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Mycobacterium vaccae immunotherapy for treating tuberculosis

  1. Guy de Bruyn1,*,
  2. 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

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. 1

    Wits Health Consortium, Perinatal HIV Research Unit, Johannesburg, Guateng, South Africa

  2. 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

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

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ARTICLE TOOLS

Summary (59K)Standard (232K)Full (316K)
 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Immunotherapy aims to alter a person's immune response with the intention of reducing illness either by protecting against it or reducing the severity of the condition (Weber 1997). Allergen immunotherapy, for example, aims to reduce a person's sensitivity to an allergen that causes allergic symptoms, such as asthma (Abramson 2000) or allergic rhinitis (Bousquet 1998). Venom immunotherapy is used to modify the response to venoms, such as those of bees or wasps, for people who have severe reactions following prior exposure (Ewan 1998). Immunotherapy for a wide range of infectious agents has been tested, including chronic viral infections, chronic bacterial infections, and parasitic diseases (Convit 1989; Straus 1997; Kahn 2000).

In tuberculosis, the host immune response influences the damage caused by the infection (Rook 1996). Experiments in animals suggest that a type 1 lymphocyte response is less likely to be associated with death of local tissues than a mixed lymphocyte response that includes both type 1 and type 2 responses (Grange 1998). A person's immunity to tuberculosis is thought in part to be related to a type 1 response, characterized by production of interferon-gamma (Barnes 2000).

Mycobacterium vaccae is a rapid-growing mycobacterium species found in the environment. The use of this bacterium as a whole-cell killed vaccine has been advocated as immunotherapy for tuberculosis (Stanford 1990a; Stanford 1994). Although the mechanisms of its potential effect are unknown, it has been proposed that immunotherapy allows immune recognition of antigens common to all mycobacteria or that immunotherapy directs T-lymphocyte responses towards a type 1 pattern. There is some indirect experimental evidence that this occurs in humans (Rook 1994). More recently, the reduction of allergic responses through induction of regulatory T cells by immunization with M. vaccae has been demonstrated (Zuany-Amorim 2002). Immunotherapy is thought to enable the host to destroy organisms and achieve a more rapid cure of infection.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

To evaluate M. vaccae immunotherapy as an adjunct to chemotherapy in people with tuberculosis.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized and quasi-randomized controlled trials. We excluded trials with high losses of follow up for the main outcome (> 25%).

 

Types of participants

People with tuberculosis infection as diagnosed by direct sputum smear microscopy, culture of sputum, or culture of material from a clinically affected anatomical site.

 

Types of interventions

 

Intervention

Inoculation with preparations of whole killed M. vaccae.

 

Control

Placebo.

Other treatments, including chemotherapy for tuberculosis, when used, must be the same regimen in both intervention and control groups.

 

Types of outcome measures

 

Primary

  • Death.
  • Sputum smear conversion to negative at two months.
  • Sputum culture negative at two months and at the end of chemotherapy.

 

Secondary

  • Changes in chest x-ray appearance, assessed using scoring systems.
  • Erythrocyte sedimentation rate.
  • Weight gain.
  • Tuberculin skin test reaction.
  • Delayed hypersensitivity responses.
  • Need for retreatment.

 

Adverse events

  • Local (eg vaccine site ulceration and induration).
  • Systemic (eg fever).
  • Immunological (eg increase in HIV viral load, as measured by polymerase chain reaction).

 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress). We used the following search terms for all trial registers and databases: tuberculosis and vaccae.

We searched the Cochrane Infectious Diseases Group Specialized Register (October 2002), Cochrane Controlled Trials Register (published in The Cochrane Library 2002, Issue 3), MEDLINE (1966 to October 2002), EMBASE (1980 to September 2002), and LILACS (September 2002).

We contacted organizations and individuals working in the field for information regarding unpublished data and work in progress. We also drew on existing reviews of this topic (Stanford 1990a; Stanford 1994) and checked the citations of all the trials identified by the above methods.

