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Principal Investigator: ROBERT A SEDER
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $1,847,416
Funding agency: National Institute of Allergy and Infectious Diseases
Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide. Intradermal (ID) vaccination with BCG has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission. We showed that the route and dose of BCG vaccination alters circulating and lung resident T cells and subsequent protection against Mtb challenge in nonhuman primates (NHP). NHP immunized with BCG by the intravenous (IV) route induced substantially higher antigen-specific CD4 (Th1 or Th17) and CD8 responses in blood, spleen, bronchoalveolar lavage (BAL), and lung lymph nodes compared to the same BCG dose administered by ID or aerosol (AE) routes. Moreover, IV immunization was the only route that induced a high frequency of antigen-specific tissue resident T cells in lung parenchyma. Six months after BCG vaccination, NHP were challenged with virulent Mtb. Strikingly, 9 of 10 NHP that received BCG IV were highly protected, with 6 NHP showing no detectable infection as determined by PET CT imaging, mycobacterial growth, pathology, granuloma formation, or de novo immune responses to Mtb-specific antigens. Follow up efficacy experiments in NHP have repeated these initial findings and shown that IV BCG immunization provides robust protection against Mtb challenge even at 10-100-fold lower doses. The finding that BCG IV prevents or significantly limits Mtb infection in NHP has important implications for vaccine development and provides a model for determining immune correlates and mechanisms of protection against Mtb.
Terms: <0-11 years old><21+ years old><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Adolescent><Adolescent Youth><Adult><Adult Human><Aerosols><Antigens><Attenuated><BCG Live><BCG Vaccine><BCG immunization><BCG vaccination><BCG-vaccinated><Bacille Calmette Guerin vaccine><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacille Calmette-Guérin><Bacillus Calmette Guerin Vaccine><Bacillus Calmette Guérin><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Bacillus Calmette-Guérin vaccine><Birth><Blood><Blood Reticuloendothelial System><Body Tissues><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><CAT scan><CD8><CD8B><CD8B1><CD8B1 gene><CT X Ray><CT Xray><CT imaging><CT scan><Cause of Death><Cell Body><Cells><Cessation of life><Child><Child Youth><Children (0-21)><Computed Tomography><Confocal Microscopy><Death><Development><Disease><Disorder><Dose><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><Gene Transcription><Generalized Growth><Genetic Transcription><Goals><Granuloma><Granulomatous Lesion><Growth><HIV><Health Priorities><Human Immunodeficiency Viruses><Immune><Immune response><Immunes><Immunity><Immunization><Immunize><Immunodominant Antigens><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Individual><Infant><Infection><Intravenous><LAV-HTLV-III><LYT3><Lung><Lung Lavage><Lung Parenchyma><Lung Respiratory System><Lung TB><Lung Tissue><Lung Tuberculosis><Lung diseases><Lung infections><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><M bovis><M tb><M tuberculosis><M tuberculosis genome><M tuberculosis infection><M. bovis><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis genome><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Maps><Meningeal Tuberculosis><Miliary Tuberculosis><Modeling><Mtb genome><Mycobacterium bovis><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><Mycobacterium tuberculosis var. bovis><Non-Polyadenylated RNA><PET><PET Scan><PET imaging><PETSCAN><PETT><Parturition><Pathology><Peptides><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Pulmonary Diseases><Pulmonary Disorder><Pulmonary TB><Pulmonary Tuberculosis><RNA><RNA Expression><RNA Gene Products><RNA vaccine><Rad.-PET><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Ribonucleic Acid><Route><Spleen><Spleen Reticuloendothelial System><Structure of parenchyma of lung><T cell response><T-Cells><T-Lymphocyte><TB infection><Tissue Growth><Tissues><Tomodensitometry><Transcription><Tuberculosis><Tuberculosis Meningitis><Tuberculous Meningitis><Vaccination><Vaccines><Virulent><Virus-HIV><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><active followup><adulthood><bronchopulmonary lavage therapy><catscan><children><childrens'><communicable disease transmission><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><develop a vaccine><development of a vaccine><developmental><disease of the lung><disease transmission><disorder of the lung><disseminated TB><disseminated tuberculosis><experiment><experimental research><experimental study><flow cytophotometry><follow up><follow-up><followed up><followup><global health><host response><immunogen><immunogenicity><immunoresponse><infection due to Mycobacterium tuberculosis><infectious disease transmission><juvenile><juvenile human><lung disorder><lymph gland><lymph nodes><lymphnodes><mRNA vaccine><mortality><mtb><mycobacterial><mycobacterium tuberculosis genome><non-human primate><nonhuman primate><ontogeny><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><prevent><preventing><pulmonary><pulmonary infections><response><thymus derived lymphocyte><tuberculosis infection><tuberculous spondyloarthropathy><vaccine development><vaccine formulation><youngster>