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. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 2. Chronic or relapsed disease. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 1. Newly-diagnosed pulmonary disease. Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial. An investigation of patients with pulmonary tuberculosis in Kuwait in preparation for studies of immunotherapy with Mycobacterium vaccae. Intravesical chemotherapy (mitomycin C) versus immunotherapy (bacillus Calmette-Guérin) in superficial bladder cancer.
Adjunctive immunotherapy with heat-killed Mycobacterium vaccae was studied in a randomized, placebo-controlled trial of 120 non-human immunodeficiency virus-infected adults with newly diagnosed pulmonary tuberculosis. Patients were randomized to a single dose of M. vaccae or placebo 1 week after beginning chemotherapy and were followed up for 1 year. M. vaccae was safe and well tolerated. The rate of sputum culture conversion after 1 month of tuberculosis treatment was 35% in the M. vaccae group and only 14% in the placebo group (P=.01) but was comparable at 2 months and thereafter. Patients receiving M. vaccae had greater improvement on chest radiography at 6 months (91% vs. 77% for placebo recipients; P=.04) and 12 months (94% vs. 80%; P=.04) after initiation of tuberculosis treatment. These data provide evidence of an early increase in sputum culture conversion and greater radiographic improvement among patients who received M. vaccae. Further studies are warranted. Mycobacterium vaccae, an environmental saprophyte, has immunogenic properties that enhance the host immune response. Immunotherapy with M. vaccae has been suggested to shorten short-course antituberculosis chemotherapy. We tested the hypothesis that the addition of M. vaccae to standard short-course antituberculosis chemotherapy would decrease the time to achieve a negative sputum culture.
                Patients with newly diagnosed tuberculosis were randomly assigned an injection of saline (placebo) or M. vaccae on day 8. All patients received antituberculosis chemotherapy with rifampicin, isoniazid, pyrazinamide, and ethambutol. Sputum samples were checked by microscopy and culture every week for the first 8 weeks and monthly until the end of chemotherapy at 6 months. The primary outcome was the time to a negative sputum culture in the first 8 weeks. Intention-to-treat analysis was used and time to sputum clearance was assessed by log-rank test and Cox's proportional-hazards regression.
                172 patients received M. vaccae and 175 patients received placebo. At 8 weeks, 70 patients in the M. vaccae group and 65 patients in the placebo group had a negative culture; there was no difference between groups in the time to a negative culture (p=0.83). There was no interaction between HIV status and treatment.
                M. vaccae immunotherapy has no benefit when added to standard antituberculosis chemotherapy. In this study of 102 patients with culture-positive chronic treatment failure or repeatedly relapsed pulmonary tuberculosis receiving chemotherapy, 56 received an injection of killed Mycobacterium vaccae as immunotherapy after 1 month of treatment. At the start of treatment, there was little difference between those receiving immunotherapy and the 46 patients in the control group receiving chemotherapy alone. Thereafter, the two groups diverged so that 1 yr later, 43 of 56 (77%) patients receiving M. vaccae had a successful outcome, in comparison with 24 of 46 (52%) patients receiving chemotherapy alone (P < 0.02). Successful results were obtained from patients infected with drug-resistant bacilli, 20 of 32 (63%) patients compared with 11 of 25 (44%) patients, respectively, as well as from fully drug-sensitive cases (23 of 24 compared with 12 of 21 patients; P = 0.004). At the final follow-up after 22 months, 13 of 56 patients receiving immunotherapy had an unfavourable outcome compared with 26 of 46 members of the control group (P = 0.0006). During the study, 16 patients died of tuberculosis (six after immunotherapy), and 12 were lost to follow-up. Not only was bacteriological success improved by immunotherapy, chest X-ray showed markedly better resolution of cavities and other radiological lesions, recovery of body weight was improved, and the mean erythrocyte sedimentation rate returned almost to normal (P < 0.001) in comparison with those receiving chemotherapy alone. These changes were seen even in those failing bacteriological cure, suggesting that the immunotherapy had been effective, but that bacilli were replicating in an extracellular situation, protecting them from its effects. In this study, 206 previously untreated patients with sputum culture positive pulmonary tuberculosis were randomized to receive an injection of killed Mycobacterium vaccae as immunotherapy, or of saline as placebo, after 1 month of a 6-month chemotherapeutic regime. Not surprisingly in a disease for which there is good chemotherapy, the difference in numbers which were culture negative at the end of treatment was small, and the final outcome at the latest post-treatment follow-up did not reach statistical significance between the two arms of the study. Nonetheless, those receiving immunotherapy showed better progression in every parameter measured, suggesting faster and more complete cure. Whereas seven of 97 patients receiving immunotherapy required a course of re-treatment and five still had active disease after a mean follow-up of 2 yr, 13 of 109 placebo recipients required re-treatment and nine still had active disease at the end of the study. Only one patient receiving M. vaccae plus chemotherapy died of tuberculosis, compared with four of those receiving chemotherapy alone. A degree of drug resistance was shown by the bacilli cultured from 25 of 175 (14%) patients, and seven of them (4.0%) were multi-drug resistant. Fourteen patients received immunotherapy of whom 13 were cured, including all three of those showing multi-drug resistance. Of the 11 patients with drug resistance in the control group, eight were cured, and one patient with multi-drug-resistant disease died of tuberculosis during re-treatment. Mortality rates of HIV-infected patients treated for tuberculosis remain high. This study aimed to assess the effect on mortality of immunotherapy with single-dose SRL172 added to standard antituberculosis chemotherapy in such patients.