 

Data collection and analysis

The first author screened the full articles of potentially relevant studies for eligibility. In cases of doubt, both authors reviewed the papers and reached a consensus decision. Both authors assessed the risk of bias in the trials, and the second author checked data extraction. We assessed the risk of bias in relation to the method of generation of allocation sequence and allocation concealment (adequate, inadequate, or unclear as defined by Jüni 2001), the use of blinding, and losses to follow up.

Data were extracted for outcome variables and entered and analysed in Review Manager 5. We expressed dichotomous outcomes as risk ratio (RR) with 95% confidence intervals (CI), and continuous outcomes as mean difference (MD) with the same CI. Sensitivity analysis of effect estimates were performed on the adequacy of allocation concealment.

In trials that recruited people infected with human immunodeficiency virus (HIV-positive) and people not infected (HIV-negative), we would have stratified the analyses by HIV status had the data been available. This is because the number of deaths in the HIV-positive group would be likely to be higher than in the HIV-negative group and imbalance in numbers could confound the results. We combined the results if no difference was evident visibly in the analyses or statistically.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Eight trials met the inclusion criteria (see 'Characteristics of included studies') and 11 trials were excluded for reasons including that they were of poor quality, abstracts with little information, or trials that had been carried out and no data were available (see 'Characteristics of excluded studies'). The included trials were conducted in China (Wang 1999), Kuwait (Stanford 1990a), Romania (Corlan 1997a; Corlan 1997b), South Africa (DITG 1999), Uganda (Johnson 2000), and the United Kingdom (Kon 1998). Mwinga 2002 was conducted in Malawi and Zambia. The trials enrolled 2140 adults, of whom slightly more than 60% were males. Participants ranged from 15 to 80 years in age. Two trials enrolled HIV-positive participants (DITG 1999; Mwinga 2002).

In all but two of the trials the participants were undergoing treatment for a first episode of pulmonary tuberculosis. The exceptions were one trial that enrolled people with recurrent disease (Corlan 1997b) and another that did not state whether participants were receiving retreatment (Mwinga 2002). BCG scars were present in 49% and 83% of patients from Uganda and South Africa, respectively, and in 38% of control patients from the trial in Kuwait.

The participants were all on standard chemotherapeutic regimens, as routinely prescribed in the country where the trial was being conducted. Mwinga 2002 used an eight-month regimen, Stanford 1990 used a nine-month regimen, and the other six trials used six-month regimens. All but Mwinga 2002 used rifampicin and isoniazid in the continuation phase, which lasted four to seven months. Differences between the trials mainly involved the drugs used for the initial eight weeks.

Chemotherapy was given on an inpatient basis for two to four months in two trials (Stanford 1990; DITG 1999) and in the Malawian participants in another (Mwinga 2002). Otherwise, drug therapy was self-administered (Corlan 1997a; Corlan 1997b), or self-administered with monitoring of dispensing records and monthly urine testing for metabolites of isoniazid (Johnson 2000; Mwinga 2002). One trial reported that participants received 25 mg of pyridoxine daily (DITG 1999).

Immunotherapy was generally a single dose of 109 heat-killed organisms. Five trials reported the strain used (NCTC 11659). Immunotherapy was given on day eight of chemotherapy (DITG 1999, Johnson 2000), between days seven and 14 (Kon 1998), in the first two weeks of antituberculous chemotherapy (Mwinga 2002), or day 28/one month in three trials (Stanford 1990a; Corlan 1997a; Corlan 1997b). One trial administered 0.1 mg of the vaccine product (equivalent number of organisms not stated) in sterile water at the end of week two of chemotherapy, and at week four increased to 0.5 mg every two weeks for an unstated duration (Wang 1999).

 

Risk of bias in included studies

The allocation sequence was generated using computer-generated randomization in two trials (Corlan 1997a; Corlan 1997b), computer-generated block randomization in two trials (Johnson 2000; Mwinga 2002), and by means of random, permuted blocks in one trial (DITG 1999). The other three trials did not report the method used.

