Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: KEGG:D03063 (BCG vaccine)
 1,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the last few years, some of our experiments in which mycobacterial heat-shock protein (HSP) antigens were presented to the immune system as if they were viral antigens have had a significant impact on our understanding of protective immunity against tuberculosis. They have also markedly enhanced the prospects for new vaccines. We now know that the mycobacterial HSP65 antigen can confer protection equal to that from live BCG vaccine in mice.
 ...
PMID:The potential use of heat-shock proteins to vaccinate against mycobacterial infections. 1060 75

We have developed two novel tuberculosis (TB) vaccines: a DNA vaccine combination expressing mycobacterial heat shock protein 65 (Hsp65) and interleukin-12 (IL-12) by using the hemagglutinating virus of Japan (HVJ)-liposome (HSP65+IL-12/HVJ) and a recombinant BCG harboring the 72f fusion gene (72f rBCG). These vaccines provide remarkable protective efficacy in mouse and guinea pig models, as compared to the current by available BCG vaccine. In the present study, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis, to evaluate the HSP65+IL-12/HVJ and 72f rBCG vaccines. Vaccination with HSP65+IL-12/HVJ as well as 72f rBCG vaccines provided better protective efficacy as assessed by the Erythrocyte Sedimentation Rate, chest X-ray findings and immune responses than BCG. Most importantly, HSP65+IL-12/HVJ resulted in an increased survival for over a year. This is the first report of successful DNA vaccination and recombinant BCG vaccination against M. tuberculosis in the monkey model.
 ...
PMID:Novel recombinant BCG and DNA-vaccination against tuberculosis in a cynomolgus monkey model. 1575 83

We investigated the immunogenicity and protective efficacy of DNA vaccine combinations expressing mycobacterial heat shock protein 65 (Hsp65) and interleukin-12 (IL-12) using gene gun bombardment and the hemagglutinating virus of Japan (HVJ)-liposome method. A mouse IL-12 expression vector (mIL-12 DNA) encoding single-chain IL-12 proteins comprised of p40 and p35 subunits were constructed. In a mouse model, a single gene gun vaccination with the combination of Hsp65 DNA and mIL-12 DNA provided a remarkably high degree of protection against challenge with virulent Mycobacterium tuberculosis; bacterial numbers were 100-fold lower in the lungs compared to BCG-vaccinated mice. To explore the clinical use of the DNA vaccines, we evaluated HVJ-liposome encapsulated Hsp65 DNA and mIL-12DNA (Hsp65 + mIL-12/HVJ). The HVJ-liposome method improved the protective efficacy of the Hsp65 DNA vaccine compared to gene gun vaccination. Hsp65 + mIL-12/HVJ induced CD8+ cytotoxic T lymphocyte activity against Hsp65 antigen. Most importantly, Hsp65+mIL-12/HVJ vaccination resulted in a greater degree of protection than that evoked by BCG. This protective efficacy was associated with the emergence of IFN-gamma-secreting T cells and activation of proliferative T cells and cytokines (IFN-gamma and IL-2) production upon stimulation with Hsp65 and antigens from M. tuberculosis. These results suggest that Hsp65 + IL-12/HVJ could be a promising candidate for a new tuberculosis DNA vaccine, which is superior to BCG vaccine.
 ...
PMID:DNA vaccine using hemagglutinating virus of Japan-liposome encapsulating combination encoding mycobacterial heat shock protein 65 and interleukin-12 confers protection against Mycobacterium tuberculosis by T cell activation. 1621 94

