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Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-08-2014 | Award Amount: 25.06M | Year: 2015

The TBVAC2020 proposal builds on the highly successful and long-standing collaborations in subsequent EC-FP5-, FP6- and FP7-funded TB vaccine and biomarker projects, but also brings in a large number of new key partners from excellent laboratories from Europe, USA, Asia, Africa and Australia, many of which are global leaders in the TB field. This was initiated by launching an open call for Expressions of Interest (EoI) prior to this application and to which interested parties could respond. In total, 115 EoIs were received and ranked by the TBVI Steering Committee using proposed H2020 evaluation criteria. This led to the prioritisation of 52 R&D approaches included in this proposal. TBVAC2020 aims to innovate and diversify the current TB vaccine and biomarker pipeline while at the same time applying portfolio management using gating and priority setting criteria to select as early as possible the most promising TB vaccine candidates, and accelerate their development. TBVAC2020 proposes to achieve this by combining creative bottom-up approaches for vaccine discovery (WP1), new preclinical models addressing clinical challenges (WP2) and identification and characterisation of correlates of protection (WP5) with a directive top-down portfolio management approach aiming to select the most promising TB vaccine candidates by their comparative evaluation using objective gating and priority setting criteria (WP6) and by supporting direct, head-to head or comparative preclinical and early clinical evaluation (WP3, WP4). This approach will both innovate and diversify the existing TB vaccine and biomarker pipeline as well as accelerate development of most promising TB vaccine candidates through early development stages. The proposed approach and involvement of many internationally leading groups in the TB vaccine and biomarker area in TBVAC2020 fully aligns with the Global TB Vaccine Partnerships (GTBVP).


Lee M.,International Tuberculosis Research Center | Lee J.,International Tuberculosis Research Center | Carroll M.W.,National Institute of Allergy and Infectious Diseases | Choi H.,International Tuberculosis Research Center | And 24 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.) Copyright © 2012 Massachusetts Medical Society.


Chakravorty S.,Rutgers University | Lee J.S.,International Tuberculosis Research Center | Cho E.J.,International Tuberculosis Research Center | Roh S.S.,Rutgers University | And 8 more authors.
Journal of Clinical Microbiology | Year: 2015

Resistance to amikacin (AMK) and kanamycin (KAN) in clinical Mycobacterium tuberculosis strains is largely determined by specific mutations in the rrs gene and eis gene promoter. We developed a rapid, multiplexed sloppy molecular beacon (SMB) assay to identify these mutations and then evaluated assay performance on 603 clinical M. tuberculosis DNA samples collected in South Korea. Assay performance was compared to gold-standard phenotypic drug susceptibility tests, including Lowenstein- Jensen (LJ) absolute concentration, mycobacterial growth indicator tubes (MGIT), and TREK Sensititre MycoTB MIC plate (MycoTB) methods. Target amplicons were also tested for mutations by Sanger sequencing. The SMB assay correctly detected 115/116 mutant and mixed sequences and 487/487 wild-type sequences (sensitivity and specificity of 99.1 and 100%, respectively). Using the LJ method as the reference, sensitivity and specificity for AMK resistance were 92.2% and 100%, respectively, and sensitivity and specificity for KAN resistance were 87.7% and 95.6%, respectively. Mutations in the rrs gene were unequivocally associated with high-level cross-resistance to AMK and KAN in all three conventional drug susceptibility testing methods. However, eis promoter mutations were associated with KAN resistance using the MGIT or MycoTB methods but not the LJ method. No testing method associated eis promoter mutations with AMK resistance. Among the discordant samples with AMK and/or KAN resistance but wild-type sequence at the target genes, we discovered four new mutations in the whiB7 5= untranslated region (UTR) in 6/22 samples. All six samples were resistant only to KAN, suggesting the possible role of these whiB7 5= UTR mutations in KAN resistance. Copyright © 2015, American Society for Microbiology. All Rights Reserved.


