Vaccination Against RSV with Capsid-modified Ad Vectors

使用衣壳修饰的广告载体进行 RSV 疫苗接种

• 批准号: 7654470
• 负责人: Stefan Worgall
• 金额: $ 42.23万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654470
• 关键词: Adenovirus Vector; Adenovirus hexon capsid protein; Adenoviruses; Adjuvant; Adult; Antigen-Presenting Cells; Antigens; Binding; CD8B1 gene; Capsid; Capsid Proteins; Cell membrane; Cells; Child; Clinical; Data; Dendritic Cells; Development; Disease; Effectiveness; Elderly; Engineering; Epithelial; Epitopes; Failure; Fiber; Formalin; GTP-Binding Proteins; Gene Transfer; Genes; Goals; Gold; HIV; Histology; Human; Human Adenoviruses; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Inbred BALB C Mice; Infant; Infection; Intramuscular; Knowledge; Liquid substance; Lower respiratory tract structure; Lung; Lung diseases; Marketing; Measures; Mediating; Modification; Mucosal Immunity; Mus; Neonatal; Nose; Peptides; Population; Proteins; RGD (sequence); Recombinants; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Role; Serotyping; Subunit Vaccines; Surface; T-Lymphocyte; Technology; Testing; Transgenes; United States National Institutes of Health; Vaccination; Vaccines; Viral; Virus; Virus Diseases; base; comparative; cytokine; gene transfer vector; genetic vaccine; immunogenicity; neutralizing antibody; nonhuman primate; prevent; response; vaccination strategy; vaccine development; vector

Infections with RSV are one of the major causes of viral lower respiratory tract illness. Protection against RSV may be achieved with an efficient vaccination strategy that induces neutralizing humoral immunity and a Th1-dominant cellular response and that does not predispose to Th2-dominant vaccine-induced exaggerated RSV disease. Based on the knowledge that adenovirus (Ad) gene transfer vectors can be used to evoke robust systemic and mucosal immunity against an immunogen expressed as a transgene and that Ad functions as a potent adjuvant, this proposal focuses on the development of a vaccine against RSV using modified Ad vectors. The Ad modifications include the addition of an RGD motif to the fiber knob, a modification known to enhance infection of antigen presenting cells and enhance Th1 immunity, as well as the incorporation of RSV epitopes into the Ad capsid. To assess if anti-RSV immunity can be elicited even in the presence of anti-human Ad immunity, the vectors will be based on the non-human primate serotype AdC7, against which humans do not have immunity. These modified vectors will be assessed for the ability to induce immunity and protection against RSV in mice, with particular focus on potential vaccine-enhanced RSV lung disease. Two specific aims outline the studies to achieve these goals. Aim 1. To evaluate the hypothesis that an optimized AdC7 vector, which is engineered to increase activation and infection of antigen presenting cells, and which expresses the RSV F protein, as a transgene, will evoke robust protective immunity against RSV without causing vaccine-induced RSV disease and in the context of pre-existing human Ad immunity. Aim 2. To evaluate the hypothesis that modified AdC7 vectors engineered to contain epitopes of the RSV F and G proteins in the capsid hexon protein, a strategy that enables boosting of the immune response with the identical vector, will evoke robust immunity against RSV without predisposing to vaccine-induced RSV lung disease.

RSV感染是病毒下呼吸道疾病的主要原因之一。可以通过有效的疫苗接种策略来实现对RSV的保护，该策略可诱导中和体液免疫力和Th1占主导地位的细胞反应，并且不容易诱发Th2-主导疫苗诱导的夸张的RSV疾病。基于以下知识：腺病毒（AD）基因转移载体可用于唤起针对以转基因表达的免疫原的稳健的全身性和粘膜免疫，并且AD作为有效的辅助剂的作用，该提案的重点是使用修饰的AD载体针对RSV的疫苗开发。 AD修饰包括在纤维旋钮中添加RGD基序，这是一种已知的修饰，可增强抗原呈递细胞的感染并增强Th1免疫力，以及将RSV表位掺入AD Capsid中。为了评估即使存在抗人AD免疫，抗RSV免疫是否也可以引起，矢量将基于非人类灵长类动物血清型ADC7，人类没有免疫力。这些修饰的向量将被评估，以诱导小鼠的免疫力和保护RSV的能力，特别关注潜在的疫苗增强RSV肺部疾病。两个具体的目的概述了实现这些目标的研究。目的1。为了评估以下假设：为了增加抗原呈递细胞的激活和感染而设计的优化ADC7载体，并且表达RSV F蛋白作为转基因的表达RSV F蛋白将引起对RSV的强劲保护免疫，而无需导致疫苗诱导的RSV疾病，而无需引起RSV疾病，并且在预先使用人类Ad Ad Immunity的情况下。目的2。要评估修饰的ADC7载体的假设，该假说设计为包含Capsid Hexon蛋白中RSV F和G蛋白的表位，该策略可以增强与相同的载体的免疫反应，将引起与RSV抗疫苗的强大免疫力，而无需触发RSV诱导的RSV LSV LSV LSV LSV LSV LSV LSV LSV LSSV。