CDC and ACET in U.S.A. reported that novel vaccines instead of BCG are required for the protection against infection of Mycobacterium tuberculosis worldwide. However, no novel vaccine for clinical use has not yet been developed in the world including U.S.A. and Europe. We have developed two novel tuberculosis (TB) vaccines; a DNA vaccine combination expressing mycobacterial heat shock protein 65 (HSP 65) and interleukin-12 (IL-12) by using the hemagglutinating virus of Japan (HVJ)-liposome (HSP 65 + IL-12/HVJ). A mouse IL-12 expression vector (mIL-12 DNA) encoding single-chain IL-12 proteins comorised of p40 and p35 subunits were constructed. In a mouse model, a single gene gun vaccination with the combination of HSP 65 DNA and mIL-12 DNA provided a remarkably high degree of protection against challenge with virulent Mycobacterium tuberculosis; bacterial numbers were 100 fold lower in the lungs compared to BCG-vaccinated mice. To explore the clinical use of the DNA vaccines, we evaluated HVJ-liposome encapsulated HAP 65 DNA and mIL-12 DNA (HSP 65 + mIL-12/ HVJ). The HVJ-liposome method improved the protective efficacy of the HSP 65 DNA vaccine compared to gene gun vaccination. This vaccine provide remarkable protective efficacy in mouse and guinea pig models, as compared to the current by available BCG vaccine. HSP 65 + IL-12/HVJ vaccine induced CD8+cytoxic T lymphocyte activity against HSP 65 antigen. Protective efficacy of this vaccine was associated with the emergence of IFN-gamma-secreting T cells and activation of proliferative T cells as well as CTL induction upon stimulation with the HSP 65 and antigens from M. tuberculosis. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis, to evaluate the HSP 65 + IL-12/HVJ vaccine. Vaccination with HSP 65 + IL-12/HVJ provided better protective efficacy as assessed by the Erythrocyte Sedimentation Rate, chest X-ray findings, and immune responses than BCG. Most importantly, HSP 65 + IL-12/HVJ resulted in an increased survival for over a year. This is the first report of successful DNA vaccination against M. tuberculosis in the monkey model. Novel TB vaccines using the monkey model will be discussed in this issue. The development of novel vaccines against tuberculosis was also studied in murine and cynomolgus monkey systems. Four distinct methods; DNA vaccination (1. plasmid, 2. adenovirus vector, 3. adenoassouated virus), 4. recombinant BCG, and 5. subunit (recombinant protein) were used for the development of novel vaccines. Genes (HSP 65 gene, IL-12 gene as well as Ag 85A-, 85B-, MPB51-gene) and IL-6 related genes (IL-6 gene + IL-6R gene +gp130 gene) were administered into the Balb/c mice infected (i.v. or intra-tracheal injection) with Mycobacterium tuberculosis (M. tuberculosis). Elimination of M. tuberculosis in lungs, liver, and spleen of these mice and survival were studied in these models. HSP 65 gene + IL-12 gene vaccination, or recombinant BCG (BA51 : Antigen 85B(-) + Antigen 85A(-) + MPB51-gene recombinant BCG) were more prophylactically efficient than parental BCG Tokyo vaccination. In contrast, IL-6 related genes vaccination using adenovirus vector showed therapeutic effect on M. tuberculosis infected mice. Cytotoxic T cells (CTL) activity against M. tuberculosis in the spleen cells from mice treated with IL-6 related genes vaccination were significantly augmented. Furthermore, NOD-SCID-PBL/hu mice treated with anti-IL-2 receptor beta-chain antibody provide an useful tool for analyzing in vivo human T cell immunity against tuberculosis. In conclusion, we demonstrate the development of a novel HVJ-liposome DNA vaccine encapsulating HSP 65 DNA plus IL-12 DNA. These results suggest that HSP 65 + IL-12/HVJ could be a promising candidate for a new tuberculosis DNA vaccine, which is superior to the currently available BCG vaccine. The goal of our study is to develop a new tuberculosis vaccine superior to BCG. To this aim, we believe that the protective efficacy and protective immune responses for vaccine candidates should be addressed in larger animals, such as nonhuman primates, before proceeding to human clinical trials. Although other DNA vaccine candidates that appear to protect against virulent M. tuberculosis in mice better than BCG have failed to provide better protection than BCG in guinea pigs against aerosol challenge of a low dose of virulent M. tuberculosis, some of them are being prepared to enter early human clinical trials. More recently, we evaluated the HSP 65 + hIL-12/HVJ vaccine in the cynomolgus monkey model, which is currently the best non-human primate animal model of human tuberculosis. Monkeys were subsequently challenged with virulent M. tuberculosis by the intra-tracheal route after the third vaccination. This challenge dose normally causes death from acute respiratory infection within 4-6 months. In this particular experiment, monkeys vaccinated with HSP 65 + hIL-12/HVJ induced HSP 65-specific T-cell proliferation and improvement of chest X-P findings, resulting in an increased survival for over a year, superior to BCG group. Thus, we are taking advantage of the availability of multiple animal models (mouse, guinea pig, and monkey) to accumulate essential data of the HVJ-liposome DNA vaccine, including the vaccine efficacy and safety, for up-coming Phase I clinical trials.
 ...
PMID:[Novel vaccines against M. tuberculosis]. 1724 Sep 20

