Mycobacterium vaccae immunotherapy for treating tuberculosis

doi:10.1002/14651858.CD001166

Intervention Review

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Mycobacterium vaccae immunotherapy for treating tuberculosis

Guy de Bruyn^1,*,
Paul Garner²

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 20 JAN 2010

Assessed as up-to-date: 4 OCT 2002

DOI: 10.1002/14651858.CD001166

Database Title

The Cochrane Library

Additional Information

How to Cite

de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001166. DOI: 10.1002/14651858.CD001166.

Author Information

¹
Wits Health Consortium, Perinatal HIV Research Unit, Johannesburg, Guateng, South Africa
²
Liverpool School of Tropical Medicine, International Health Group, Liverpool, Merseyside, UK

^*Guy de Bruyn, Perinatal HIV Research Unit, Wits Health Consortium, PO Box 114, Diepkloof, Johannesburg, Guateng, 1864, South Africa. debruyng@phru.co.za.

Publication History

Publication Status: Stable (no update expected for reasons given in 'What's new')
Published Online: 20 JAN 2010

ARTICLE TOOLS

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Characteristics of included studies [ordered by study ID]

Corlan 1997a

Methods	Generation of allocation sequence: computer-generated randomization Allocation concealment: no information Blinding: participants blinded; provider aware of allocation Losses to follow up at 11 months after entry: Mycobacterium vaccae 6/97 (6.2%); placebo 8/109 (7.3%)

Participants	Number: 206 Description: adult male and female patients with newly diagnosed, sputum culture positive pulmonary tuberculosis Exclusion criteria: no indication of number of exclusions

Interventions	1. M. vaccae strain NCTC 11659, batch A5 (0.1 mL, 10 mg/mL; approximately 10⁹ bacilli) given as intradermal injection; given over the deltoid region 1 month after starting chemotherapy 2. Placebo: saline Both groups: 2 months of isoniazid, rifampicin, pyrazinamide, and streptomycin twice weekly (usually in hospital); followed by 4 months of isoniazid and rifampicin taken twice weekly

Outcomes	No primary outcome specified 1. Death 2. Sputum positivity and culture at 6 months 3. Body weight 4. Erythrocyte sedimentation rate 5. X-ray cavities

Notes	Location: Bucharest and Brasov, Romania Adherence: "treatment not strictly supervised" Second-line drugs not generally available in Romania at the time of the study Number of participants requiring changes in prescribed drugs during the trial not disclosed

Corlan 1997b

Methods	Generation of allocation sequence: computer-generated randomization Allocation concealment: no information Blinding: participants blinded; provider aware of allocation Losses to follow up at 11 months after entry: Mycobacterium vaccae = 2/56 (3.6%) placebo = 2/46 (4.3%) Ascertainment bias present: "...the most severely ill patients tended to be directed to the immunotherapy group" (pg 23)

Participants	Number: 102 Description: adult patients with pulmonary tuberculosis who attended for therapy for chronic treatment failure or multiply relapsed disease Exclusion criteria: none; no disclosure of the number of people refusing entry to the trial

Interventions	1. M. vaccae strain NCTC 11659 batch A5: 0.1 mL given as intradermal injection (10 mg/mL; approximately 10⁹ bacilli); given over the deltoid muscle 1 month after starting chemotherapy 2. Placebo: saline Both groups: 2 months of rifampicin, isoniazid, streptomycin, and pyrazinamide taken twice weekly (usually in hospital); followed by 4 months of rifampicin and isoniazid taken twice weekly

Outcomes	No primary outcome specified 1. Death 2. Sputum positivity and culture at 6 months 3. Body weight 4. Erythrocyte sedimentation rate 5. X-ray cavities

Notes	Location: Bucharest and Bresov, Romania Adherence: "treatment not strictly supervised" Second-line drugs not generally available in Romania at the time of the study Number of participants requiring changes in prescribed drugs during the trial not disclosed Fewer women received immunotherapy than received placebo; M. vaccae = 9/56 (16.1%), placebo = 14/46 (30.4%).

DITG 1999

Methods	Generation of allocation sequence: "random, permuted blocks of size 20" Allocation concealment: "A person independent of the study labelled and packaged the supplies. Sealed disclosure envelopes were supplied for each vial and were stored in the hospital pharmacy." (pg 117) Blinding: double blind; the injection site covered with a bandage to avoid unblinding other patients and staff; local adverse effects monitored by independent assessors Losses to follow up: all participants accounted for at trial's conclusion

Participants	Number: 374 Descriptions: patients with newly diagnosed, sputum smear positive pulmonary tuberculosis; tuberculosis bacilli were susceptible to chemotherapy; included HIV-positive people Exclusion criteria: persons with AIDS, leukopoenia, signs of liver disease, diabetes, or malignancy