Three trials described adequate allocation concealment (DITG 1999; Johnson 2000; Mwinga 2002). The method was not described in the other trial reports.

Five trials were described as double blind (Stanford 1990; Kon 1998; DITG 1999; Johnson 2000; Mwinga 2002). Two trials blinded participants (Corlan 1997a;Corlan 1997b). No details were given for blinding in Wang 1999.

Adverse reactions were evaluated by the person who gave the injections or separate assessors. The two trials conducted in Romania blinded only the participants (Corlan 1997a; Corlan 1997b); Corlan 1997b reports on a apparent corruption of randomization: "rather fewer women (9/56) received immunotherapy than received placebo (14/46) probably because the most severely ill patients tended to be directed towards immunotherapy".

In relation to reporting of participants enrolled, the two Romanian trials lost fewer than 10% of randomized participants at 11 months of follow up (Corlan 1997a; Corlan 1997b). All of the participants in the China, South Africa, and Ugandan trials were accounted for at conclusion of the trial (Wang 1999; DITG 1999; Johnson 2000). In Mwinga 2002, approximately 12% of 1145 participants were lost to follow up or had moved from the district by 12 months after the start of chemotherapy. The Kuwaiti trial did not disclose losses to follow up (Stanford 1990); and no participants were reported as lost to follow up in Kon 1998.

 

Effects of interventions

 

Primary outcomes

Four trials assessed the number of deaths to the completion of chemotherapy (Corlan 1997b; DITG 1999; Johnson 2000; Mwinga 2002) and, when combined, did not demonstrate a difference between the immunotherapy and placebo groups (RR 1.09, 95% CI 0.83 to 1.42; 1741 participants,  Analysis 1.1). A sensitivity analysis that only included trials with adequate allocation concealment did not change this finding (analysis not shown).

Three trials measured the number of participants whose sputum smear converted to negative at two months (Corlan 1997a; Corlan 1997b; Wang 1999). More conversions occurred in the immunotherapy group (RR 1.26, 95% CI 1.11 to 1.43; 356 participants,  Analysis 1.2). No sensitivity analysis was possible as these trials all had unclear allocation concealment.

The number of participants who were sputum culture negative at two months was examined in five trials (Corlan 1997a; Corlan 1997b; DITG 1999; Johnson 2000; Mwinga 2002). The forest plot suggests heterogeneity (chi-square 10.55, P = 0.03, 1441 participants,  Analysis 1.3). The analysis of trials with adequate allocation concealment was not statistically significant (1136 participants, 3 trials,  Analysis 1.3). When measured at completion of chemotherapy, no statistically significant difference was apparent (RR 1.01, 95% CI 0.97 to 1.06; 1490 participants, 5 trials,  Analysis 1.4).

 

Secondary outcomes

Three trials reported the number of people with chest cavities (Corlan 1997a; Corlan 1997b; Johnson 2000); see  Analysis 1.5. There were fewer with cavities at trial entry in the placebo group (RR 1.15, 95% CI 1.05 to 1.27; 447 participants, 3 trials), but no significant difference was detected between the groups for the number of cavities seen at completion of chemotherapy (240 participants, 2 trials) or at six months after completing chemotherapy (226 participants, 2 trials).

The combined results of two trials, Corlan 1997a and Corlan 1997b, also found no significant differences in x-ray scores at entry to the trial ( Analysis 1.6), as defined by the trial authors (307 participants, 2 trials). The scores tended to improve in the treatment group at completion of treatment and at six months after treatment had ended, and were significant in Corlan 1997b. Neither trial reported on methods to blind the radiographic assessors to the treatment group.

The M. vaccae immunotherapy group was associated with a lower erythrocyte sedimentation rate at the end of chemotherapy compared with the placebo group (WMD 8.96 mm/h, 95% CI 12.95 to 4.97; 299 participants, 2 trials,  Analysis 1.7).

