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

• 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
• 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

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.

项目总体概要 范德比尔特艰难梭菌疫苗 VANDy-CdV 抗体和抗原发现 艰难梭菌是一种产芽孢厌氧细菌，是医院感染的主要原因。 在美国获得胃肠道感染。社区发病率不断上升 健康成年人获得性艰难梭菌感染 (CDI) 与抗生素使用增加有关 以及新菌株的出现。 CDI 症状和病理由两大因素介导 同源毒素 TcdA 和 TcdB，因此这些毒素代表了有吸引力的目标 预防和治疗策略。虽然努力的重点是使用类毒素 免疫接种已显示出减轻症状严重程度的希望，类毒素方法已显示出希望 临床试验中并未导致 CDI 发生率降低。有几个机会 改进现有的疫苗策略。首先，大规模基因组研究表明 TcdB 经历快速的进化变化；可以使用保守毒素表位的鉴定 引导免疫反应产生广泛的中和反应。第二， 鉴定营养细菌或孢子表面的保守抗原 可以作为免疫原，使宿主能够引发粘膜免疫反应，从而预防 细菌定植。预计粘膜免疫途径的纳入将进一步 提高疫苗功效和持久性。 VANDy-CdV 计划的总体目标是 识别毒素亚基和新型细胞表面抗原，当它们组合在一起时，可促进持久 预防艰难梭菌感染和症状。在众多创新优势中， 方法包括使用人类 CDI 患者样本作为了解什么的资源 抗原在自然感染中促进 IgG、IgA 和 sIgA 反应。该方法还包括 使用强大的单 B 细胞分选和测序方法。识别配对的能力 来自结合毒素和/或细菌的个体记忆 B 细胞的重链和轻链序列 允许生产独特的抗体，然后可以将其用作表位作图工具 和新抗原的发现。该方法的第三个亮点涉及使用新创建的 艰难梭菌转座子文库，将用于在体内鉴定新抗原 疫苗接种/激发实验。其他创新包括结构引导方法 识别有效的中和表位并系统评估肠道淋巴细胞如何 反应因免疫途径而异。疫苗功效与粘膜相关性 将在定植、感染和复发的临床前模型中评估保护作用。在 五年结束后，我们预计将获得推进新型抗原所需的临床前数据 鸡尾酒和免疫策略进入人体安全性和功效试验。