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Advancing Innovative Next_generation Heterologous Vaccines Against Tuberculosis

推进创新的下一代抗结核异源疫苗

基本信息

批准号：
10439334
负责人：
GILLIAN L BEAMER
金额：
$ 55.66万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-10 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439334
关键词：
Address Adjuvant Aliquot Animal Model Animals Antigens BCG Live Bacille Calmette-Guerin vaccination Binding Biological Assay Biological Response Modifiers Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cavia Cells Cellular Assay Cellular Immunity Clinical Trials Communicable Diseases Databases Development Disease Emulsions Ensure Epidemiology Equilibrium Experimental Animal Model Failure Formulation Future Genes Genetic Variation Genotype Goals Human Humoral Immunities Immune Immunity Immunize Immunoglobulin A Immunoglobulin G Inbred Mouse Inbred Strain Infection Inflammatory Response Interferons Interleukin-17 Intramuscular Ligands Liposomes Lung Measurable Measures Mediating Mind Modality Modeling Modern 1601-history Morbidity - disease rate Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Mycobacterium bovis Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Newly Diagnosed Outcome Patients Persons Phase Phenotype Population Pre-Clinical Model Predisposition Proteins Pulmonary Tuberculosis RNA RNA amplification RNA vaccine Reproducibility Reproduction Rodent Model Route Sampling Studies Serum Spleen Squalene T cell response T-Lymphocyte Testing Tissue Sample Tissues Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccines Work World Health Organization aluminum sulfate burden of illness candidate selection clinical candidate combat design disease transmission efficacy testing immunogenic immunogenicity innovation insight lead candidate next generation novel novel vaccines pathogen pre-clinical pre-clinical assessment response screening statistics success thermostability transmission process tuberculosis immunity vaccine candidate vaccine development vaccine discovery vaccine evaluation vaccine platform vaccine trial

项目摘要

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.

项目总结/文摘