Weight gain was measured in five trials. Stanford 1990a reported a mean difference of 1.60 kg in weight from the start to end of treatment in the M. vaccae group (95% CI 0.41 to 2.79; 112 participants,  Analysis 1.8). DITG 1999 and reported no difference, but no standard deviation was given. Corlan 1997b and Corlan 1997a reported greater weight gain in the intervention group, but no statistical test or standard deviation was given; however, in these two trials, weight at the completion of treatment did suggest higher mean weight in the M. vaccae group (WMD 2.63, 95% CI 0.51 to 4.78; 299 participants,  Analysis 1.9).

The mean size of tuberculin skin test reactions showed no difference between immunotherapy and placebo groups when measured at entry (106 participants) and three months after starting chemotherapy (90 participants, Stanford 1990); see  Analysis 1.10.

There was a trend towards immunotherapy being associated with fewer participants requiring retreatment, but the difference was not statistically significant (308 participants, 3 trials,  Analysis 1.11).

 

Adverse events

Local adverse reactions were reported in four trials (Kon 1998; DITG 1999; Johnson 2000; Mwinga 2002); see  Analysis 1.12. They were more common overall in immunotherapy recipients (RR 18.82, 95% CI 5.47 to 64.77; 131 participants, 2 trials). Swelling and redness were significantly more common in recipients of immunotherapy (RR 10.71, 95% CI 6.81 to 16.85; 374 participants, 1 trial), as was ulceration (RR 17.79, 95% CI 5.05 to 62.70; 505 participants, 3 trials). Immunotherapy also resulted in more reports of scarring in the two trials that contained events (RR 10.33, 95% CI 6.61 to 16.13; 706 participants).

One trial, DITG 1999, systematically monitored serious adverse events and did not demonstrate a statistically significant difference between the groups for any systemic adverse events (RR 1.07, 95% CI 0.70 to 1.62; 385 participants,  Analysis 1.13).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Three of the eight included trials had adequate concealment of allocation (DITG 1999; Johnson 2000; Mwinga 2002). Of these three trials, no impact was demonstrated on death, sputum culture at three months, and sputum culture at completion of treatment; nor was there any trend with these outcomes. Overall, the analysis showed no consistent evidence of a benefit of immunotherapy over placebo for people with pulmonary tuberculosis receiving antituberculous chemotherapy, nor has an effect of immunotherapy on mortality been demonstrated.

Two of the trials, Corlan 1997a and Corlan 1997b, did not assess adherence to prescribed chemotherapy. Also, participants found to have resistance to prescribed agents may not have received a second-line drug because of the lack of availability of these agents in Romania at the time the trials were conducted. The number of participants in each group requiring a change in therapy because of resistance to prescribed agents was not disclosed. These factors may have influenced the effect of drug therapy on the course of the illness, making drug treatment a source of potential bias in the outcome of these trials.

Overall, the earlier trials were small and had methodological weaknesses around allocation concealment, blinding, and accuracy of reporting losses to follow up. In these trials, some benefits with some outcomes were apparent. The recent rigorous trials from South Africa (DITG 1999), Uganda (Johnson 2000), and Malawi and Zambia (Mwinga 2002) have consistently shown no effect of this intervention.

There is no evidence that immunotherapy recipients, including those with HIV infection, had a greater rate of serious adverse events recorded in the same trial. No trials have as yet reported on important outcomes such as the effect of immunotherapy on HIV disease progression, although the impact of tuberculosis itself on survival was clearly demonstrated in the Zambian trial by the 10-fold difference in mortality rate over the trial period between those infected with HIV and those without.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

M. vaccae immunotherapy does not benefit people with tuberculosis.

 
Implications for research

The results of this systematic review underline the importance of carefully planned and executed randomized controlled trials, with strict adherence to concealment of allocation.

