Vaccination Against RSV with Capsid-modified Ad Vectors

RSV感染是病毒性下呼吸道疾病的主要原因之一。可通过有效的疫苗接种策略实现针对RSV的保护，该策略诱导中和体液免疫和Th 1-显性细胞应答，并且不会使Th 2-显性疫苗诱导的严重RSV疾病易感。基于腺病毒（Ad）基因转移载体可用于引起针对表达为转基因的免疫原的稳健的全身和粘膜免疫以及Ad作为有效佐剂的功能的知识，该提议集中于使用修饰的Ad载体开发针对RSV的疫苗。Ad修饰包括向纤维球添加RGD基序，这是一种已知增强抗原呈递细胞感染和增强Th 1免疫力的修饰，以及将RSV表位掺入Ad衣壳中。为了评估即使在存在抗人Ad免疫的情况下是否可以引发抗RSV免疫，载体将基于非人灵长类动物血清型AdC 7，人类对其没有免疫力。将评估这些经修饰的载体在小鼠中诱导免疫力和针对RSV的保护的能力，特别关注潜在的疫苗增强的RSV肺病。两个具体目标概述了实现这些目标的研究。目标1.为了评估以下假设：经工程改造以增加抗原呈递细胞的活化和感染并且表达RSV F蛋白的优化的AdC 7载体作为转基因将在不引起疫苗诱导的RSV疾病的情况下并且在预先存在的人Ad免疫的情况下引起针对RSV的稳健的保护性免疫。目标2.为了评估以下假设，即经改造以在衣壳六邻体蛋白中含有RSV F和G蛋白的表位的经修饰的AdC 7载体（一种能够用相同载体加强免疫应答的策略）将引起针对RSV的稳健免疫而不诱发疫苗诱导的RSV肺病。

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.