We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-liposome (HSP65+IL-12/HVJ). This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine, on the basis of an induction of the CTL activity and improvement of the histopathological tuberculosis lesions, respectively. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses. Furthermore, the combination of HSP65+IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis for human clinical trials.
 ...
PMID:Evaluation of a novel vaccine (HVJ-liposome/HSP65 DNA+IL-12 DNA) against tuberculosis using the cynomolgus monkey model of TB. 1728 Jul 53

Vaccines are considered by many to be one of the most successful medical interventions against infectious diseases. But many significant obstacles remain, such as optimizing DNA vaccines for use in humans or large animals. The amount of doses, route and easiness of administration are also important points to consider in the design of new DNA vaccines. Heterologous prime-boost regimens probably represent the best hope for an improved DNA vaccine strategy. In this study, we have shown that heterologous prime-boost vaccination against tuberculosis (TB) using intranasal BCG priming/DNA-HSP65 boosting (BCGin/DNA) provided significantly greater protection than that afforded by a single subcutaneous or intranasal dose of BCG. In addition, BCGin/DNA immunization was also more efficient in controlling bacterial loads than were the other prime-boost schedules evaluated or three doses of DNA-HSP65 as a naked DNA. The single dose of DNA-HSP65 booster enhanced the immunogenicity of a single subcutaneous BCG vaccination, as evidenced by the significantly higher serum levels of anti-Hsp65 IgG2a Th1-induced antibodies, as well as by the significantly greater production of IFN-gamma by antigen-specific spleen cells. The BCG prime/DNA-HSP65 booster was also associated with better preservation of lung parenchyma. The improvement of the protective effect of BCG vaccine mediated by a DNA-HSP65 booster suggests that our strategy may hold promise as a safe and effective vaccine against TB.
 ...
PMID:Improve protective efficacy of a TB DNA-HSP65 vaccine by BCG priming. 1771 84

