Dendritic Cell Targeting of Anthrax Vaccine

描述（由申请方提供）：炭疽作为生物战剂构成重大威胁。目前的炭疽疫苗（AVA）需要在18个月内多次接种。因此，除了现有的疫苗，改进的炭疽疫苗策略将为公众健康提供。炭疽保护性抗原（PA）抗体在炭疽特异性免疫中起重要作用。然而，细胞介导的免疫应答也很重要。专职抗原呈递树突状细胞（DC）具有引发体液和细胞免疫应答的能力。这些细胞准备捕获病原体，迁移到引流淋巴结，并选择抗原特异性T细胞来调节T、B和NK细胞、巨噬细胞和嗜酸性粒细胞，所有这些都可能有助于保护性免疫。本提案的目的是开发一种新的疫苗策略，直接针对炭疽PA的DC。最近，我们已经表明，树突状细胞诱导显着的T细胞活化在体内和体外。此外，我们的初步数据表明，重组PA激活DC，诱导共刺激分子的上调，和LC体内迁移。我们已经从噬菌体展示文库中产生了与DC亚群特异性结合的肽。我们假设PA直接靶向DC将增加特异性免疫应答的水平和持续时间，从而更好地保护免受炭疽。因此，我们将通过将PA与DC特异性肽融合来将PA靶向DC。本发明的具体目的是：1.确定PA特异性靶向DC是否增强针对B的特异性免疫应答。炭疽PA和2：为了测试通过皮下施用递送的PA-DC肽融合蛋白是否在免疫感受态细胞中诱导强烈的免疫应答。这种通过DC结合肽将免疫原性PA特异性靶向DC的新疫苗策略可能增强PA的免疫原性，从而引发针对B的PA的更强免疫应答。炭疽病

DESCRIPTION (provided by applicant): Anthrax poses a significant threat as an agent of biological warfare. The current anthrax vaccine (AVA) requires multiple doses over an 18 month period. Therefore, in addition to the current vaccine, improved anthrax vaccine strategies will offer the public health. Antibodies to the protective antigen (PA) play an important role in specific immunity to anthrax. However, cell mediated immune responses are also important. Professional antigen presenting dendritic cells (DCs) possess the ability to elicit both humoral and cellular immune responses. These cells are poised to capture pathogens, migrate to draining lymph nodes, and select antigen-specific T cells to regulate T, B, and NK cells, macrophages and eosinophils, all of which may contribute to protective immunity. The objective of this proposal is to develop a novel vaccine strategy targeting anthrax PA directly to DCs. Recently we have shown that DCs induce significant T cell activation in vivo and in vitro. Moreover, our preliminary data demonstrate that recombinant PA activates DCs, inducing up-regulation of co-stimulatory molecules, and LC migration in vivo. We have generated peptides that specifically bind to DC subsets from a phage display library. We hypothesize that targeting PA directly to DCs will increase the levels and duration of a specific immune response resulting in better protection against anthrax. Thus, we will target PA to DCs by fusing it to DC-specific peptides. The specific aims of this proposal are 1: To determine whether targeting PA specifically to DCs enhances specific immune responses against B. anthracis PA and 2: To test whether PA-DC peptide fusion protein delivered by subcutaneous administration induces strong immune responses in the immune competent cells. This novel vaccine strategy to target specifically immunogenic PA to DCs via DC-binding peptides may enhance the immunogenicity of PA and thus elicit stronger immune responses against PA of B. anthracis.