Eum S.-Y.,International Tuberculosis Research Center | Kong J.-H.,International Tuberculosis Research Center | Hong M.-S.,International Tuberculosis Research Center | Lee Y.-J.,International Tuberculosis Research Center | And 5 more authors.
Chest | Year: 2010

Background: The exact role of neutrophils in the pathogenesis of TB is poorly understood. Recent evidence suggests that neutrophils are not simply scavenging phagocytes in Mycobacterium tuberculosis (Mtb) infection. Methods: Three different types of clinical specimens from patients with active pulmonary TB who underwent lung surgery were examined: sputum, BAL fluid, and cavity contents. Differential cell separation and quantification were performed for intracellular and extracellular bacteria, and bacterial length was measured using microscopy. Results: Neutrophils were more abundant than macrophages in sputum (86.6% ± 2.2% vs 8.4% ± 1.3%) and in BAL fluid (78.8% ± 5.8% vs 11.8% ± 4.1%). Inside the cavity, lymphocytes (41.3% ± 11.2%) were the most abundant cell type, followed by neutrophils (38.8% ± 9.4%) and macrophages (19.5% ± 7.5%). More intracellular bacilli were found in neutrophils than macrophages in sputum (67.6% ± 5.6% vs 25.2% ± 6.5%), in BAL fluid (65.1% ± 14.4% vs 28.3% ± 11.6%), and in cavities (61.8% ± 13.3% vs 23.9% ± 9.3%). The lengths of Mtb were shortest in cavities (1.9 ± 0.1 m m), followed by in sputum (2.9 ± 0.1 m m) and in BAL fluid (3.6 ± 0.2 m m). Conclusions: Our results show that neutrophils are the predominant cell types infected with Mtb in patients with TB and that these intracellular bacteria appear to replicate rapidly. These results are consistent with a role for neutrophils in providing a permissive site for a final burst of active replication of the bacilli prior to transmission. © 2010 American College of Chest Physicians.


Sakamuri R.M.,Los Alamos National Laboratory | Price D.N.,Los Alamos National Laboratory | Lee M.,International Tuberculosis Research Center | Cho S.N.,International Tuberculosis Research Center | And 4 more authors.
Tuberculosis | Year: 2013

Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We have also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum, and demonstrate that the circulating concentrations of 'monomeric' LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. This phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilic in nature and may also be associated with host lipid carriers. Such interactions are likely to affect host-pathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics. © 2013 Elsevier Ltd. All rights reserved.


Coleman M.T.,University of Pittsburgh | Chen R.Y.,National Institute of Allergy and Infectious Diseases | Lee M.,International Tuberculosis Research Center | Lin P.L.,University of Pittsburgh | And 15 more authors.
Science Translational Medicine | Year: 2014

Oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (XDR) tuberculosis (TB) despite modest effects in rodents and no demonstrable early bactericidal activity in human phase 2 trials. We show that monotherapy with either linezolid or AZD5847, a second-generation oxazolidinone, reduced bacterial load at necropsy in Mycobacterium tuberculosis-infected cynomolgus macaques with active TB. This effect coincided with a decline in 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography (FDG PET) imaging avidity in the lungs of these animals and with reductions in pulmonary pathology measured by serial computed tomography (CT) scans over 2 months of monotherapy. In a parallel phase 2 clinical study of linezolid in patients infected with XDR-TB, we also collected PET/CT imaging data from subjects receiving linezolid that had been added to their failing treatment regimens. Quantitative comparisons of PET/CT imaging changes in these human subjectswere similar inmagnitude to those observed inmacaques, demonstrating that the therapeutic effect of these oxazolidinones can be reproduced in this model of experimental chemotherapy. PET/CT imaging may be useful as an early quantitative measure of drug efficacy against TB in human patients. © 2014; American Association for the Advancement of Science. All rights reserved.


Wong S.Y.,National Institute of Allergy and Infectious Diseases | Lee J.S.,International Tuberculosis Research Center | Kwak H.K.,International Tuberculosis Research Center | Via L.E.,National Institute of Allergy and Infectious Diseases | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

The global threat posed by drug-resistant strains of Mycobacterium tuberculosis demands a greater understanding of the genetic basis and molecular mechanisms that govern how such strains develop resistance against various antituberculous drugs. In this report, we examine a new genetic basis for resistance to one of the oldest and most widely used second-line drugs employed in tuberculosis therapy, streptomycin (SM). This marker for SM resistance was first discovered on the basis of genomic data obtained from drug-resistant M. tuberculosis strains collected in Japan, wherein an association was observed between SM resistance and a mutation in gidB, a putative 16S rRNA methyltransferase. By evaluating an isogenic ΔgidB mutant strain constructed from strain H37Rv, we demonstrate the causal role of gidB in conferring a low-level SM-resistant phenotype in M. tuberculosis with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a gidB mutation leads to an MIC distribution of gidB mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some gidB mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that are found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant will likely respond poorly. This report provides the first microbiological evidence for the contribution of gidB in streptomycin resistance and examines the clinical implications of mutations in the gidB gene. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Motiwala A.S.,Rutgers University | Dai Y.,Rutgers University | Jones-Lopez E.C.,Rutgers University | Hwang S.-H.,National Masan Tuberculosis Hospital | And 5 more authors.
Journal of Infectious Diseases | Year: 2010

