Development of a Vaccine for Viral Exacerbation of Asthma

开发治疗病毒性哮喘恶化的疫苗

• 批准号: 8220465
• 负责人: DENNIS M LINDELL
• 金额: $ 42.6万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220465
• 关键词: Accident and Emergency department; Accounting; Adjuvant; Adult; Age; Agonist; Allergic; Allergic Disease; Animal Model; Antigens; Asthma; Attenuated; Cells; Child; Communicable Diseases; Data; Dendritic Cells; Development; Disease; Drug Formulations; Epithelial Cells; Epithelium; Genetic; Goals; Health Benefit; Hospitalization; Human; Immune; Immune response; Immune system; Immunity; Immunologic Adjuvants; In Vitro; Individual; Life; Liposomes; Lung diseases; Mediating; Mediator of activation protein; Methods; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Nature; Nose; Pattern; Pattern recognition receptor; Phenotype; Population; Public Health; Receptor Activation; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Screening procedure; Signal Transduction; Structure of respiratory epithelium; System; Testing; Toll-like receptors; United States; Vaccination; Vaccine Adjuvant; Vaccines; Viral; Viral Antigens; Viral Vaccines; Virus; Virus Diseases; Visit; asthmatic patient; base; care systems; cockroach allergen; cost effective; immunogenic; immunogenicity; in vivo; influenza virus vaccine; mortality; mouse model; mucosal vaccination; pathogen; prevent; reconstitution; respiratory; respiratory virus; response; vaccine candidate; vaccine development; vaccine-induced immunity

DESCRIPTION (provided by applicant): Viral exacerbation of allergic lung disease is a significant cause of morbidity and mortality in asthmatics of all ages. Each year in the United States, asthma exacerbation accounts for 2 million emergency department visits, and 500,000 hospitalizations, and the overwhelming majority of severe asthma exacerbations in both children and adults are associated with respiratory viral infections. Vaccination is among the most cost- effective methods of reducing the burden of infectious disease. Thus, safe and effective vaccination of asthmatics against respiratory viruses would be of tremendous public health benefit. In the proposed studies, we will refine a candidate intranasal, inactivated respiratory syncytial virus (RSV) vaccine. We have selected RSV as a model pathogen based on its association with asthmatic disease, limited genetic variability, as well as the suitability of animal models. Our previous studies that this vaccine promotes protective immunity to RSV, without promoting vaccine enhanced disease observed with other inactivated RSV vaccines. In the proposed studies, we will use a rational vaccine refinement approach to evaluate the potential of an inactivated, nasally administered viral vaccine to prevent or attenuate viral asthma exacerbation. Accumulating evidence suggests that the early signals generated by the innate immune system control the nature of the adaptive immune response to vaccination. However, little is known about which signals in resident airway cells are critical for protective vaccine induced immunity. We hypothesize that the innate immune response generated by resident airway epithelial cells and dendritic cells generates an immune "signature" of proinflammatory signals, which in turn, control the development of the adaptive immune response. Our studies will focus on the following Specific Aims: 1) Define the innate immune signals induced by live versus inactivated RSV in airway epithelial cells and dendritic cells, as well as select adjuvants. 2) Identify the in vitro vaccine induced signals associated with vaccine-mediated efficacy in vivo. 3) Assess the efficacy of inactivated intranasal vaccines in viral exacerbation of asthma. To investigate these aims, we will use a combination of well-characterized in vivo animal models, as well as in vitro studies using epithelial cells from carefully phenotyped healthy and asthmatic patients. PUBLIC HEALTH RELEVANCE: Viral exacerbation of asthma is a significant burden on asthmatic patients of all ages, and the heath care system in general. Vaccination is among the most cost-effective methods of reducing the burden of infectious disease. Currently, no vaccines are available for the majority of viruses implicated asthma exacerbation, and thus, safe and effective vaccination of asthmatics against respiratory viruses would be of tremendous public health benefit.

描述（由申请方提供）：过敏性肺病的病毒性加重是所有年龄段哮喘患者发病和死亡的重要原因。在美国，每年有200万人因哮喘急性发作急诊就诊，50万人住院治疗，绝大多数儿童和成人重度哮喘急性发作与呼吸道病毒感染有关。接种疫苗是减少传染病负担的最具成本效益的方法之一。因此，对哮喘患者进行安全有效的呼吸道病毒疫苗接种将具有巨大的公共卫生效益。在拟议的研究中，我们将完善候选鼻内，灭活呼吸道合胞病毒（RSV）疫苗。我们选择RSV作为模型病原体，是基于其与哮喘疾病的相关性、有限的遗传变异性以及动物模型的适用性。我们先前的研究表明，该疫苗可促进对RSV的保护性免疫，而不会促进其他灭活RSV疫苗观察到的疫苗增强疾病。在拟定的研究中，我们将使用合理的疫苗改良方法来评价灭活的经鼻给药病毒疫苗预防或减轻病毒性哮喘急性发作的潜力。越来越多的证据表明，先天免疫系统产生的早期信号控制着对疫苗接种的适应性免疫应答的性质。然而，很少有人知道，在居民气道细胞的信号是至关重要的保护性疫苗诱导的免疫。我们假设，固有的气道上皮细胞和树突状细胞产生的先天性免疫反应产生的免疫"签名"的促炎信号，这反过来又控制了适应性免疫反应的发展。我们的研究将集中在以下具体目的：1）定义气道上皮细胞和树突状细胞中由活RSV与灭活RSV诱导的先天免疫信号，以及选择佐剂。2)识别与疫苗介导的体内功效相关的体外疫苗诱导信号。3)评估鼻内灭活疫苗在病毒性哮喘急性发作中的疗效。为了研究这些目标，我们将使用一个良好的特点，在体内动物模型的组合，以及在体外研究中使用上皮细胞仔细表型健康和哮喘患者。 公共卫生相关性：病毒性哮喘急性发作对所有年龄段的哮喘患者和整个医疗保健系统都是一个重大负担。接种疫苗是减少传染病负担的最具成本效益的方法之一。目前，没有疫苗可用于大多数涉及哮喘急性发作的病毒，因此，针对呼吸道病毒的哮喘患者的安全有效的疫苗接种将具有巨大的公共卫生益处。