.5 megarads, or by any other means, for example chemically, it is preferred to kill the microorganisms by autoclaving, for example at 10 psi for 10 minutes (115°-125°C) . It has been discovered that autoclaving yields a more effective preparation than irradiation.
The immunotherapeutic agent is in general administered by injection in a volume in the range 0.1-0.2 ml, preferably 0.1 ml, given intradermally. A single dosage will generally contain from 107 to 1010 killed M. vaccae microorganisms. It is preferred to administer to patients a single dose containing 108 to 109 killed M. vaccae. However, the dose may be repeated depending on the condition of the patient.
Although the i munotherapeutic agent will generally be administered by intradermal injection, other routes, e.g. oral administration, can also be used.
The invention includes within its scope a method for the treatment of HIV infection with or without AIDS, including AIDS associated with tuberculosis, which comprises administering to a subject suffering from HIV infection with or without AIDS, and with or without associated tuberculosis, antigenic and/or immunoregulatory material derived from Mycobacterium vaccae in an amount sufficient to provoke an immune response effective against the AIDS symptoms. For 20 to 50% of African patients with HIV infection tuberculosis is the first symptom in development of AIDS. Among a group of patients being treated for tuberculosis were seventeen who were seropositive by the Wellcome ELISA for HIV1. All the patients were prescribed streptomycin, isoniazid, rifampicin and pyrazinamide for their tuberculosis. Therapy was abbreviated and did not last longer than three months in any case. Eight of the seventeen patients received the therapeutic agent of the present invention and nine received placebo (saline) . At follow up about one year later only three of the patients who had received the anti-tuberculosis drugs only had survived and all three of these had advanced tuberculosis. Seven of the eight patients treated with the therapeutic agent of the present invention had become sputum smear negative for acid fast bacilli (i.e. tubercule bacilli) and the general improvement in their condition was similar to that in tuberculosis patients who were not HIV positive. Five of the eight patients had generalised lymphadenopathy at the time of diagnosis. This had resolved at the time of follow-up. The only two patients who were retested serologically at the follow-up were found to be negative for HIV1.
It may be advantageous and is within the scope of the invention to use more than one strain of M. vaccae. and/or to include in the therapeutic agent other mycobacterial antigens. Tuberculin may also be included. The therapeutic agent may also contain BCG
(Bacillus Calmette-Guerin) vaccine, in particular the freeze-dried form of the vaccine, to promote its effect.
The therapeutic agent can contain further ingredients such as adjuvants, preservatives, stabilisers etc. It may be supplied in sterile injectable liquid form or in sterile freeze-dried form which is reconstituted prior to use.
M. vaccae may be used as such or as an extract or fractionated portion of the organism to prepare therapeutic agents according to the invention.
The following Example describes the preparation of a therapeutic agent as used in the invention. EXAMPLE M. vaccae is grown on a solid medium comprising modified Sauton's medium solidified with 1.3% agar. The medium is inoculated with the microorganism and incubated for 10 days at 32°C to enable growth of the microorganism to take place. The microorganisms are then harvested and weighed and suspended in diluent to give 100 mg of microorganisms/ml of diluent. The suspension is then further diluted with buffered saline to give a suspension containing 10 mg wet weight of microorganisms/ml of diluent and dispensed into 5 ml multidose vials. The vials containing the live microorganism are then autoclaved for 10 minutes at 10 psi to kill the microorganisms and give the immunotherapeutic agent of the invention, which may (if desired) be further diluted for use.
This immunotherapeutic agent may be administered by intradermal injection in the manner already described.