Background. Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency virus (HIV)-infected patients by the Broad Institute identified 22 novel mutations which were unique to the XDR genome or shared only by the MDR and XDR genomes and not already known to be associated with drug resistance. Methods. We studied the 12 novel mutations which were not located in highly-repetitive genes to identify mutations that were truly associated with drug resistance or were likely to confer a specific fitness advantage. Results. None of these mutations could be found in a phylogenetically and geographically diverse set of drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates, suggesting that these mutations are unique to the KZN clone. Examination of the 600-basepair region flanking each mutation revealed 26 new mutations. We searched for a convergent evolutionary signal in the new mutations for evidence that they emerged under selective pressure, consistent with increased fitness. However, all but 1 rare mutation were monophyletic, indicating that the mutations were markers of strain phylogeny rather than fitness or drug resistance. Conclusions. Our results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected patients can evolve without generalizable fitness changes or other XDR-specific mutations. © 2010 by the Infectious Diseases Society of America. All rights reserved.


Lienhardt C.,International Union Against Tuberculosis and Lung Disease | Cook S.V.,International Union Against Tuberculosis and Lung Disease | Burgos M.,University of New Mexico | Yorke-Edwards V.,Medical Research Council Clinical Trials Unit | And 6 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context Fixed-dose combinations (FDCs) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance. Objective To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis. Design, Setting, and Patients The Study C trial, a parallel-group, open-label, noninferiority, randomized controlled trial conducted in 11 sites in Africa, Asia, and Latin America between 2003 and 2008. Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis. Interventions Patients were randomized to receive daily treatment with 4 drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) given as an FDC (n=798 patients) or separately (n=787) in the 8-week intensive phase of treatment. Main OutcomeMeasure Favorable treatment outcome, defined as negative culture result at 18 months post randomization and not having already been classified as unfavorable. Noninferiority was dependent on consistent results from a per-protocol and modified intention-to-treat analysis, using 2 different models for the latter, classifying all changes of treatment or refusal to continue treatment (eg, bacteriological failure/relapse, adverse event, default, drug resistance) as unfavorable (model 1) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available (post hoc model 2). The prespecified noninferiority margin was 4%. Results In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, -0.7% [90% confidence interval {CI}, -3.0% to 1.5%]). In the model 1 analysis, 570 of 684 patients (83.3%) had a favorable outcome in the FDC group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, -1.5% [90% CI, -4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 patients (89.8%) in the FDC group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, -1.2% [90% CI, -3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups. Conclusions Compared with a regimen of separately administered drugs, a 4-drug FDC regimen for treatment of tuberculosis satisfied prespecified noninferiority criteria in 2 of 3 analyses. Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial, use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations. © 2011 American Medical Association. All rights reserved.


Jeon B.-Y.,Yonsei University | Kim S.-C.,Yonsei University | Eum S.-Y.,International Tuberculosis Research Center | Cho S.-N.,Yonsei University
Microbes and Infection | Year: 2011

The anti-tuberculosis vaccine, Mycobacterium bovis BCG, has been used worldwide, but its protective efficacy is variable against adult pulmonary tuberculosis. In this study, immune responses of antigen 85A (Ag85A) and heat-shock protein X (HspX) antigen of Mycobacterium tuberculosis were investigated during acute and stationary stage of infection in the murine aerosol TB challenge model and their protective effects were evaluated against progressive tuberculosis. A high level of Ag85A-specific IFN-γ production was induced from the early stage of the infection, whereas HspX-specific IFN-γ production was increased in the later stationary stage. As a subunit vaccine, Ag85A and HspX antigen vaccine induced high levels of IFN-γ, and a vaccine comprising both antigens induced the highest level of IFN-γ. At 30 days post-challenge, the Ag85A subunit vaccine was protective against M. tuberculosis challenge, but the HspX subunit vaccine was not. Interestingly, the HspX antigen vaccine induced significant protective efficacy at 90 days post-challenge. Moreover, the combined antigen vaccine induced the highest protective efficacy against M. tuberculosis challenge both at 30 days and 90 days post-challenge. These results suggest that the vaccine comprising Ag85A and HspX antigen which react in different stages of infection is highly protective against progressive tuberculosis. © 2010 Institut Pasteur.

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