Interventions	1. Heat-killed Mycobacterium vaccae given as intradermal injection (0.1 mL 10⁹) on day 8 of treatment 2. Placebo: intradermal saline injection given on day 8 of treatment Both groups: daily rifampicin 450 mg (600 mg if > 50 kg), isoniazid 300 mg (400 mg if > 50 kg), pyrazinamide 1.5 g (2.0 g if > 50 kg), and ethambutol (1200 mg) for the first 8 weeks. Followed by 4 months of continuation therapy; rifampicin and isoniazid at same doses 3 times a week; pyridoxine 25 mg daily. Treatment given in hospital for the first 8 weeks and if still sputum positive at 8 weeks, a further 4 weeks. Monthly review to completion of 6 months of treatment Participants received 25 mg pyridoxine daily

Outcomes	1. Time to sputum culture conversion in first 8 weeks (primary outcome) 2. Culture status at 6 months 3. Radiographic score at day 56 4. Change in erythrocyte sedimentation rate from day 1 to day 56 5. Change in weight from day 8 to day 56

Notes	Location: South Africa BCG scar present in 83% of participants

Johnson 2000

Methods	Generation of allocation sequence: "computer-generated randomization sequence with a permuted fixed block size of 8" Allocation concealment: "concealed by assigning a dedicated nurse-injector, who made no other subject assessments, to administer the test article. The nurse-injector administered the contents of the next consecutively numbered vial to the subject by intradermal injection (Mantoux method) into the skin over the upper arm." (pg 1305) Blinding: double blind; injection site covered with an opaque bandage to avoid unblinding; separate clinical assessors used for local and systemic responses Losses to follow up: all participants accounted for at trial's conclusion

Participants	Number: 120 Description: HIV-negative ambulatory adults with first episode of sputum-smear positive pulmonary tuberculosis; radiographically, patients had moderate to severe disease

Interventions	1. Heat-killed Mycobacterium vaccae (0.1 mL) given as intradermal injection on 8^th day of antituberculous chemotherapy 2. Placebo: sterile borate- buffered saline (0.1 mL), given on 8^th day of treatment Both groups: 2 months of daily self-administered isoniazid, rifampicin, pyrazinamide, and ethambutol. Followed by 4 months of daily isoniazid and rifampicin

Outcomes	1. Rates of local and systemic adverse events (primary) 2. Rate of sputum culture conversion (primary) 3. Other immunological measures (primary) 4. Improvement in self-reported fever, cough

Notes	Location: Uganda Adherence monitored through self reporting, review of dispensing records, and testing of urine for isoniazid metabolites BCG scar present in 49% of participants

Kon 1998

Methods	Generation of allocation sequence: randomization method not described Allocation concealment: method not described Blinding: double blind; outcomes assessors blinded to allocation Loss to follow up: none reported

Participants	Number: 11 Description: adults (10 male, 1 female) with fully drug-sensitive pulmonary tuberculosis

Interventions	1. Mycobacterium vaccae given as intradermal injection (0.1 mL) given 1 to 2 weeks after diagnosis 2. Placebo: saline (0.1 mL) injected intradermally Dosing interval (daily/3 times a week/twice weekly) not reported Both groups: 2 months of rifampicin, isoniazid, and pyrazinamide, followed by 4 months of rifampicin and isoniazid

Outcomes	No primary outcome stated 1. Adverse events (local and systemic) 2. Change in body weight 3. Change in chest radiographic appearance (score) 4. Erythrocyte sedimentation rate 5. C-reactive protein 6. Immunological measures

Notes	Location: UK Adherence: not reported

Mwinga 2002

Methods	Generation of allocation sequence: "randomisation schedule was prepared by the MRC HIV Clinical Trials Unit, London, UK, by means of computer-generated balanced randomised blocks" (pg 1051) Allocation concealment: "name of an eligible patient was entered on the next available line of the study register to obtain a study number, which identified the prelabelled treatment vial" (pg 1051); "Treatment assignment was concealed from all clinical staff involved in the management of the patient." (pg 1051) Blinding: double blind Losses to follow up: approximately 12% of 1145 lost to follow up or had moved from the district by 12 months after the start of chemotherapy

Participants	Number: 1145 adults (642 male, 503 female) Description: with smear positive pulmonary tuberculosis; included HIV-positive people

