Commensal bacteria as vehicles for robust mucosal vaccination against lung pathogens

共生细菌作为针对肺部病原体的强力粘膜疫苗接种的载体

• 批准号: 10749817
• 负责人: Layla Barkal
• 金额: $ 7.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10749817
• 关键词: Adjuvant; Anatomy; Antigens; Award; B-Lymphocytes; Biological Assay; Cells; Characteristics; Clinic; Data; Development; Dose; Economics; Effector Cell; Engineering; Flow Cytometry; Foundations; Genetic Engineering; Goals; Grant; Immune; Immune response; Immune system; Immunity; Immunology; Individual; Inflammation; Inflammatory; Influenza A virus; Inhalation; Intramuscular; K-Series Research Career Programs; Label; Lung; Lung infections; Mentorship; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Nasopharynx; Nose; Patients; Pattern; Physicians; Population; Prevalence; Research; Resources; Respiratory Mucosa; Respiratory Tract Infections; Safety; Scientist; Serum; Severities; Signal Transduction; Site; Skin; Staphylococcus epidermidis; Stimulus; Structure of mucous membrane of nose; Surface; T cell response; T-Cell Activation; Technology; Testing; Tissues; Training; Universities; Vaccinated; Vaccination; Vaccines; Viral Antigens; Viral Respiratory Tract Infection; Virus Diseases; Work; adaptive immune response; antigen-specific T cells; bacterial genetics; burden of illness; career; commensal bacteria; cytokine; cytotoxic CD8 T cells; host-microbe interactions; improved; influenza virus vaccine; interest; lung pathogen; microbial; mouse model; mucosal vaccination; mucosal vaccine; novel therapeutics; pathogenic virus; programs; recruit; respiratory; response; skills; skin vaccination; vaccination strategy; vaccine delivery; vaccine efficacy

PROJECT SUMMARY/ABSTRACT The prevalence and severity of respiratory infections is in part because vaccines struggle to elicit robust immunity at the nasal and lung mucosal barriers where early, strong defense is most needed. Specifically, vaccines delivered intramuscularly generate good serum responses but poor mucosal responses; alternatively, vaccinating the mucosa directly, such as with a nasal spray, requires high doses of adjuvants that cause local inflammation and resulting safety concerns. Commensal bacteria safely live at barrier surfaces such as the skin and nose where they generate antigen-specific immunity without any associated inflammation. The goal of this proposal is to investigate commensal bacteria as safe and effective vaccine vehicles. Preliminary data suggests that engineered strains of Staphylococcus epidermidis, a ubiquitous skin commensal, that express influenza A virus (IAV) antigens (S. epi-IAV) can be applied to the skin and function as partially protective vaccines. In the first aim of my proposal, I will elucidate the cells that respond in the skin and subsequently provide pulmonary protection. Specifically, I will use a T cell activation assay to assess for antigen-specific responding cells; I will also label and track immune cells originating in the skin using the ROSA mouse, which will allow me to profile innate cellular effectors too. In my second aim, I will evaluate for improved pulmonary protection in the case when vaccination on the skin is followed by subsequent antigen exposure at the respiratory mucosa. Finally, I will move to the nasopharynx. I will determine if commensal vaccination in the nose more effective than skin vaccination at eliciting pulmonary protection. My project will provide a deeper understanding of the immune- commensal interactions in the nasopharynx, how commensal-generate immunity is shared between barrier surfaces, and lay the foundation for using commensals to generate mucosal vaccines that are both safer and more effective than existing vaccines. This project builds off my expertise modeling host-microbe interactions in the lung from my graduate work and allows me to expand into the fields of mucosal immunology and microbial engineering. Support from the F32 program, the Fischbach lab, the Stanford Pulmonary Division, and the resources available at Stanford University will allow me to develop critical new skills in flow cytometry, bacterial genetic engineering, and mouse models. The training and mentorship I will receive during my F32 award will let me take a critical step towards my career goal of becoming an independent physician scientist engineering new therapies for my clinic and ICU patients with lung infections.

项目概要/摘要 呼吸道感染的流行和严重程度部分是因为疫苗难以激发强大的免疫力 在鼻腔和肺粘膜屏障处，最需要早期、强有力的防御。具体来说，疫苗 肌肉注射产生良好的血清反应，但粘膜反应较差；或者， 直接对粘膜进行疫苗接种，例如使用鼻喷雾剂，需要高剂量的佐剂，这会导致局部感染 炎症和由此产生的安全问题。共生细菌安全地生活在皮肤等屏障表面 和鼻子，它们产生抗原特异性免疫，而没有任何相关的炎症。此举的目标 建议研究共生细菌作为安全有效的疫苗载体。初步数据表明 改造了表皮葡萄球菌菌株，这是一种普遍存在的皮肤共生菌，可表达甲型流感病毒 病毒（IAV）抗原（S. epi-IAV）可应用于皮肤并起到部分保护性疫苗的作用。在 我的提案的第一个目标是，我将阐明皮肤中反应的细胞，并随后提供肺部 保护。具体来说，我将使用 T 细胞激活测定来评估抗原特异性应答细胞；我会 还使用 ROSA 小鼠标记和跟踪源自皮肤的免疫细胞，这将使我能够分析 也是先天细胞效应器。在我的第二个目标中，我将评估该案例中肺保护的改善情况 当在皮肤上接种疫苗后，随后在呼吸道粘膜处暴露抗原。最后，我 会移动到鼻咽部。我将确定鼻子共生疫苗接种是否比皮肤接种更有效 疫苗接种可引起肺部保护。我的项目将提供对免疫的更深入的了解 鼻咽部的共生相互作用，共生免疫如何在屏障之间共享 表面，并为使用共生体生产更安全、更安全的粘膜疫苗奠定基础 比现有疫苗更有效。这个项目建立在我对宿主-微生物相互作用进行建模的专业知识的基础上 我的研究生工作中的肺部，使我能够扩展到粘膜免疫学和微生物领域 工程。来自 F32 计划、Fischbach 实验室、斯坦福大学肺科和 斯坦福大学的可用资源将使我能够开发流式细胞术、细菌 基因工程和小鼠模型。我在 F32 获奖期间接受的培训和指导将使 我朝着成为一名独立的医师科学家工程新的职业目标迈出了关键的一步 为我的诊所和 ICU 肺部感染患者提供治疗。