Phase III, placebo-controlled, randomized, double-blind trial of tableted, therapeutic TB vaccine (V7) containing heat-killed M. vaccae administered daily for one month.

OBJECTIVE: Immunotherapy of tuberculosis (TB) to shorten treatment duration represents an unmet medical need. Orally delivered, tableted TB vaccine (V7) containing heat-killed Mycobacterium vaccae (NCTC 11659) has been demonstrated in prior clinical studies to be safe and fast-acting immune adjunct. METHODS: The outcome of Phase III trial of V7 containing 10 µg of hydrolyzed M. vaccae was evaluated in 152 patients randomized at 2:1 ratio: V7 (N = 100), placebo (N = 52). Both arms received conventional 1st or 2nd line TB drugs co-administered with daily pill of V7 or placebo. RESULTS: After one month mycobacterial clearance was observed in 68% (P < 0.0001) and 23.1% (P = 0.04) of patients on V7 and placebo. Stratified conversion rates in V7 recipients with drug-sensitive and multidrug-resistant TB were 86.7% and 55.6% vs 27.2% and 15% in placebo. Patients on V7 gained on average 2.4 kg (P < 0.0001) vs 0.3 kg (P = 0.18) in placebo. Improvements in hemoglobin levels, erythrocyte sedimentation rate and leukocyte counts were significantly better than in controls. Liver function tests revealed that V7 can prevent chemotherapy-induced hepatic damage. CONCLUSION: Oral M. vaccae is safe, can overcome TB-associated weight loss and inflammation, reduce hepatotoxicity of TB drugs, improve sputum conversion three-fold OR 3.15; 95%CI (2.3,4.6), and cut treatment length by at least six-fold. Longer follow-up studies might be needed to further substantiate our findings (Clinicaltrials.gov: NCT01977768).

Randomized, placebo-controlled Phase II trial of heat-killed Mycobacterium vaccae (Immodulon batch) formulated as an oral pill (V7).

AIM: A 1-month Phase II trial was conducted in 41 patients with pulmonary TB who were randomized into treatment (n = 20) and placebo (n = 21) arms to investigate the safety and efficacy of an orally-administered therapeutic TB vaccine (V7) containing 10 µg heat-killed Mycobacterium vaccae provided by Immodulon Therapeutics Ltd (London, UK). MATERIALS & METHODS: Both arms received conventional anti-TB therapy administered along with a daily pill of V7 or placebo. The subject population had four categories of TB: drug-sensitive TB; retreated TB; drug-resistant TB; and TB with HIV distributed in V7 and placebo arms at 9:4:7:6 and 14:1:6:8 ratios, respectively. RESULTS: The mycobacterial clearance in sputum smears was observed in 72.2% (p < 0.0001) and 19% (p = 0.03) of patients on V7 and placebo, respectively. The average weight accrual among V7 recipients was 2.6 kg (p = 0.002) versus -0.2 kg (p = 0.69) in the control group. Except reduction in fever and increased lymphocyte counts, the changes in other secondary end points, such as hemoglobin, erythrocyte sedimentation rate and leukocyte counts, were not statistically different, although the proportion of patients responding favorably to V7 was invariably higher compared with placebo (p = 0.002). In control patients, no difference from baseline levels was noted except decreased hemoglobin content (p = 0.02). CONCLUSION: Oral M. vaccae was safe and has potential as an adjunct immunotherapy, targeting mucosal immunity, to improve efficacy and shorten treatment duration of TB chemotherapy.

Randomized, placebo-controlled phase II trial of heat-killed Mycobacterium vaccae (Longcom batch) formulated as an oral pill (V7).

One-month Phase II trial was conducted in 43 sputum smear-positive patients with pulmonary tuberculosis randomized into treatment (n = 22) and placebo (n = 21) arms to investigate the safety and efficacy of an orally-administered therapeutic TB vaccine (V7) containing 10 µg of heat-killed Mycobacterium vaccae provided by Longcom company. Immunotherapy and control groups comprised 8 newly diagnosed (1stDx TB; 18.6%), 6 re-treated (RTB; 14%), and 29 multidrug-resistant (MDR-TB; 67.4%) cases distributed at 5:4:13 and 3:2:16 ratios, respectively. Both arms received conventional TB drugs administered under directly observed therapy. The average weight gain in V7 arm was modest, but statistically significant (0.6 kg; p = 0.004), while placebo patients lost 0.1 kg (p = 0.77). Except defervescence and increased lymphocyte percentage, other secondary endpoints such as erythrocyte sedimentation rate (ESR), leukocyte counts and hemoglobin content were not significantly affected. In control patients only one secondary endpoint, ESR, has improved. After one month mycobacterial clearance in sputum smears was observed in 31.8% (p = 0.03) and 9.5% (p = 0.83) of patients on V7 and placebo. However, the difference between outcomes in two arms was below significance threshold (p = 0.07). Thus, larger population of patients with prolonged follow-up is required to support these preliminary findings.

