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。对RSV的保护可以通过有效的疫苗接种策略来实现，该策略可以诱导中和性体液免疫和th1显性细胞反应，并且不会导致th2显性疫苗诱导的夸大的RSV疾病。基于腺病毒（Ad）基因转移载体可用于引起针对转基因表达的免疫原的强大的全身和粘膜免疫以及Ad作为一种有效的佐剂的知识，本建议侧重于使用修饰的Ad载体开发针对RSV的疫苗。Ad修饰包括在纤维突起上添加RGD基序，这种修饰已知可增强抗原呈递细胞的感染并增强Th1免疫，以及将RSV表位整合到Ad衣壳中。为了评估即使存在抗人类Ad免疫，是否也能引起抗rsv免疫，载体将基于非人类灵长类动物血清型AdC7，人类对其没有免疫力。将评估这些改良载体在小鼠中诱导免疫和保护RSV的能力，特别关注疫苗增强的潜在RSV肺部疾病。两个具体目标概述了实现这些目标的研究。目的1。为了评估优化的AdC7载体的假设，该载体被设计为增加抗原呈递细胞的激活和感染，并表达RSV F蛋白，作为一个转基因，将在不引起疫苗诱导的RSV疾病的情况下，在预先存在的人类Ad免疫的背景下，唤起对RSV的强大保护性免疫。目标2。为了评估经过修饰的AdC7载体在衣壳六元蛋白中含有RSV F和G蛋白的表位的假设，一种能够增强相同载体免疫反应的策略，将激发对RSV的强大免疫，而不会诱发疫苗诱导的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.