Claims

1. Use of antigenic and/or immunoregulatory material derived from Mycobacterium vaccae for the manufacture of a medicament useful in the therapy of HIV infection with or without AIDS.
2. The use according to claim 1, wherein the antigenic and/or immunoregulatory material derived from M. vaccae comprises dead cells of M. vaccae.
3. The use according to claim 2, wherein the cells of M. vaccae have been killed by autoclaving.
4. The use according to any one of the preceding claims wherein the material derived from M. vaccae is derived from the strain as deposited at the National Collection of Type Cultures (NCTC) Central Public Health Laboratory, Colindale Avenue, London NW9 5HT, United Kingdom on February 13th, 1984 under the number NCTC 11659.
5. The use according to any one of the preceding claims wherein the material derived from M. vaccae is contained in a medicament comprising from 107 to 1010 microorganisms per dose.
6. The use according to any one of the preceding claims wherein the HIV infection with or without AIDS is associated with tuberculosis.
7. A method for the treatment of HIV infection with or without AIDS which comprises administering to a subject, for example a subject who is HIV positive and shows overt symptoms of AIDS, antigenic and/or immunoregulatory material derived from Mycobacterium vaccae in an amount sufficient at least to arrest the progression of said symptoms of AIDS.
8. A method according to claim 7 wherein the subject also shows symptoms of tuberculosis.
9. A method according to claim 7 or 8, wherein the material derived from M. vaccae is as defined in any one of claims 2 to 5.
10. Products comprising material derived from Mycobacterium vaccae for use in the therapy of HIV infection with or without AIDS and with or without associated tuberculosis.
11. Products according to claim 10, wherein the material derived from M. vaccae is as defined in any one of claims 2 to 5.
12. An immunotherapeutic agent comprising antigenic and/or immunoregulatory material derived from Mycobacterium vaccae for use in the therapy of HIV infection with or without AIDS and with or without associated tuberculosis.
13. An agent according to claim 12, wherein the material derived from M. vaccae is as defined in any one of claims 2 to 5.
PCT/GB1993/000463 1992-09-14 1993-03-05 Therapeutic agent from mycobacterium vaccae and its use against hiv infection Ceased WO1994006466A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
DE69322280T DE69322280T2 (en) 1992-09-14 1993-03-05 THERAPEUTIC AGENCY FROM MYCOBACTERIUM VACCAE AND ITS USE AGAINST HIV INFECTION WITH AIDS
DK93905520T DK0661998T3 (en) 1992-09-14 1993-03-05 Therapeutic agent of mycobacterium vaccae and its use against HIV infection with AIDS
KR1019950701002A KR100272743B1 (en) 1992-09-14 1993-03-05 Antigen substance for useful hiv infection therapy from mycobacterium vaccae
EP93905520A EP0661998B1 (en) 1992-09-14 1993-03-05 Therapeutic agent from mycobacterium vaccae and its use against hiv infection with aids
HK98112443.1A HK1011289B (en) 1992-09-14 1993-03-05 Therapeutic agent from mycobacterium vaccae and its use against hiv infection with aids
AU36420/93A AU683835B2 (en) 1992-09-14 1993-03-05 Therapeutic agent from mycobacterium vaccae and its use against HIV infection

Applications Claiming Priority (2)

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GB929219425A GB9219425D0 (en) 1992-09-14 1992-09-14 Therapeutic agent and its use
GB9219425.7 1992-09-14

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JP (1) JPH06100457A (en)
KR (1) KR100272743B1 (en)
CN (1) CN1060937C (en)
AP (1) AP510A (en)
AT (1) ATE173633T1 (en)
AU (1) AU683835B2 (en)
BR (1) BR9303762A (en)
CA (1) CA2105646A1 (en)
DE (1) DE69322280T2 (en)
DK (1) DK0661998T3 (en)
ES (1) ES2125331T3 (en)
GB (1) GB9219425D0 (en)
RU (1) RU2106878C1 (en)
SG (1) SG72610A1 (en)
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Cited By (14)

