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

ABSTRACT: 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 ?g 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.

SUBMITTER: Efremenko YV

PROVIDER: S-EPMC3906348 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Efremenko Yuri V YV Butov Dmytro A DA Prihoda Natalia D ND Zaitzeva Svetlana I SI Yurchenko Larisa V LV Sokolenko Nina I NI Butova Tetyana S TS Stepanenko Anna L AL Kutsyna Galyna A GA Jirathitikal Vichai V Bourinbaiar Aldar S AS

Human vaccines & immunotherapeutics 20130619 9

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 distri ...[more]

PMID: 23782489

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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:Tuberculosis (TB) is one of the leading causes of death worldwide, especially in developing countries. Neonatal BCG vaccination occurs in various regions, but the level of protection varies in different populations. Recently, Mycobacterium vaccae is found to be an immunomodulating therapeutic agent that could confer a significant level of protection against TB. It is the only vaccine in a phase III trial from WHO to assess its efficacy and safety in preventing TB disease in people with latent TB infection. However, the mechanism of immunotherapy of M. vaccae remains poorly understood. In this study, the full genome of M. vaccae was obtained by next-generation sequencing technology, and a proteogenomic approach was successfully applied to further perform genome annotation using high resolution and high accuracy MS data. A total of 3,387 proteins (22,508 unique peptides) were identified, and 581 proteins annotated as hypothetical proteins in the genome database were confirmed. Furthermore, 38 novel protein products not annotated at the genome level were detected and validated. Additionally, the translational start sites of 445 proteins were confirmed, and 98 proteins were validated through extension of their translational start sites based on N terminus-derived peptides. The physicochemical characteristics of the identified proteins were determined. Thirty-five immunogenic proteins of M. vaccae were identified by immunoproteomic analysis, and 20 of them were selected to be expressed and validated by Western blot for immunoreactivity to serum from patients infected with M. tuberculosis The results revealed that eight of them showed strong specific reactive signals on the immunoblots. Furthermore, cellular immune response was further examined and one protein displayed a higher cellular immune level in pulmonary TB patients. Twelve identified immunogenic proteins have orthologous in H37Rv and BCG. This is the first study to obtain the full genome and annotation of M. vaccae using a proteogenomic approach, and some immunogenic proteins that were validated by immunoproteomic analysis could contribute to the understanding of the mechanism of M. vaccae immunotherapy.

Dataset Information

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

Publications

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

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