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

Aldar S Bourinbaiar, Uyanga Batbold, Yuri Efremenko, Munkhburam Sanjagdorj, Dmytro Butov, Narantsetseg Damdinpurev, Elena Grinishina, Otgonbayar Mijiddorj, Mikola Kovolev, Khaliunaa Baasanjav, Tetyana Butova, Natalia Prihoda, Ochirbat Batbold, Larisa Yurchenko, Ariungerel Tseveendorj, Olga Arzhanova, Erkhemtsetseg Chunt, Hanna Stepanenko, Nina Sokolenko, Natalia Makeeva, Marina Tarakanovskaya, Vika Borisova, Alan Reid, Valeryi Kalashnikov, Peter Nyasulu, Satria A Prabowo, Vichai Jirathitikal, Allen I Bain, Cynthia Stanford, John Stanford, Aldar S Bourinbaiar, Uyanga Batbold, Yuri Efremenko, Munkhburam Sanjagdorj, Dmytro Butov, Narantsetseg Damdinpurev, Elena Grinishina, Otgonbayar Mijiddorj, Mikola Kovolev, Khaliunaa Baasanjav, Tetyana Butova, Natalia Prihoda, Ochirbat Batbold, Larisa Yurchenko, Ariungerel Tseveendorj, Olga Arzhanova, Erkhemtsetseg Chunt, Hanna Stepanenko, Nina Sokolenko, Natalia Makeeva, Marina Tarakanovskaya, Vika Borisova, Alan Reid, Valeryi Kalashnikov, Peter Nyasulu, Satria A Prabowo, Vichai Jirathitikal, Allen I Bain, Cynthia Stanford, John Stanford

Abstract

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).

Keywords: Immunotherapy; MDR; Mycobacterium vaccae; Therapeutic vaccine; XDR.

Conflict of interest statement

ASB, VB, MT, VK, VJ, AR and AIB are officers of Immunitor and affiliated companies. Late John Stanford and his colleague and spouse Cynthia Stanford are founders and owners of BioEos company. Remaining authors declare no conflict of interest.

© 2019 The Author(s).

Figures

Fig. 1
Fig. 1
Sputum clearance percentage in V7 and placebo arms depending on TB form. Post-treatment sputum conversion rates, expressed in % on the Y-axis, among patients with DS-TB; MDR-TB; DS-TB/HIV; MDR-TB/HIV and XDR-TB after one month on V7 vs. placebo had the following P values by Fisher's exact test in 2 × 2 contingency table: P < 0.0001; P = 0.0021; P = 0.077; P = 1.0 and P = 1.0 respectively.
Fig. 2
Fig. 2
The proportion of patients who responded favorably to treatment. The proportion expressed in % on Y-axis. The P values resulting from comparison of V7 vs. placebo analyzed by Chi-square 2 × 2 contingency table are as follows: HB (P = 0.015); ESR (P = 0.013); WBC (P = 0.43); Lymphocytes (P=0.45); ALT (P = 0.03); AST (P = 0.025); Bilirubin (P = 0.35); Protein (P = 0.006); Weight (P < 0.0001); BMI (P < 0.0001). The statistical analysis of other data relating to each of above shown parameter are described in detail in the Results, see paragraphs 3.3–3.8.

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