Dataset Information

Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology.

ABSTRACT: Tuberculosis (TB) remains a major health threat. Although a vaccine has been available for almost 100 years termed Bacille Calmette-Guérin (BCG), it is insufficient and better vaccines are urgently needed. This treatise describes first the basic immunology and pathology of TB with an emphasis on the role of T lymphocytes. Better understanding of the immune response to Mycobacterium tuberculosis (Mtb) serves as blueprint for rational design of TB vaccines. Then, disease epidemiology and the benefits and failures of BCG vaccination will be presented. Next, types of novel vaccine candidates are being discussed. These include: (i) antigen/adjuvant subunit vaccines; (ii) viral vectored vaccines; and (III) whole cell mycobacterial vaccines which come as live recombinant vaccines or as dead whole cell or multi-component vaccines. Subsequently, the major endpoints of clinical trials as well as administration schemes are being described. Major endpoints for clinical trials are prevention of infection (PoI), prevention of disease (PoD), and prevention of recurrence (PoR). Vaccines can be administered either pre-exposure or post-exposure with Mtb. A central part of this treatise is the description of the viable BCG-based vaccine, VPM1002, currently undergoing phase III clinical trial assessment. Finally, new approaches which could facilitate design of refined next generation TB vaccines will be discussed.

SUBMITTER: Kaufmann SHE

PROVIDER: S-EPMC7056705 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology.

Kaufmann Stefan H E SHE

Frontiers in immunology 20200227

Tuberculosis (TB) remains a major health threat. Although a vaccine has been available for almost 100 years termed Bacille Calmette-Guérin (BCG), it is insufficient and better vaccines are urgently needed. This treatise describes first the basic immunology and pathology of TB with an emphasis on the role of T lymphocytes. Better understanding of the immune response to <i>Mycobacterium tuberculosis (Mtb)</i> serves as blueprint for rational design of TB vaccines. Then, disease epidemiology and th ...[more]

PMID: 32174919

Similar Datasets

Project description:Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies.ImportanceBCG remains the only licensed vaccine against TB. Parenterally administered BCG has variable efficacy against pulmonary TB, and thus, improved prevention strategies and a more refined understanding of correlates of vaccine protection are required. Induction of memory T cells has been shown to be essential for protective TB vaccines. Mimicking the natural infection route by mucosal vaccination has been known to generate superior protection against TB in animal models; however, the mechanisms of protection have remained elusive. Here we performed an in-depth analysis to dissect the immunological mechanisms associated with superior mucosal protection in the mouse model of TB. We found that mucosal, and not subcutaneous, BCG vaccination generates lung-resident memory T cell populations that confer protection against pulmonary TB. We establish a comprehensive phenotypic characterization of these populations, providing a framework for future vaccine development.

Project description:Ten million cases of tuberculosis (TB) were reported in 2018 with a further 1.5 million deaths attributed to the disease. Improved vaccination strategies are urgently required to tackle the ongoing global TB epidemic. In the absence of a validated correlate of protection, highly characterised pre-clinical models are required to assess the protective efficacy of new vaccination strategies. In this study, we demonstrate the application of a rhesus macaque ultra-low dose (ULD) aerosol M. tuberculosis challenge model for the evaluation of TB vaccination strategies by directly comparing the immunogenicity and efficacy of intradermal (ID) and aerosol BCG vaccination delivered using a portable vibrating mesh nebulizer (VMN). Aerosol- and ID-delivered Bacille Calmette-Guérin (BCG) induced comparable frequencies of IFN-γ spot forming units (SFU) measured in peripheral blood mononuclear cells (PBMCs) by ELISpot, although the induction of IFN-γ SFU was significantly delayed following aerosol immunisation. This delayed response was also apparent in an array of secreted pro-inflammatory and chemokine markers, as well as in the frequency of antigen-specific cytokine producing CD4 and CD8 T-cells measured by multi-parameter flow cytometry. Interrogation of antigen-specific memory T-cell phenotypes revealed that vaccination-induced CD4 and CD8 T-cell populations primarily occupied the central memory (TCM) and transitional effector memory (TransEM) phenotype, and that the frequency of CD8 TCM and TransEM populations was significantly higher in aerosol BCG-vaccinated animals in the week prior to M. tuberculosis infection. The total and lung pathology measured following M. tuberculosis challenge was significantly lower in vaccinated animals relative to the unvaccinated control group and pathology measured in extra-pulmonary tissues was significantly reduced in aerosol BCG-vaccinated animals, relative to the ID-immunised group. Similarly, significantly fewer viable M. tuberculosis CFU were recovered from the extra-pulmonary tissues of aerosol BCG-vaccinated macaques relative to unvaccinated animals. In this study, a rhesus macaque ULD M. tuberculosis aerosol challenge model was applied as a refined and sensitive system for the evaluation of TB vaccine efficacy and to confirm that aerosol BCG vaccination delivered by portable VMN can confer a significant level of protection that is equivalent, and by some measures superior, to intradermal BCG vaccination.

Dataset Information

Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology.

Publications

Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets