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Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines

艰难梭菌疫苗的范德比尔特抗体和抗原发现

基本信息

批准号：
10625686
负责人：
Dana Borden Lacy
金额：
$ 157万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-03 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625686
关键词：
Address Adult Age Anaerobic Bacteria Animal Testing Antibiotics Antibodies Antibody titer measurement Antigens B-Lymphocytes Bacteria Binding Biochemical Blood Cell Separation Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Clinical Clinical Trials Clostridium difficile Colon Communities Complement Data Development Diarrhea Disease Elderly Ensure Epitope Mapping Epitopes Evaluation Foundations Genetic Genomics Goals Hospitalization Hospitals Human Immune Immune response Immunity Immunization Immunoglobulin A Immunoglobulin G Immunologics Incidence Individual Infection Inflammation Intestines Lead Libraries Life Light Link Lymphocyte Mediating Membrane Proteins Memory B-Lymphocyte Methods Mucosal Immune Responses Mucous Membrane Pathology Patients Persons Pre-Clinical Model Prevalence Prevention Production Pseudomembranous Colitis Recurrence Reporting Reproduction spores Research Research Personnel Resources Route Safety Sampling Secretory Immunoglobulin A Services Severities Severity of illness Structure Surface Surface Antigens Symptoms Therapeutic Tissues Toxin Toxoids Transferase Translating United States Vaccination Vaccines Virulence Factors Work antibiotic-associated diarrhea antitoxin design efficacy trial experience experimental study gastrointestinal infection improved in vivo innovation member mouse model multidisciplinary novel novel vaccines pre-clinical prevent programs recurrent infection response tool vaccination strategy vaccine development vaccine efficacy vaccine formulation vaccine strategy vaccine trial

项目摘要

OVERALL PROJECT SUMMARY Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines VANDy-CdV Clostridioides difficile is a spore-forming anaerobic bacterium that is the leading cause of hospital- acquired gastrointestinal infection in the United States. The rising incidence of community- acquired C. difficile infection (CDI) in otherwise healthy adults is linked to increased antibiotic use and the emergence of new strains. CDI symptoms and pathology are mediated by two large homologous toxins, TcdA and TcdB, and therefore the toxins represent attractive targets for prevention and therapeutic strategies. While efforts centered around the use of toxoids for immunization have shown promise in reducing the severity of symptoms, the toxoid approach has not resulted in a decreased incidence of CDI in clinical trials. There are several opportunities to improve upon existing vaccine strategies. First, large scale genomic studies show that TcdB is undergoing rapid evolutionary change; the identification of conserved toxin epitopes can be used to direct the immune response toward the production of broadly neutralizing responses. Second, the identification of conserved antigens on the surface of the vegetative bacteria or spores that can serve as immunogens will allow the host to elicit mucosal immune responses that prevent bacterial colonization. The inclusion of mucosal immunization routes is expected to further enhance vaccine efficacy and durability. The overarching goal of the VANDy-CdV program is to identify toxin subunits and novel cell surface antigens that, when combined, promote durable protection against C. difficile infection and symptoms. Among many innovative strengths, the approach includes the use of human CDI patient samples as a resource for understanding what antigens promote IgG, IgA, and sIgA responses in natural infection. The approach also includes the use of powerful single B cell sorting and sequencing methods. The ability to identify paired heavy and light chain sequences from individual memory B cells binding toxins and/or bacteria allows for the production of unique antibodies that can then be used as tools for epitope mapping and novel antigen discovery. A third highlight of the approach involves the use of a newly created C. difficile transposon library which will be used to identify novel antigens in an in vivo vaccination/challenge experiment. Other innovations include a structure-guided approach to identifying potent, neutralizing epitopes and a systematic evaluation of how intestinal lymphocyte responses vary with routes of immunization. Vaccine efficacy and the mucosal correlates of protection will be evaluated in pre-clinical models of colonization, infection, and recurrence. At the end of five years, we expect to have the pre-clinical data needed to advance a novel antigen cocktail and immunization strategy forward into human safety and efficacy trials.

项目总体总结