Interventions	1. Mycobacterium vaccae strain NCTC 11659 (0.1 mL of SRL172 containing 10⁹ heat-killed organisms in sterile borate-buffered saline) given as 1 injection within the first 2 weeks of initiating antituberculous chemotherapy 2. Placebo: sterile borate-buffered saline (0.1 mL) Both groups' antituberculous chemotherapy varied by trial site: Lusaka: self-administered outpatient therapy with daily doses of rifampicin (450 mg if < 50 kg, 600 mg if 50 kg or more), pyrazinamide (1.5 g or 2.0 g), isoniazid (300 mg), ethambutol (800 mg or 1200 mg) for weeks 1 to 8, followed by isoniazid (300 mg) and ethambutol (600 mg or 800 mg) for weeks 9 to 32 Karonga: participants admitted to hospital for the first 8 weeks of therapy, which consisted of daily doses of streptomycin (0.75 g if < 33 kg, 0.75 g if 33 to 49 kg, or 1 g if > 50 kg), isoniazid (200 mg, 300 mg, 300 mg), rifampicin (300 mg, 450 mg, 600 mg), and pyrazinamide (1 g, 1.5 g, 2 g). During weeks 9 to 32, participants were discharged to self-administer isoniazid (200 mg, 300 mg, 300 mg), and ethambutol (400 mg, 600 mg, 800 mg) daily

Outcomes	1. Death (primary outcome) 2. Time to death in HIV-infected participants 3. Sputum culture status at 2 months 4. Bacteriologic status at 12 months 4. Safety

Notes	Locations: Lusaka, Zambia and Karonga, Malawi Adherence was assessed by self-reporting, review of dispensing records, and urine tests for isoniazid metabolites

Stanford 1990

Methods	Generation of allocation sequence: randomization method not described Allocation concealment: no information Blinding: double blind; participants covered their shoulders in the presence of physicians recording data about them, other than data regarding local reactions, which were evaluated by the person who gave the injections Loss to follow up: not disclosed Length of follow up: 4 months from entry

Participants	Number: 112 Description: adult male and female adults admitted to the Kuwait Chest Diseases Hospital with pulmonary tuberculosis

Interventions	1. Mycobacterium vaccae strain NCTC 11659 given as intradermal injection (0.1 mL; 10 mg/mL; approximately 10⁹ bacilli) and given 28 days after starting chemotherapy 2. Placebo: saline Both groups: 2 months of isoniazid, rifampicin, and streptomycin given in hospital; followed by 7 months of isoniazid and rifampicin

Outcomes	No primary outcome stated 1. Body weight 2. Erythrocyte sedimentation rate 3. X-ray cavities

Notes	Location: Kuwait Results only reported for data showing differences between groups. Some participants were given ethambutol and pyrazinamide based on drug sensitivity testing 38% of placebo participants had a BCG scar (data for immunotherapy group not reported)

Wang 1999

Methods	Generation of allocation sequence: randomization method not described Allocation concealment: no comment Blinding: no details Loss to follow up: all participants accounted for at trial's conclusion

Participants	Number: 70 Description: previously untreated adults with 3 successive sputum smears positive for acid-fast bacilli

Interventions	1. Mycobacterium vaccae given as intramuscular injection (0.1 mg, reconstituted in 2 mL sterile water) at end of week 2 of chemotherapy; further M. vaccae intramuscular injections (0.5 mg of diluted in 2 mL sterile water) given at 2-weekly intervals 2. Both arms: 2 months of rifampicin, isoniazid, pyrazinamide, plus ethambutol or streptomycin as initial therapy, followed by 6 months of isoniazid and ethambutol

Outcomes	No primary outcome stated 1. Improvement in clinical symptoms 2. X-ray appearance after 2 and 4 months of chemotherapy 3. Sputum smear conversion 4. Skin test conversion 5. Immunological responses at 4 months

Notes	Location: China

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion

Bahr 1990	This trial of improved immunotherapy in Kuwait was excluded because it did not report pooled data for all patients receiving immunotherapy. It selectively reported specific secondary outcomes for specific immunotherapy subgroups

Bottasso 1995	Abstract only; insufficient detail for full assessment

Corrah unpublished	We were unable to obtain further information about this unpublished trial from the Medical Research Council Unit in The Gambia

Dlugovitzky 1999	This study of 40 patients reported data from 2 separate trials with different timing of the immunotherapeutic intervention; trial excluded because data from each trial were not presently separately in the published report

Huong unpublished	We were unable to obtain further information about this unpublished trial

Luo 2000	"Random pair" design: methods indicate use of matched controls, rather than a clear description of random allocation

Luo 2001	"Random pair" design: methods indicate use of matched controls, rather than a clear description of random allocation

Mayo 2000a	This trial of 204 participants randomized to immunotherapy and control (intradermal tetanus toxoid) was excluded as more than 30% of participants had been lost to follow up by the completion of treatment, which meant that a significant change in primary study outcomes was possible had a more complete follow up been achieved

Onyebujoh 1995	This trial of 90 participants randomized to immunotherapy and control was excluded because of significant losses at follow up (52% of control group and 62% of the immunotherapy group), which puts the trial at a high risk of bias

Vacirca 1994	Abstract only; insufficient detail for full assessment

Waddell 2000b	Immunological outcomes only; no comparison group