No further trials are warranted and, as a result, the authors do not intend to update this review.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

This document is an output from a project funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Mycobacterium vaccae immunotherapy versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Death41741Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.83, 1.42]
 2 Sputum smear negative by 2 months3356Risk Ratio (M-H, Fixed, 95% CI)1.26 [1.11, 1.43]
 3 Sputum culture negative at 2 months51441Risk Ratio (M-H, Fixed, 95% CI)1.08 [1.01, 1.16]
    3.1 Adequate allocation concealment
31136Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.97, 1.12]
    3.2 Unclear allocation concealment
2305Risk Ratio (M-H, Fixed, 95% CI)1.25 [1.08, 1.45]
 4 Sputum culture negative at completion of chemotherapy51490Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.97, 1.06]
 5 Number with cavities present3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    5.1 At entry
3447Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.05, 1.27]
    5.2 At completion of chemotherapy
2240Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.77, 1.08]
    5.3 At 6 months after completing chemotherapy
2226Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.51, 1.01]
 6 Change in x-ray score2Mean Difference (IV, Fixed, 95% CI)Subtotals only
    6.1 At entry
2307Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.18, 0.10]
    6.2 At completion of chemotherapy
2289Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.39, -0.11]
    6.3 At 6 months after completing chemotherapy
2259Mean Difference (IV, Fixed, 95% CI)-0.21 [-0.35, -0.07]
 7 Erythrocyte sedimentation rate (mm/h) at completion of chemotherapy2299Mean Difference (IV, Fixed, 95% CI)-8.96 [-12.95, -4.97]
 8 Weight change (kg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 9 Weight (kg) at completion of chemotherapy2299Mean Difference (IV, Fixed, 95% CI)2.63 [0.51, 4.76]
 10 Tuberculin skin test reaction: mean size (mm)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
    10.1 At entry
1Mean Difference (IV, Fixed, 95% CI)Not estimable
    10.2 At 3 months
1Mean Difference (IV, Fixed, 95% CI)Not estimable
 11 Number requiring retreatment2308Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.37, 1.14]
 12 Adverse events (local)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    12.1 Any
2131Risk Ratio (M-H, Fixed, 95% CI)18.82 [5.47, 64.77]
    12.2 Swelling and redness
1374Risk Ratio (M-H, Fixed, 95% CI)10.71 [6.81, 16.85]
    12.3 Ulceration
3505Risk Ratio (M-H, Fixed, 95% CI)17.79 [5.05, 62.70]
    12.4 Scarring
3717Risk Ratio (M-H, Fixed, 95% CI)10.33 [6.61, 16.13]
 13 Adverse events (any systemic)2385Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.70, 1.62]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 4 October 2002.

DateEventDescription
10 November 2009Review declared as stableM. vaccae immunotherapy does not benefit people with tuberculosis. No further trials are warranted and, as a result, the authors do not intend to update this review.

This decision was taken in August 2008, prior to the introduction of a formal Cochrane policy, hence the necessity to republish now.


 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 2, 1998
Review first published: Issue 3, 1998

DateEventDescription
29 July 2008New citation required but conclusions have not changed2000, Issue 3: (substantive update): One new trial added; title changed from “Mycobacterium vaccae immunotherapy for TB” to Mycobacterium vaccae immunotherapy for treating tuberculosis”; and time points specified for sputum smear conversion and sputum culture negative.
21 July 2008AmendedConverted to new review format with minor editing.
20 February 2008New search has been performed2008, Issue 1 (minor update): Of the five studies awaiting assessment in the de Bruyn 2003 version, we included one (Wang 1999), and excluded two because they did not meet the inclusion criteria (Luo 2000; Luo 2001) and two because we could not obtain additional information on these unpublished reports (Corrah unpublished; Linh unpublished). We changed the odds ratios to risk ratios, which are thought to be more accessible to readers. The review has also had a substantive edit.
7 October 2002New citation required and conclusions have changed2003, Issue 1 (substantive update): Mwinga 2002 added; conclusions altered in the light of this.


 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Guy de Bruyn drafted the protocol, data extraction forms, applied the inclusion criteria, assessed quality, extracted data, and prepared the review. Paul Garner helped develop the protocol, checked inclusion criteria, assessed quality, checked data extraction, and contributed to writing the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • Liverpool School of Tropical Medicine, UK.

