Adenoviral-based vaccine platform to overcome neutralizing immunity

基于腺病毒的疫苗平台克服中和免疫

• 批准号: 8070415
• 负责人: ANDREA GAMBOTTO
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070415
• 关键词: A549; Address; Adenovirus Vector; Adenoviruses; Animal Model; Antibodies; Antigen-Presenting Cells; Antigens; Arginine; Biological Models; Cell Line; Cellular Immunity; Chemicals; Communicable Diseases; Complex; Coupled; Coupling; Data; Dendritic Cells; Development; Dose; Epitopes; Exhibits; General Population; Generations; Hemagglutinin; Heparan Sulfate Proteoglycan; Human; Human Adenoviruses; Humoral Immunities; Immune; Immune response; Immunity; Immunization; In Vitro; Inbred BALB C Mice; Influenza; Influenza Hemagglutinin; Light; Malignant Epithelial Cell; Measurable; Modeling; Mus; Names; Phase; Prevalence; Proteins; Public Health; Recombinant Vaccines; Route; Serotyping; T cell response; Testing; Therapeutic Uses; Vaccinated; Vaccination; Vaccines; base; cell type; immunogenicity; in vivo; lung Carcinoma; mouse model; neutralizing antibody; nonhuman primate; novel; particle; public health relevance; receptor; research clinical testing; response; vaccine development; vector; vector-based vaccine; vector-induced

DESCRIPTION (provided by applicant): The potential therapeutic use of adenoviral vector platforms for vaccine applications is considerable. An adenoviral-based vaccine platform offers several advantages over other vaccine platforms, but a few important limitations currently hamper its optimal implementation as a pharmacological agent. The most relevant limitation is host pre- existing immunity against the vector, which, when present, mitigates the immunogenicity of Ad5 vector-based vaccines. Even in hosts in which such responses are initially absent, anti-vector immunity is developed soon after vector application, thereby limiting the efficiency of homologous boost immunizations or heterologous vaccine products based on this same platform. Several strategies have been attempted to overcome such neutralizing immunity. Here, we propose to use adenovirus-specific antibodies in order to overcome pre-existing immunity. Recently, we have chemically coupled mouse and human polyclonal adenovirus-specific antibodies with poly-arginine, which serves as a protein transduction domain (PTD), to generate complex adenovirus-antibody particles that we have named adenobodies. When the antibody-PTD conjugated reacts with adenoviral particles, they engage the epitopes targeted by neutralizing antibodies and redirect the entry of adenoviral particles thru the heparan sulfate proteoglycans receptors expressed by several cell types, including antigen presenting cells (APCs). Our preliminary studies show that replication-incompetent adenovirus serotype 5-complex adenobodies are able, in this format, to overcome neutralizing immunity and infect lung carcinoma cell line A549 and human dendritic cells in vitro. In light of these observations, we hypothesize that adenoviral vectors carrying antigen, when coupled with PTD-modified anti-adenovirus antibodies, will be able to overcome pre-existing neutralizing immunity in vivo and stimulate specific humoral and cellular immunity directed against the vaccine-incorporated antigen(s). To address this hypothesis, we will use influenza hemagglutinin (HA) as a model antigen to test the ability of adenobodies to efficiently vaccinate mice that exhibit existing neutralizing reactivity against adenovirus and to study specific immunity, as well as, mechanisms that underline immune responsiveness to vaccination. PUBLIC HEALTH RELEVANCE: The potential contribution of an effective vaccine platform applicable to several infectious disease targets is invaluable to public health. We propose to develop a vaccine platform that is capable of inducing a prolonged and specific immune response to an H5N1avian influenza infection. This study will be performed in an animal model system; however, if successful, the results may be a prelude to Phase I clinical testing in humans.

描述（由申请人提供）：腺病毒载体平台在疫苗应用中的潜在治疗用途是相当可观的。与其他疫苗平台相比，基于腺病毒的疫苗平台具有多种优势，但目前一些重要的限制阻碍了其作为药物制剂的最佳实施。最相关的限制是宿主对载体预先存在的免疫力，当存在时，会减轻基于 Ad5 载体的疫苗的免疫原性。即使在最初不存在此类反应的宿主中，在应用载体后很快就会产生抗载体免疫，从而限制了同源加强免疫或基于同一平台的异源疫苗产品的效率。已经尝试了几种策略来克服这种中和免疫力。在这里，我们建议使用腺病毒特异性抗体来克服预先存在的免疫力。最近，我们将小鼠和人类多克隆腺病毒特异性抗体与聚精氨酸（作为蛋白质转导结构域（PTD））进行化学偶联，以产生复杂的腺病毒抗体颗粒，我​​们将其命名为腺体。当抗体-PTD缀合物与腺病毒颗粒反应时，它们与中和抗体靶向的表位结合，并通过多种细胞类型（包括抗原呈递细胞（APC））表达的硫酸乙酰肝素蛋白聚糖受体重新引导腺病毒颗粒的进入。我们的初步研究表明，复制无能的腺病毒血清型5复合体腺体能够以这种形式克服中和免疫并在体外感染肺癌细胞系A549和人树突状细胞。根据这些观察结果，我们假设携带抗原的腺病毒载体与 PTD 修饰的抗腺病毒抗体结合时，将能够克服体内预先存在的中和免疫，并刺激针对疫苗掺入的特异性体液和细胞免疫抗原。为了解决这一假设，我们将使用流感血凝素（HA）作为模型抗原来测试腺体有效接种具有针对腺病毒的现有中和反应性的小鼠的能力，并研究特异性免疫以及强调对腺病毒的免疫反应的机制。疫苗接种。 公共卫生相关性：适用于多种传染病目标的有效疫苗平台的潜在贡献对公共卫生而言是无价的。我们建议开发一种疫苗平台，能够针对 H5N1 禽流感感染诱导长期且特异性的免疫反应。这项研究将在动物模型系统中进行；然而，如果成功，结果可能会成为人体一期临床测试的前奏。