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

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).

SUBMITTER: Bourinbaiar AS

PROVIDER: S-EPMC6933248 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Bourinbaiar Aldar S AS Batbold Uyanga U Efremenko Yuri Y Sanjagdorj Munkhburam M Butov Dmytro D Damdinpurev Narantsetseg N Grinishina Elena E Mijiddorj Otgonbayar O Kovolev Mikola M Baasanjav Khaliunaa K Butova Tetyana T Prihoda Natalia N Batbold Ochirbat O Yurchenko Larisa L Tseveendorj Ariungerel A Arzhanova Olga O Chunt Erkhemtsetseg E Stepanenko Hanna H Sokolenko Nina N Makeeva Natalia N Tarakanovskaya Marina M Borisova Vika V Reid Alan A Kalashnikov Valeryi V Nyasulu Peter P Prabowo Satria A SA Jirathitikal Vichai V Bain Allen I AI Stanford Cynthia C Stanford John J

Journal of clinical tuberculosis and other mycobacterial diseases 20191212

<h4>Objective</h4>Immunotherapy of tuberculosis (TB) to shorten treatment duration represents an unmet medical need. Orally delivered, tableted TB vaccine (V7) containing heat-killed <i>Mycobacterium vaccae</i> (NCTC 11659) has been demonstrated in prior clinical studies to be safe and fast-acting immune adjunct.<h4>Methods</h4>The outcome of Phase III trial of V7 containing 10 µg of hydrolyzed <i>M. vaccae</i> was evaluated in 152 patients randomized at 2:1 ratio: V7 (<i>N</i> = 100), placebo ( ...[more]

PMID: 31890902

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Project description:The hygiene hypothesis or "Old Friends" hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits and a failure to terminate inappropriate inflammatory responses. Inappropriate inflammation is also emerging as a risk factor for anxiety disorders, affective disorders, and trauma-and stressor-related disorders, including posttraumatic stress disorder (PTSD), which is characterized as persistent re-experiencing of the trauma after a traumatic experience. Traumatic experiences can lead to long-lasting fear memories and fear potentiation of the acoustic startle reflex. The acoustic startle reflex is an ethologically relevant reflex and can be potentiated in both humans and rats through Pavlovian conditioning. Mycobacterium vaccae is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to enhance fear extinction in the fear-potentiated startle paradigm when given prior to fear conditioning. To determine if immunization with M. vaccae after fear conditioning also has protective effects, adult male Sprague Dawley rats underwent fear conditioning on days -37 and -36 followed by immunizations (3x), once per week beginning 24 h following fear conditioning, with a heat-killed preparation of M. vaccae NCTC 11659 (0.1 mg, s.c., in 100 µl borate-buffered saline) or vehicle, and, then, 3 weeks following the final immunization, were tested in the fear-potentiated startle paradigm (n = 12 per group). Rats underwent fear extinction training on days 1 through 6 followed by spontaneous recovery 14 days later (day 20). Rats were euthanized on day 21 and brain tissue was sectioned for analysis of Tph2, Htr1a, Slc6a4, Slc22a3, and Crhr2 mRNA expression throughout the brainstem dorsal and median raphe nuclei. Immunization with M. vaccae did not affect fear expression on day 1. However, M. vaccae-immunized rats showed enhanced enhanced within-session fear extinction on day 1 and enhanced between-session fear extinction beginning on day 2, relative to vehicle-immunized controls. Immunization with M. vaccae and fear-potentiated startle had minimal effects on serotonergic gene expression when assessed 42 days after the final immunization. Together with previous studies, these data are consistent with the hypothesis that immunoregulatory strategies, such as immunization with M. vaccae, have potential for both prevention and treatment of trauma- and stressor-related psychiatric disorders.

Project description:Influenza A(H1N1)pdm virus caused the first human pandemic of the 21st century. Although various probiotic Lactobacillus species have been shown to have anti-microbial effects against pneumonia-inducing pathogens, the prophylactic efficacy and mechanisms behind their protection remain largely unknown. Here, we evaluated the prophylactic efficacy of heat-killed Lactobacillus pentosus b240 against lethal influenza A(H1N1)pdm virus infection in a mouse model. To further define the protective responses induced by b240, we performed virologic, histopathologic, and transcriptomic analyses on the mouse lungs. Although we did not observe an appreciable effect of b240 on virus growth, cytokine production, or histopathology, gene expressional analysis revealed that oral administration of b240 differentially regulates antiviral gene expression in mouse lungs. Our results unveil the possible mechanisms behind the protection mediated by b240 against influenza virus infection and provide new insights into probiotic therapy. Six-week-old female BALB/c mice were used in the study. Oral administration of b240 was initiated in mice at six weeks of age. Mice were orally administered heat-killed Lactobacillus pentosus b240 every day at a dose of 10 mg/mouse in 200 Î¼l of buffered saline for 5 weeks. The control group received saline. To investigate the effects of oral administration of b240 on host immune responses to CA04 virus infection, 9 mice per group were infected with 10 MLD50 of CA04 virus on day 21 post-b240 administration. Three mice per group were euthanized on days 1, 3, and 6 post-infection and their lungs were collected. To investigate the immune responses induced by oral administration of b240 in the lungs of uninfected mice, 15 mice per group were mock-infected with PBS on day 21 post-b240 administration. Three mice per group were euthanized on days 14, 21, 22, 24, and 27 post-b240 administration (-7, 0, 1, 3, and 6 days post-mock infection) and their lungs were collected. These lung tissues were subjected to microarray analysis (three biological replicates per each group).

Dataset Information

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

Publications

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

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