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WO1998026790A1 (en) * 1996-12-18 1998-06-25 Stanford Rook Limited Mycobacterium vaccae for down-regulation of the th2 activity of the immune system
US5968524A (en) * 1997-12-23 1999-10-19 Genesis Research & Development Corp. Methods and compounds for the treatment of immunologically-mediated psoriasis
US5985287A (en) * 1996-08-29 1999-11-16 Genesis Research And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US6001361A (en) * 1996-08-29 1999-12-14 Genesis Research & Development Corporation Limited Mycobacterium vaccae antigens
WO2000048615A3 (en) * 1999-02-16 2000-12-14 Stanford Rook Ltd TREATMENT OF CHRONIC VIRAL INFECTIONS WITH $i(M. VACCAE)
US6328978B1 (en) 1997-12-23 2001-12-11 Genesis Research & Development Corp. Ltd. Methods for the treatment of immunologically-mediated skin disorders
US6350457B1 (en) 1999-06-02 2002-02-26 Genesis Research & Development Corporation Limited Methods and compounds for the treatment of immunologically-mediated diseases using mycobacterium vaccae
US6406704B1 (en) 1996-08-29 2002-06-18 Genesis Research And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
WO2002056906A3 (en) * 2001-01-17 2003-02-20 Bakulesh Mafatlal Khamar Use of mycobacterium w for the treatment of human immunodeficiency virus (hiv) disease infection
GB2382529A (en) * 2001-01-17 2003-06-04 Bakulesh Mafatlal Khamar Immunomodulator for the management of human immunodficiency virus (hiv) disease/infection
WO2003063897A1 (en) * 2002-01-29 2003-08-07 Modi, Rajiv, Indravadan Method of providing prophylaxis for tuberculosis in hiv positive individuals
WO2003063896A1 (en) * 2002-01-29 2003-08-07 Modi, Rajiv, Indravadan Process of preparing a pharmaceutical composition for immunity against tuberculosis in hiv positive individuals
WO2003075825A3 (en) * 2002-03-08 2003-11-13 Bakulesh Mafatlal Khamar The method of treating tuberculosis
US6878377B2 (en) 1996-12-18 2005-04-12 Stanford Rook Limited Mycobacterium vaccae for down-regulation of the Th2 activity of the immune system

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RU2380114C1 (en) * 2008-06-25 2010-01-27 Людмила Анатольевна Шовкун Method of treating pulmonary tuberculosis in hiv-patients
JP7760151B2 (en) * 2021-09-09 2025-10-27 国立大学法人東京海洋大学 DNA vaccine for mycobacteriosis and method for preventing mycobacteriosis using the same

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284255B1 (en) 1996-08-29 2001-09-04 Genesis Research & Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US5985287A (en) * 1996-08-29 1999-11-16 Genesis Research And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US6001361A (en) * 1996-08-29 1999-12-14 Genesis Research & Development Corporation Limited Mycobacterium vaccae antigens
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AU730548B2 (en) * 1996-12-18 2001-03-08 Stanford Rook Limited Mycobacterium vaccae for down-regulation of the TH2 activity of the immune system
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AU3642093A (en) 1994-04-12
GB9219425D0 (en) 1992-10-28
ES2125331T3 (en) 1999-03-01
HK1011289A1 (en) 1999-07-09
SG72610A1 (en) 2001-07-24
DK0661998T3 (en) 1999-08-09
JPH06100457A (en) 1994-04-12
CN1089478A (en) 1994-07-20
RU2106878C1 (en) 1998-03-20
ATE173633T1 (en) 1998-12-15
DE69322280T2 (en) 1999-04-22
ZA935575B (en) 1994-03-01
KR950703360A (en) 1995-09-20
DE69322280D1 (en) 1999-01-07
CA2105646A1 (en) 1994-03-15
AP9300555A0 (en) 1993-10-31
CN1060937C (en) 2001-01-24
KR100272743B1 (en) 2000-11-15
EP0661998A1 (en) 1995-07-12
EP0661998B1 (en) 1998-11-25
AU683835B2 (en) 1997-11-27
AP510A (en) 1996-07-23
BR9303762A (en) 1994-03-22

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