                The double-blind trial enrolled 1229 patients aged 18-60 years, who had never received antiretroviral treatment and who presented with newly diagnosed, sputum-smear-positive pulmonary tuberculosis to referral centres in Lusaka, Zambia, and Karonga, Malawi. Both HIV-positive and HIV-negative patients were enrolled, to avoid stigmatisation. Participants were randomly assigned a single injection of SRL172 or matching placebo within 2 weeks of starting 8 months of antituberculosis chemotherapy and followed up for at least 12 months. The primary endpoint was time to death in the HIV-infected population. Analyses were based on 760 HIV-positive patients after exclusion of 84 patients with errors in storage of the injection, no bacteriological confirmation, or no HIV result.
                Of 760 HIV-infected patients, 374 received SRL172 and 386 received placebo. SRL172 did not cause any serious adverse events. The follow-up rate was 88% at 12 months in both groups. Of the HIV-positive patients, 109 (19.5 per 100 person-years) of 372 assigned SRL172 and 107 (19.3 per 100 person-years) of 386 assigned placebo died. In the Cox's regression analysis, stratified by centre, the hazard ratio of deaths (SRL172/placebo) was 1.03 (95% CI 0.79-1.35). There was no evidence of benefit to the group assigned SRL172.
                Immunotherapy with single-dose SRL172 as an adjunct to standard antituberculosis treatment in HIV-positive adults with pulmonary tuberculosis had no significant effect on survival or bacteriological outcome, though the treatment was safe and well tolerated. Sixty-five patients, many of them immigrant to Kuwait, with bacteriologically proven, adult type, pulmonary tuberculosis were studied by many parameters over the 4 months following diagnosis. Twelve were infected with tubercle bacilli resistant to at least one anti-tuberculosis drug. Preliminary evidence suggested that this was frequently primary resistance in patients infected in their countries of origin. The Kuwaiti environment results in very high skin test and lymphocyte proliferative responses (LTT) to shared and species specific antigens of mycobacteria in healthy persons. In comparison, patients with tuberculosis lacked cellular responses to group i and group ii antigens, but had increased IgG and IgA binding to mycobacterial antigens in general. LTT responses to added interleukin 2, and production of alpha interferon, were normal in our patients, but induction of gamma interferon in response to phytohaemagglutinin was reduced initially, rising towards normal during treatment. Biochemical and haematological abnormalities present at the time of diagnosis rapidly corrected. The disease differed from that reported in most previous studies in that fever was uncommon, the disease was never fatal, and most tuberculin tests were not necrotising. This implied that a detrimental immunopathological component is less pronounced in those exposed to the Kuwaiti environment, and a hypothesis is put forward to explain this. Both intravesical mitomycin C (MMC) and bacillus Calmette-Guérin (BCG; Pasteur strain F) were effective in the present prospective randomized multicenter study consisting of 91 patients with frequently recurrent superficial (Ta-T1) bladder cancer. The result was in favour of BCG, as shown by the measurements with complete response (CR), disease-free interval and recurrence rate. CR of 58% with MMC and 40% with BCG were reached in 22 instillation series on carcinoma in situ of 18 patients. Due to side effects, MMC instillations were discontinued in 8.6%, and BCG instillations in 19.6%, respectively. After the 2-year follow-up also 1 case of pulmonary tuberculosis occurred in the BCG group.
M. 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.