E1 DELETED ADENOVIRAL HIV RECOMBINANT AS MUCOSAL VACCINE

E1 缺失腺病毒 HIV 重组体作为粘膜疫苗

• 批准号: 2887888
• 负责人: Hildegund C. J. Ertl
• 金额: $ 24.46万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887888
• 关键词: AIDS vaccines; Adenoviridae; HIV envelope protein gp120; Macaca mulatta; cellular immunity; cytokine; drug administration routes; human immunodeficiency virus 1; humoral immunity; immunization; laboratory mouse; mucosal immunity; plasmids; recombinant virus; simian immunodeficiency virus; vaccine development; vector vaccine

DESCRIPTION (Adapted from applicant's abstract): The aim of this application is to test the suitability of El-deleted adenoviral recombinants to serve as vaccine carriers for mucosal immunization to HIV-1. Such recombinants induce potent central T and B cell mediated immune responses to the transgene product upon systemic inoculation or upon application to mucosal surfaces. They also induce immunity at distant mucosal sites, including the genital tract, especially after application to the airways. The magnitude of the mucosal immune response can be augmented by using prime-boost regimens. In order to test if El-deleted adenoviral recombinants are suitable to induce genital immunity to HIV-1, the applicants propose in the first aim to construct El-deleted adenoviral recombinants and plasmid vectors expressing either the gpl20 of the HIV(IIIB) or of the HIV (89.6P) strain. Upon in vitro analysis, the adenoviral construct expressing gpl20 of the HIV(IIIB) strain will be tested in mice for induction of mucosal B and T cell responses to HIV-1. Prime-boost experiments using the adenoviral recombinant, either alone or in combination with a DNA vaccine expressing the same antigen, will be conducted to enhance and prolong the genital immune response. Provided these studies show induction of good immunity to HIV-1 in the mouse model, the applicant will then in the 3rd aim, in collaboration with Dr. N. Letvin, conduct a limited trial in rhesus monkeys using the adenoviral recombinant expressing the gpl20 of HIV(89.6P) virus for which a challenge model is available. In the 4th aim the applicant will attempt, using the mouse model, to enhance the magnitude and duration of the mucosal immune response to HIV- 1 by using genetic adjuvants, i.e., plasmid vectors expressing mouse cytokines, for priming with the DNA vaccine followed by an i.n. booster immunization with the adenoviral recombinant. Again, these studies will be conducted with constructs expressing gpl20 of the HIV(IIIB) strain.

描述（改编自申请人的摘要）：此目的 应用是测试El缺失腺病毒重组体的适用性 作为HIV-1粘膜免疫的疫苗载体。 这样的 重组体诱导有效的中枢 T 和 B 细胞介导的免疫反应 全身接种或施用后的转基因产物 粘膜表面。 它们还能诱导远处粘膜部位的免疫力， 包括生殖道，尤其是在气道上使用后。 粘膜免疫反应的强度可以通过使用来增强 初免-加强方案。 为了测试El缺失的腺病毒重组体是否适合 诱导对 HIV-1 的生殖器免疫力，申请人在第一个目标中提出 构建E1缺失的腺病毒重组体和表达的质粒载体 HIV(IIIB) 或 HIV (89.6P) 毒株的 gpl20。 当在 体外分析，表达 HIV (IIIB) gpl20 的腺病毒构建体 菌株将在小鼠中进行粘膜 B 和 T 细胞诱导测试 对 HIV-1 的反应。 使用腺病毒进行初免-加强实验 重组，单独或与表达 DNA 疫苗组合 相同的抗原，将进行增强和延长生殖器 免疫反应。 如果这些研究表明可以诱导良好的免疫力 小鼠模型中的 HIV-1，申请人将在第三个目标中， 与 N. Letvin 博士合作，在恒河猴中进行有限试验 使用表达HIV(89.6P)病毒gpl20的腺病毒重组体 对此有一个挑战模型可用。 在第四个目标中，申请人将 尝试使用小鼠模型来增强 使用遗传佐剂（即质粒）对 HIV-1 产生粘膜免疫反应 表达小鼠细胞因子的载体，用于启动 DNA 疫苗 后面跟着一个 i.n.用重组腺病毒进行加强免疫。 同样，这些研究将使用表达 gpl20 的构建体进行 HIV(IIIB)毒株。