Modulating the immune response to adenovirus vectors through NF-kB/IRF3 activatio

说明(申请人提供)：尽管疫苗在限制传染病传播方面取得了巨大成功，但针对艾滋病毒等主要人类病原体的疫苗开发仍有大量未得到满足的需求。在这种背景下，表达靶抗原的复制缺陷的5型腺病毒载体(ADV)疫苗因其相对安全和诱导体液和细胞介导性反应的能力而受到相当大的关注。宿主对感染性物质或疫苗的反应需要高度保守的先天免疫诱导模式识别受体(PRR)，包括Toll样受体(TLRs)和Rig-I样受体。尽管存在多个PRR，但只有少数细胞内途径被认为对PRR诱导宿主反应至关重要。其中的关键是属于核因子-kB和IRF家族的转录因子。因此，这些转录因子在促进免疫反应方面起到了细胞内佐剂的作用。这里提出的研究的主要目标是确定是否可以通过表达关键的细胞内佐剂来增强ADV的疫苗潜力。为此，这里提出的研究将系统地评估激活核因子-kB和IRF通路的不同关键分子的佐剂潜力和作用机制。如果成功，我们的研究将对未来针对传染病和癌症的ADV疫苗和潜在的非ADV疫苗的设计产生重大影响。提出了两个具体目标。目的1：表达不同细胞内佐剂的ADV的构建、体外和体内鉴定。目的：明确1型干扰素在细胞内佐剂增强ADV免疫应答中的作用。

DESCRIPTION (provided by applicant): Despite the tremendous success of vaccines in limiting the spread of infectious diseases, there remains a large unmet need for development of vaccines against major human pathogens such as HIV. Within this context, replication-deficient type 5 adenovirus vector (AdV) vaccines expressing target antigens have received considerable attention because of their relative safety and ability to induce humoral and cell-mediated responses. Host responses against infectious agents or vaccines require highly conserved innate immunity-inducing pattern recognition receptors (PRR), including Toll-like Receptors (TLRs) and RIG-I-like receptors. Despite the presence of multiple PRR, only a few intracellular pathways are thought to be critically important for induction of host responses by PRR. Key amongst them are transcription factors belonging to the NF-kB and IRF families. These transcription factors therefore serve as intracellular adjuvants in promoting immune responses. The main goal of studies proposed here is to determine whether the vaccine potential of AdV can be enhanced through expression of key intracellular adjuvants. To this end, the studies proposed here will systematically evaluate the adjuvant potential and mechanism of action of different key molecules that activate NF-kB and IRF pathways. If successful, our studies can have a major impact on the future design of AdV and potentially non-AdV vaccines for both infectious diseases and cancer. Two specific aims are proposed. Aim 1: Generation, in vitro and in vivo characterization of AdV expressing distinct intracellular adjuvants. Aim 2: Defining the role of type 1 IFN in intracellular adjuvant-induced enhancement of AdV immune responses.