 

External sources

  • Department for International Development (DFID), UK.
  • European Commission (Directorate General XII), Belgium.

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Corlan 1997a {published data only}
  • Corlan E, Marica C, Macavei C, Stanford JL, Stanford CA. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 1. Newly-diagnosed pulmonary disease. Respiratory Medicine 1997;91(1):13-9.
Corlan 1997b {published data only}
  • Corlan E, Marica C, Macavei C, Stanford JL, Stanford CA. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 2. Chronic or relapsed disease. Respiratory Medicine 1997;91(1):21-9.
DITG 1999 {published data only}
  • Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999;354(9173):116-9.
Johnson 2000 {published data only}
  • Johnson JL, Kamya RM, Okwera A, Loughlin AM, Nyole S, Hom SL, et al. Randomized controlled trial of Mycobacterium vaccae immunotherapy in non-human immunodeficiency virus-infected Ugandan adults with newly diagnosed pulmonary tuberculosis. The Uganda-Case Western Reserve University Research Collaboration. Journal of Infectious Diseases 2000;181(4):1304-12.
Kon 1998 {published data only}
Mwinga 2002 {published data only}
  • Mwinga A, Nunn A, Ngwira B, Chintu C, Warndorff D, Fine P, et al. Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial. Lancet 2002;360(9339):1050-5.
Stanford 1990 {published data only}
  • Bahr GM, Stanford JL, Chugh TD, Shaaban MA, Gabriel M, Al-Shimali B, et al. An investigation of patients with pulmonary tuberculosis in Kuwait in preparation for studies of immunotherapy with Mycobacterium vaccae. Tubercle 1990;71(2):77-86.
  • Stanford JL, Bahr GM, Rook GA, Shaaban MA, Chugh TD, Gabriel M, et al. Immunotherapy with Mycobacterium vaccae as an adjunct to chemotherapy in the treatment of pulmonary tuberculosis. Tubercle 1990;71(2):87-93.
Wang 1999 {published data only}
  • Wang W, Jin G, Ye Y, Xia X, Wang A, Zhang Y, et al. A clinical study on vaccine of Mycobacterium vaccae in treating pulmonary tuberculosis. Zhonghua Jiehe He Huxi Zazhi [Chinese Journal of Tuberculosis and Respiratory Diseases] 1999;22(2):108-10.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Bahr 1990 {published data only}
Bottasso 1995 {published data only}
  • Bottasso OA, Vacirca A, Dominino J, Valentini E, Hartopp R. Immunotherapy applied [a pilot study of immunotherapy with M.vaccae against tuberculosis]. Tubercle and Lung Disease 1995;76 Suppl 2:9.
Corrah unpublished {unpublished data only}
  • Corrah T. Trial of M. vaccae from the Medical Research Council Unit in The Gambia. Unpublished.
Dlugovitzky 1999 {published data only}
  • Dlugovitzky D, Bottasso O, Dominino JC, Valentini E, Hartopp R, Singh M, et al. Clinical and serological studies of tuberculosis patients in Argentina receiving immunotherapy with Mycobacterium vaccae (SRL 172). Respiratory Medicine 1999;93(8):557-62.
Huong unpublished {unpublished data only}
  • Professors Huong, Linh. Trial of M. vaccae. Unpublished.
Luo 2000 {published data only}
  • Luo Y, Lu S, Guo S. Immunotherapeutic effect of Mycobacterium vaccae on multi-drug resistant pulmonary tuberculosis. Zhonghua Jiehe He Huxi Zazhi [Chinese Journal of Tuberculosis and Respiratory Diseases] 2000;23(2):85-8.
Luo 2001 {published data only}
  • Luo Y, National Cooperation Group on Clinical Study of Mycobacterium Vaccae Vaccine. The immunotherapeutic effect of Mycobacterium vaccae vaccine on initially treated pulmonary tuberculosis. Zhonghua Jiehe He Huxi Zazhi [Chinese Journal of Tuberculosis and Respiratory Diseases] 2001;24(1):43-7.
Mayo 2000a {published data only}
