Vaccination Against RSV with Capsid-modified Ad Vectors

呼吸道合胞病毒感染是病毒性下呼吸道疾病的主要原因之一。对RSV的保护可以通过一种有效的疫苗接种策略来实现，该策略诱导中和体液免疫和Th1显性细胞反应，并且不容易发生Th2显性疫苗诱导的夸大RSV疾病。基于腺病毒(Ad)基因转移载体可以激发对以转基因表达的免疫原的强大的系统和粘膜免疫，以及Ad作为一种有效的佐剂的知识，本建议致力于利用改良的Ad载体开发针对RSV的疫苗。Ad修饰包括在纤维结节上添加RGD基序，这种修饰可以增强抗原提呈细胞的感染和增强Th1免疫，以及将RSV表位整合到Ad衣壳中。为了评估即使在存在抗人Ad免疫的情况下是否也能诱导抗RSV免疫，载体将基于非人类灵长类血清型AdC7，而人类对AdC7没有免疫力。这些修改后的载体将被评估在小鼠身上诱导免疫和预防RSV的能力，特别是对潜在的疫苗增强型RSV肺部疾病的评估。两个具体目标概述了为实现这些目标而进行的研究。目的1.评价一种优化的AdC7载体，它被设计成增加抗原提呈细胞的激活和感染，并以转基因的形式表达RSV F蛋白，在不引起疫苗诱导的RSV疾病的情况下，在现有的人类Ad免疫的背景下，对RSV产生强大的保护性免疫。目的2.评估一种假设，即改良的AdC7载体在衣壳六邻体蛋白中含有RSV F和G蛋白的表位，该策略能够增强对RSV的免疫应答，而不会导致疫苗引起的RSV肺部疾病。

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.