Mycobacterium tuberculosis is one of the most successful bacterial parasites of humans, infecting over one-third of the population of the world as latent infection without clinical manifestations. Over 8.8 million new cases and nearly 2 million deaths by tuberculosis (TB) occur annually. TB poses a significant health threat to the world population. The goal of this symposium is to open new avenues for combating tuberculosis. The speakers have presented their data and provided control strategies against tuberculosis and pulmonary disease due to M. avium complex (MAC) from aspects of molecular epidemiology, pathogenesis, serodiagnosis, new anti-TB drugs, and vaccine development. Drs. Maeda and Murase have reported that the 12-locus VNTR analysis is very useful for molecular epidemiology of M. tuberculosis strains isolated in Japan better than IS6110-RFLP and suggested that the analysis is powerful tool for the molecular epidemiology. Drs. Matsumoto and Kobayashi have discovered a protein, mycobacterial DNA-binding protein 1 (MDPl), overproduced in dormant M. tuberculosis that plays key roles in latent/ persistent infection, disease progression, and host protection. They have concluded that MDP1 may be a possible target for anti-tuberculosis drugs and vaccines. Drs. Kitada and Maekura have developed serodiagnosis of MAC disease based on enzyme immunoassay (EIA) by detecting anti-glycopeptidolipid (GPL) antibody in sera of human patients. GPL is specific for MAC. The EIA is a simple, rapid and accurate measure with high sensitivity and specificity. The levels of antibody also reflect disease activity. A large-scale clinical multicenter study is currently in progress. Dr. Makoto Matsumoto has discovered an innovative new anti-TB drug, OPC-67683 that is a derivative of nitroimidazole compounds. OPC-67683 inhibited mycolic acid synthesis and exerted potent antimycobacterial activity, including multidrug-resistant M. tuberculosis. Multidrug therapy using OPC-67683 could also shorten the course of chemotherapy. The drug is clearly the most promising new anti-TB agent that has been identified in many years. Dr. Okada has presented the vaccine candidates for TB, such as HVJ-liposome/HSP65 DNA+IL-12 DNA and HVJ-envelope/HSP65 DNA+IL-12 DNA. The candidates exhibited an excellent protective efficacy in mice compared to current BCG vaccine, and improved histopathologic lesions induced by M. tuberculosis infection. The candidates also exerted the therapeutic effect in mice against both drugsusceptible TB and extensively drug-resistant TB. Using the cynomolgus monkey model (similar to human TB), HVJ-liposome/ HSP65 DNA+IL-12 DNA provided higher protective efficacy than BCG assessed by mortality. The combination of BCG and HVJ-liposome/HSP65 DNA+IL-12 DNA by the prime-booster procedure could lead to a synergistic effect of 100% survival in infected monkeys. These data suggest that the novel DNA vaccine is a possible candidate for human clinical trials. This symposium has highlighted new advances in our understanding of molecular epidemiology and pathogenesis of "Mycobacteriology" and development of new serodiagnostics, anti-TB drugs, and vaccines. 1. The establishment of the quick genotyping method for TB in Japan using the variable numbers of tandem repeats (VNTR): Shinji MAEDA, Yoshiro MURASE (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) The 12-locus VNTR analysis that we have established optimally for Mycobacteriun tuberculosis in Japan was superior to the proposed 15-locus VNTR method in European countries. The discriminatory power of our system was also higher than that of IS6110-based restriction fragment length polymorphism analysis. In future, we will investigate the stability of copy number in each locus by using the strains that suspected epidemiological links in contact investigations. 2. A virulence factor of Mycobacterium tuberculosis, which contributes to persistent infection, reactivation, and host protection: Sohkichi MATSUMOTO (Department of Host Defense, Osaka City University Graduate School of Medicine), Kazuo KOBAYASHI (Department of Immunology, National Institute of Infectious Diseases) Majority of adult tuberculosis is caused by reactivation of previously implanted Mycobacterium tuberculosis. During latent infection, some bacilli are in dormant state, which confers some survival advantage to not only bacteria but also the host. We presented that a protein overproduced in dormant M. tuberculosis plays key roles in persistent infection, disease progression, and host protection. We also presented utility of this protein, such as development of anti-tuberculosis drug and vaccine. 3. Serodiagnosis of Mycobacterium avium complex pulmonary disease by enzyme immunoassay using glycopeptidolipid antigen: Seigo KITADA, Ryoji MAEKURA (Department of Internal Medicine, National Hospital Organization National Toneyama Hospital) The diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) and/or its discrimination from pulmonary tuberculosis is sometimes complicated and time consuming. We have developed serological test by enzyme immunoassay that detect serum antibody to glycopeptidolipid antigen. The serodiagnosis is useful for the rapid diagnosis of MAC-PD and differential diagnosis from pulmonary TB. The antibody levels reflected the disease activity including radiographic severity. 4. A novel antituberculous agent, OPC-67683: Research and development: Makoto MATSUMOTO (Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd.) We initiated a program to screen new antituberculous agents that have potential to shorten the total duration of treatment, provide improved efficacy against MDR-TB, be useful in treating HIV co-infected patients, and target latent TB infections. Our efforts led to the discovery of OPC-67683, a novel oxazo-imidazole derivative with a distinctive characteristic as a subclass mycolic acid inhibitor. Our evaluation studies confirmed OPC-67683 to possess potent in vitro and in vivo antituberculous activity, suggesting potential usefulness in alleviating the current TB problems. 5. The development of novel vaccines against M. tuberculosis: Masaji OKADA (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center) We have developed a novel tuberculosis (TB) vaccine (HVJ-liposome/ or HVJ-envelope/HSP65 DNA+ IL-12 DNA). The vaccine provided remarkable protective efficacy in mouse compared to BCG vaccine, and improved the histopathological tuberculosis lesions. This vaccine also exerted therapeutic effect in vivo against XDR-TB as well as drug-sensitive TB in mice. Furthermore, by using the cynomolgus monkey (similar to human tuberculosis), this novel vaccine provided higher protective efficacy (mortality) than BCG mortality. Furthermore, the combination of HSP65+IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). These data indicate that our novel DNA vaccine might be useful against TB for human clinical trials.
 ...
PMID:[Recent progress in mycobacteriology]. 1801 2

