[Frontiers in Bioscience 9, 1701-1719, May 1, 2004]

IMMUNOTHERAPY WITH MYCOBACTERIUM VACCAE IN THE TREATMENT OF TUBERCULOSIS

John Stanford, Cynthia Stanford, and John Grange

Department of Medical Microbiology, University College London, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JK, United Kingdom

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The theoretical basis of immunotherapy with Mycobacterium vaccae
3.1. The effects on immunopathology
3.2. The evidence from skin-testing
3.3. The evidence from mixtures of new tuberculins
4. The first preparation used for immunotherapy
5. The first studies in man of immunotherapy with M. vaccae
5.1. Studies in leprosy patients
5.2. The first studies in tuberculosis patients
6. The first trials of efficacy
6.1. The Kuwaiti studies
6.2. The Gambian study
7. Intermediate placebo-controlled trials of heat-killed M.vaccae
7.1. Studies in Vietnam
7.2. The study in India
7.3. The first South African study
7.4. The study in Nigeria
7.5. The studies in Romania
7.6. The Argentina studies
7.7. The studies in China
8. The three major trials of single dose immunotherapy
8.1. The Durban Trial
8.2. The Uganda trial
8.3. The Zambia/Malawi trial
9. Immunotherapy for multi-drug-resistant-tuberculosis (MDRTB)
9.1. The study in Iran
9.2. The studies in Vietnam
9.3. The study in China
10. Immunotherapy for tuberculosis in HIV-seropositive patients
11. Side effects of immunotherapy with M.vaccae, disadvantageous and advantageous
12. Perspective and Prospective
13. Acknowledgements
14. References

1. ABSTRACT

All the trials of immunotherapy of tuberculosis with killed Mycobacterium vaccae, published or not, that are known to the authors are reviewed here.

Following an introduction giving a brief account of some earlier immunotherapies for tuberculosis, the origins of the concept of immunotherapy with M.vaccae are considered. Progress is traced from the early work with irradiation-killed organisms in leprosy to the study in London of modulation of tuberculin skin-test responses, and the first comparative trials in The Gambia and Kuwait. In the last of these studies, dosages and different preparations were compared. As a result of this subsequent studies have used 109 heat-killed organisms, equivalent to 1mg wet-weight of bacilli, as a standard dose.

A series of small trials in Argentina, India, Nigeria, Romania, South Africa and Vietnam have pioneered the way forward, disclosing geographic variability, with South Africa as the only country where almost no effects were recorded. Together the studies have shown that a single dose may not be sufficient. These studies have confirmed the mode of action of M.vaccae to be regulation of cell-mediated immunity with enhancement of Th1 and down-regulation of Th2, and they have shown benefits in faster bacteriological conversion, reduction in ESR, recovery of body weight and resolution of radiological opacities, leading to better recovery from the disease even when given to patients receiving directly observed therapy, short-course (DOTS).

Three major randomised, placebo-controlled and partly blinded trials have been carried out in Africa. The first, in South Africa showed no M.vaccae-related effects. The second trial, in Uganda, confirmed the observations made in the earlier studies of faster sputum conversion and better radiological clearance. The third trial, in Zambia and Malawi, showed a trend towards benefits in the treatment of HIV seronegative patients but failed to show beneficial effects in HIV seropositive patients.

Studies in patients with multi-drug-resistant tuberculosis have shown that multiple doses of immunotherapy are required in most cases, and that these markedly improve cure-rates for these patients. This is especially so when they are also treated with chemotherapy tailored to the resistance pattern of their infecting organisms. A small study has just commenced in which repeated doses of M.vaccae are being administered to a group of patients who have failed treatment with DOTS-Plus (directly observed therapy with drugs selected on the basis of drug susceptibility profiles).

Late in the investigation came publications from China supporting and confirming the data in both drug-sensitive and drug-resistant disease, by the use of multiple injections of their own different preparation of M.vaccae.

The trial that is now beginning in Vietnam of 3 doses of M.vaccae in the treatment of newly diagnosed pulmonary tuberculosis, is accompanied by a chemotherapeutic regimen with a shortened continuation phase. If this important study is successful, immunotherapy with killed M.vaccae should be introduced into the treatment regimens for tuberculosis worldwide.