Overcoming pathogen-mediated immune evasion: a translational approach to pediatric Staphylococcus aureus vaccine development - Resubmission 01

克服病原体介导的免疫逃避：儿科金黄色葡萄球菌疫苗开发的转化方法 - 重新提交 01

• 批准号: 9311283
• 负责人: Christopher Montgomery
• 金额: $ 38万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311283
• 关键词: Address; Adult; Animal Model; Antibodies; Antibody Response; Antibody-mediated protection; Antigen Presentation; Antigens; Benign; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Child; Childhood; Clinical Research; Clinical Trials; Communicable Diseases; Communities; Complement; Development; Epidemic; Epitopes; Equilibrium; Exposure to; Foundations; Future; Goals; Helper-Inducer T-Lymphocyte; Human; Immune Evasion; Immune response; Immune system; Immunity; Immunization; Immunotherapeutic agent; Impairment; Infection; Infection prevention; Inflammation; Inflammatory Response; Influenza; Institute of Medicine (U.S.); Investigation; Lesion; Life; Lung; Masks; Mediating; Methicillin Resistance; Morbidity - disease rate; Mus; Older Population; Operon; Pattern; Peptide/MHC Complex; Phenotype; Pneumonia; Population; Prevention; Process; Public Health; Recurrence; Research; Role; Severities; Skin; Skin Tissue; Soft Tissue Infections; Staphylococcus aureus; T cell response; T-Lymphocyte; Testing; Tissues; United States; Vaccination; Vaccine Design; Vaccines; Virulent; base; burden of illness; early childhood; insight; leukotoxin; mortality; mouse model; novel; novel vaccines; pathogen; population based; prevent; public health relevance; response; tool; translational approach; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial

PROJECT SUMMARY/ABSTRACT Preventing infections caused by Staphylococcus aureus is a public health imperative, but there is currently no effective vaccine. Clinical trials for S. aureus vaccines and immunotherapeutics have focused on preventing infection in adults with a particularly high burden of S. aureus infections, but no efforts have been made to challenge the existing dogma and develop an immunization strategy that will afford early and broad population- based protection. We hypothesize that seemingly benign exposures to S. aureus in early childhood pattern deleterious immune responses, effectively “trapping” the immune system, a concept introduced by Francis as “original antigenic sin”. Therefore, we predict that a successful S. aureus vaccine will require an alternative, highly mechanistic approach to vaccine design with the goal of overdriving original antigen sin, and implementation in the pediatric population to deliberately drive the host immune response toward a protective phenotype prior to the establishment of natural suboptimal responses. The studies in this proposal will test this hypothesis using tractable animal models of S. aureus infection and clinical studies in healthy and S. aureus–infected children. Taking advantage of the convergence of natural and vaccine-elicited immunity in our mouse model, we will use a novel vaccine and newly synthesized peptide MHC (pMHC) tetramers as tools to precisely define the mechanisms by which synergistic antibody and T cell responses impact local inflammatory responses and bacterial outgrowth at the tissue level. A mechanistic approach to overdrive infection-patterned immunity in the mouse model will be complemented by a targeted investigation in healthy and S. aureus-infected children to determine the onset and impact of patterned immunity. This clinicotranslational approach is anticipated to lay the foundation for future vaccine trials in the pediatric population.

项目概要/摘要 预防金黄色葡萄球菌引起的感染是公共卫生的当务之急，但目前还没有 金黄色葡萄球菌疫苗和免疫治疗的临床试验重点是预防。 金黄色葡萄球菌感染负担特别高的成年人的感染，但尚未采取措施 挑战现有的教条并制定一项免疫战略，为早期和广泛的人口提供支持。 我们在幼儿时期采取了看似良性的金黄色葡萄球菌暴露模式。 有害的免疫反应，有效地“捕获”免疫系统，这是弗朗西斯提出的概念 因此，我们预测成功的金黄色葡萄球菌疫苗将需要替代方案， 高度机械化的疫苗设计方法，其目标是过度驱动原始抗原原罪，以及 在儿科人群中实施，以认真推动宿主免疫反应向保护性方向发展 在建立自然次优反应之前的表型。 本提案中的研究将使用金黄色葡萄球菌感染的易处理动物模型来检验这一假设， 利用自然融合的优势对健康儿童和金黄色葡萄球菌感染儿童进行临床研究。 和疫苗在我们的小鼠模型中引发的免疫力，我们将使用一种新型疫苗和新合成的肽 MHC (pMHC) 四聚体作为精确定义抗体和 T 细胞协同作用机制的工具 反应影响组织水平上的局部炎症反应和细菌生长。 在小鼠模型中超速感染模式免疫的方法将得到有针对性的补充 对健康儿童和金黄色葡萄球菌感染儿童进行调查，以确定模式化的发病和影响 预计这种临床转化方法将为未来的疫苗试验奠定基础。 儿科人群。