We have developed a novel tuberculosis (TB) vaccine ; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-liposome or-envelope (HSP65+IL-12/HVJ). This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine, on the basis of an induction of the CD8 positive CTL activity against TB antigens and improvement of the histopathological tuberculosis lesions, respectively. The Elispot assay showed that HSP65+IL-12 DNA/ HVJ vaccine induced a greater number of IFN-gamma producing T cells than BCG in the mouse model. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses (IFN-gamma, IL-2, IL-6 production , and lymphocyte proliferation of cynomolgus monkey). The combination of HSP65+IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, 33% of monkeys from BCG Tokyo alone group were alive (33% survival). These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis for human clinical trials.
 ...
PMID:[The development of novel vaccines against tuberculosis]. 1897 19

Heat shock promoters of mycobacteria are strong promoters that become rapidly upregulated during macrophage infection and thus serve as valuable candidates for expressing foreign antigens in recombinant BCG vaccine. In the present study, a new heat shock promoter controlling the expression of the groESL1 operon was identified and characterized. Mycobacterium tuberculosis groESL1 operon codes for the immunodominant 10 kDa (Rv3418c, GroES/Cpn10/Hsp10) and 60 kDa (Rv3417c, GroEL1/Cpn60.1/Hsp60) heat shock proteins. The basal promoter region was 115 bp, while enhanced activity was seen only with a 277-bp fragment. No promoter element was seen in the groES-groEL1 intergenic region. This operon codes for a bicistronic mRNA transcript as determined by reverse transcriptase-PCR and Northern blot analysis. Primer extension analysis identified two transcriptional start sites (TSSs) TSS1 (-236) and TSS2 (-171), out of which one (TSS2) was heat inducible. The groE promoter was more active than the groEL2 promoter in Mycobacterium smegmatis. Further, it was found to be differentially regulated under stress conditions, while the groEL2 promoter was constitutive.
 ...
PMID:Mycobacterium tuberculosis groE promoter controls the expression of the bicistronic groESL1 operon and shows differential regulation under stress conditions. 1922 81

Tuberculosis caused by Mycobacterium tuberculosis is responsible for nearly two million deaths every year globally. A single licensed vaccine derived from Mycobacterium bovis, bacille Calmette-Guerin (BCG) administered perinatally as a prophylactic vaccine has been in use for over 80 years and confers substantial protection against childhood tuberculous meningitis and miliary tuberculosis. However, the BCG vaccine is virtually ineffective against the adult pulmonary form of tuberculosis that is pivotal in the transmission of tuberculosis that has infected almost 33% of the global population. Thus, an effective vaccine to both prevent tuberculosis and reduce its transmission is urgently needed. We have generated a multi-valent, vectored vaccine candidate utilizing the modified virus Ankara (MVA) strain of vaccinia virus to tandemly express five antigens, ESAT6, Ag85A, Ag85B, HSP65 and Mtb39A of M. tuberculosis that have been reported to be protective individually in certain animal models together with an immunostimulatory cytokine interleukin-15 (MVA/IL-15/5Mtb). Although, immunological correlates of protection against tuberculosis in humans remain to be established, we demonstrate that our vaccine induced comparable CD4(+) T cell and greater CD8(+) T cell and antibody responses against M. tuberculosis in vaccinated mice in a direct comparison with the BCG vaccine and conferred protection against an aerogenic challenge of M. tuberculosis, thus warranting its further preclinical development.
 ...
PMID:A multi-valent vaccinia virus-based tuberculosis vaccine molecularly adjuvanted with interleukin-15 induces robust immune responses in mice. 1935 15


1 2 Next >>