Adjunct immune therapy of first-diagnosed TB, relapsed TB, treatment-failed TB, multidrug-resistant TB and TB/HIV.

AIM: To evaluate the effect of an adjunct immunotherapy in randomized double-blind, placebo-controlled Phase IIb trial involving 123 TB patients. METHODS: Patients were randomly allocated into two arms: one (n = 62) received a once-daily pill of V-5 Immunitor™ (V5) and the other (control; n= 61) received placebo for 30 days in addition to first- or second-line TB drugs administered under directly observed therapy. The subjects in V5 and placebo arms had first-diagnosed, relapsed, treatment-failed and multidrug-resistant TB at ratios of 17:21:11:13 and 20:19:14:8, respectively; among them, ten and seven had HIV coinfection, respectively. RESULTS: After 1 month, 55 out of 62 patients (88.7%) became sputum smear-negative in the V5 arm (p < 0.0001), whereas in the placebo group, nine out of 61 (14.8%) had converted. The conversion rate among V5 recipients was similar, regardless of whether TB was drug-sensitive, drug-resistant or with HIV. V5 downregulated TB-associated inflammation, as shown by the normalization of elevated leukocyte counts (8.7 vs 6.3 × 10 (9)/l; p < 0.0001) and decreased erythrocyte sedimentation rate (22.8 vs 12.6 mm/h; p < 0.0001), whereas among placebo recipients, changes were smaller (8.9 vs 8.2 × 10 (9)/l and 25.1 vs 19.9 mm/h). Thirty three (54.1%) placebo patients gained on average 0.8 kg (p = 0.0002); by contrast, 57 (91.9%) out of 62 patients in the V5 group gained a mean weight of 2.9 kg (p < 0.0001). No adverse side effects or reactivation of TB were seen at any time. CONCLUSION: V5 is safe and effective as an immune adjunct to chemotherapy for TB and can potentially reduce the treatment duration down to 1 month.

Immune approaches in tuberculosis therapy: a brief overview.

TB is typically caused by Mycobacterium tuberculosis, a symbiotic bacterium present in one-third of the world's population. There any many factors triggering overt clinical disease in a small proportion of humans. In our view the major role in the process is played by the host's immune response, especially self-directed, destructive inflammation. Conventional chemotherapy produces bactericidal or bacteriostatic effects, but immunopathological changes can only be corrected by immunotherapy. Various attempts have been made to identify the optimal immune intervention. Some have shown promising effects, but many have failed. It is commonly believed that the field started in 1890: the year Robert Koch announced his tuberculin therapy. In the Pên Ts'ao Kang Mu, classical Chinese materia medica, published during Ming dynasty, Li Shi Chen (1518-1593) recommended, as a remedy for hemoptysis, to collect from the sputum "…blood lumps, roast them till they are black, and take then them as a powder". In retrospect, this is perhaps the earliest recorded reference relating to immunotherapy of TB with heat-killed mycobacteria. Modern science is obviously geared toward more palatable approach, but without hindsight from often disdained empirical evidence no progress can be made. The clinical experience from various trial and error processes is briefly discussed in this review.

Clinical validation of sublingual formulations of Immunoxel (Dzherelo) as an adjuvant immunotherapy in treatment of TB patients.

Immunoxel (Dzherelo) is a water-alcohol extract of medicinal plants used in Ukraine as an adjunct immunotherapy to TB and HIV therapy. Four types of solid sublingual formulations of Immunoxel were made: sugar dragées, sugar-coated pills, gelatin pastilles and dried-honey lozenges. They were administered once-daily along with TB drugs. After 1 month, 84.1% of TB patients became sputum-negative with rates in individual groups of 89.5, 70, 76.9 and 100%, respectively. The conversion rate was independent of bodyweight, age, gender, differences in chemotherapy regimens or whether subjects had newly diagnosed TB, re-treated TB, multidrug-resistant TB or TB with HIV coinfection. Patients experienced earlier clinical improvement, faster defervescence, weight gain, a higher hemoglobin content and reduced inflammation as evidenced by lower leukocyte counts and erythrocyte sedimentation rate. By contrast, in the placebo group, only 19% of patients had converted. These findings imply that mucosal delivery of solid Immunoxel is equivalent to the original liquid formula given per os twice-daily for 2-4 months.