  • Mayo RE, Stanford JL. Double-blind placebo-controlled trial of Mycobacterium vaccae immunotherapy for tuberculosis in KwaZulu, South Africa, 1991-97. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000;94(5):563-8.
Onyebujoh 1995 {published data only}
  • Onyebujoh PC, Abdulmumini T, Robinson S, Rook GA, Stanford JL. Immunotherapy with Mycobacterium vaccae as an addition to chemotherapy for the treatment of pulmonary tuberculosis under difficult conditions in Africa. Respiratory Medicine 1995;89(3):199-207.
Vacirca 1994 {published data only}
  • Vacirca A, Dominino J, Valentini E, Hartopp R, Bottasso OA. A pilot study of immunotherapy with M. vaccae against tuberculosis. Tubercle and Lung Disease 1994;75 Suppl 1:47-8.
Waddell 2000b {published data only}
  • Waddell RD, Chintu C, Lein AD, Zumla A, Karagas MR, Baboo KS, et al. Safety and immunogenicity of a five-dose series of inactivated Mycobacterium vaccae vaccination for the prevention of HIV-associated tuberculosis. Clinical Infectious Diseases 2000;30 Suppl 3:309-15.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Abramson 2000
  • Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2000, Issue 2. [DOI: ]
Barnes 2000
  • Barnes PF, Wizel B. Type 1 cytokines and the pathogenesis of tuberculosis. American Journal of Respiratory and Critical Care Medicine 2000; Vol. 161, issue 6:1773-4.
Bousquet 1998
Convit 1989
  • Convit J, Castellanos PL, Ulrich M, Castes M, Rondon A, Pinardi ME, et al. Immunotherapy of localized, intermediate, and diffuse forms of American cutaneous leishmaniasis. Journal of Infectious Diseases 1989;160(1):104-15.
Ewan 1998
Grange 1998
  • Grange JM. Pathogenesis of mycobacterial disease. In: Gangadharam PRJ, Jenkins PA editor(s). Mycobacteria. Vol. 1: Basic Aspects, New York: Chapman-Hall, 1998:145-77.
Jüni 2001
Kahn 2000
  • Kahn JO, Cherng DW, Mayer K, Murray H, Lagakos S. Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 10(6)/L CD4 cell counts: A randomized controlled trial. JAMA 2000;284(17):2193-202.
Review Manager 5
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
Rook 1994
  • Rook GA, Onyebujoh P, Wilkins E, Ly HM, al Attiyah R, Bahr G, et al. A longitudinal study of per cent agalotosyl IgG in tuberculosis patients receiving chemotherapy, with or without immunotherapy. Immunology 1994;81(1):149-54.
Rook 1996
  • Rook GA, Stanford JL. The Koch phenomenon and the immunopathology of tuberculosis. In: Shinnick TM editor(s). Current Topics in Microbiology and Immunology. Vol. 215, Berlin: Springer-Verlag, 1996:239-62.
Stanford 1990a
Stanford 1994
Straus 1997
  • Straus SE, Wald A, Kost RG, McKenzie R, Langenberg AG, Hohman P, et al. Immunotherapy of recurrent genital herpes with recombinant herpes simplex virus type 2 glycoproteins D and B: results of a placebo-controlled vaccine trial. Journal of Infectious Diseases 1997;176(5):1129-34.
Weber 1997
Zuany-Amorim 2002
  • Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nature Medicine 2002;8(6):625-9.

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
de Bruyn 1998
  • de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for TB. Cochrane Database of Systematic Reviews 1998, Issue 3.
de Bruyn 1999
  • de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis. Cochrane Database of Systematic Reviews 1999, Issue 4. [Art. No.: CD001166. DOI: ]
de Bruyn 2000
  • de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2000, Issue 2. [Art. No.: CD001166. DOI: ]
de Bruyn 2003
  • de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: ]
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