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Principal Investigator: GILLIAN L BEAMER
Organization: TEXAS BIOMEDICAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $532,829
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Throughout modern history, tuberculosis (TB) has killed more people than any other infectious
disease to date (estimated > 2 billion people over the past 350 years) and TB continues to kill
4,000 patients each day. In 2019 alone, the World Health Organization estimated that ~1.4 million
people died of TB and 8-9 million patients were newly diagnosed. The only approved vaccine, M.
bovis Bacille Calmette-Guerin (BCG) has had many successes but its protection is variable and
BCG-vaccinated TB patients still transmit M.tb. Across the globe, an equilibrium of transmission
and disease exists such that one new case of pulmonary TB arises from each existing TB patient;
thus, efforts must be reinvigorated to drive TB rates lower. New strategies are needed to combat
TB including discovery and advancement of new vaccines to control the pathogen Mycobacterium
tuberculosis (M.tb). With that end goal in mind, we answer the call for RFA AI-21-007: Innovation
for Tuberculosis Vaccine Discovery (ITVD), forming partnerships between PIs with vaccine
development expertise, and expertise using animal models of TB. We propose three novel means
to advance TB vaccines. In the R61 phase, we develop and identify the best performing new
vaccine candidates. Specifically, we (i) combine the ID93 protein antigen with new adjuvants
designed to maximize mucosal immune responses and durability; (ii) capitalize on novel RNA
platform to create vaccines expressing ID93 and related M.tb antigens to induce rapid and durable
immunity; (iii) optimize heterologous protein/RNA prime-boost candidates for strong and durable
mucosal, humoral, and cellular anti-M.tb immunity, and select the final candidates to move into
challenge studies. To maximize early-stage development, rigor, and reproducibility, we perform
immunogenicity studies in a selected panel of Collaborative Cross (CC) inbred strains,
representing known differential susceptibility to M.tb infection. In the R33 phase, i.e., M.tb
challenge studies, we exploit the Diversity Outbred (DO) mouse population for its outstanding
representation of genotypic and phenotypic diversity equivalent to humans, a major hurdle in TB
vaccine development efforts to date. We will also test the final vaccine candidates in guinea pigs,
the classic preclinical model for TB vaccines to ensure success in 2 animal models.
Terms: <7S Gamma Globulin><Address><Adjuvant><Aliquot><Alum Adjuvant><Animal Model><Animal Models and Related Studies><Animals><Antigens><Assay><BCG Live><BCG immunization><BCG vaccination><BCG-vaccinated><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacille Calmette-Guérin><Bacillus Calmette Guérin><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Binding><Bioassay><Biological Assay><Biological Response Modifiers><Biomodulators><Blood><Blood Reticuloendothelial System><Blood Serum><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cavia><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Assay><Cellular Immunity><Clinical Trials><Communicable Diseases><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data Bases><Databases><Development><Disease><Disorder><Emulsions><Ensure><Epidemiology><Equilibrium><Euthanasia><Experimental Animal Model><Failure><Formulation><Future><Genes><Genetic Diversity><Genetic Variation><Genotype><Goals><Guinea Pigs><Guinea Pigs Mammals><Human><Humoral Immunities><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IgA><IgG><Immune><Immune Interferon><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immunes><Immunity><Immunize><Immunoglobulin A><Immunoglobulin G><Inbred Mouse><Inbred Strain><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory Response><Interferon Gamma><Interferon Type II><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Intramuscular><Ligands><Liposomal><Liposomes><Lung><Lung Respiratory System><Lung TB><Lung Tuberculosis><M bovis><M tb><M tuberculosis><M tuberculosis antigen><M tuberculosis infection><M. bovis><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis antigen><M. tuberculosis infection><M.tb antigen><M.tb infection><M.tuberculosis infection><MTB infection><MTB vaccine><Measurable><Measures><Mediating><Mercy Killing><Mice><Mice Mammals><Mind><Modality><Modeling><Modern 1601-history><Modern History><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Mtb antigen><Mucosa><Mucosal Immune Responses><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mycobacterium bovis><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><Mycobacterium tuberculosis var. bovis><Newly Diagnosed><Non-Polyadenylated RNA><Outcome><Patients><Persons><Phase><Phenotype><Population><Pre-Clinical Model><Preclinical Models><Predisposition><Proteins><Pulmonary TB><Pulmonary Tuberculosis><RNA><RNA Gene Products><RNA amplification><RNA vaccine><RNA-based vaccine><Reproducibility><Reproduction><Ribonucleic Acid><Rodent Model><Route><Sampling Studies><Serum><Spleen><Spleen Reticuloendothelial System><Squalene><Susceptibility><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TB immunity><TB infection><TB vaccine><Testing><Tissue Sample><Tissues><Transmission><Tuberculosis><Tuberculosis Vaccines><Vaccinated><Vaccination><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Work><World Health Organization><alum><aluminum sulfate><anti-TB vaccine><antibody-based immunity><balance><balance function><burden of disease><burden of illness><candidate identification><candidate selection><cell assay><clinical candidate><combat><communicable disease transmission><data base><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><discover vaccines><disease burden><disease transmission><disseminated TB><disseminated tuberculosis><efficacy testing><epidemiologic><epidemiological><immunity against M. tuberculosis><immunity against Mtb><immunity against Mycobacterium tuberculosis><immunity against TB><immunity against tuberculosis><immunity in tuberculosis><immunity to TB><immunity to tuberculosis><immunogen><immunogenic><immunogenicity><immunomodulatory biologics><infection due to Mycobacterium tuberculosis><infectious disease transmission><innovate><innovation><innovative><insight><lFN-Gamma><lead candidate><mRNA vaccine><mRNA-based vaccine><model of animal><mtb><nano><new vaccines><next generation><next generation vaccines><novel><novel vaccines><pathogen><pre-clinical><pre-clinical assessment><preclinical><preclinical assessment><pulmonary><response><screening><screenings><statistics><success><thermolability><thermostability><thymus derived lymphocyte><transmission process><tuberculosis immunity><tuberculosis infection><tuberculous spondyloarthropathy><vaccination study><vaccination trial><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against tuberculosis><vaccine candidate><vaccine candidates against tuberculosis><vaccine development><vaccine discovery><vaccine platform><vaccine study><vaccine trial>