Multi-component HIV Vaccines Using Engineered Envelopes

使用工程包膜的多成分 HIV 疫苗

• 批准号: 6531304
• 负责人: Susan W Barnett
• 金额: $ 189.41万
• 依托单位: NOVARTIS VACCINES AND DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6531304
• 关键词: AIDS vaccines; HIV envelope protein; protein engineering; vaccine development

DESCRIPTION (provided by applicant): The goal of the proposed research is to design a multi-component HIV-1 vaccine with a rationally-designed envelope (Env) antigen that can induce durable protective immunity against homologous and heterologous virus challenges in the SHIV/rhesus macaque model. Three antigenic components, Env, Gag, and Pol, will be utilized to induce an array of effector mechanisms to facilitate the most broadly protective responses. These antigens have been chosen to cover the spectrum of targets that may be desirable in an effective vaccine: Env, for protective antibody responses; Gag and Pol for protective cellular responses against a conserved viral antigen. The expression, formulation, and delivery of these antigens will be pursued by state-of4he art approaches. Vaccines will be delivered as adjuvanted (ISCOMS) or formulated proteins (on microparticles) or peptides (for Env antigens) or as DNA vaccines delivered adsorbed to polylactide coglycolide (PLG) microparticles or by electroporation, or as combinations thereof. Both parenteral and mucosal routes of vaccine administration will be tested. The program comprises 2 projects and 2 scientific cores. Both projects will focus on the design, production, and formulation of novel HIV Env immunogens for the induction of broadly reactive neutralizing antibodies that will then be supplemented with Gag and Pol antigens. Env antigen designs will be based on current structural information regarding HIV-1 envelope glycoprotein and its interactions with host cell receptors during virus binding, entry, and fusion. Project 1 will focus on novel immunogens that are structurally modified to expose important conserved epitopes through deletions of variable (V)-regions and "bridging-sheet" structures in the Env surface glycoprotein; this project will also evaluate Env proteins complexed to CD4 miniproteins. Project 2 will evaluate multivalent and primeboost strategies using ISCOM formulated proteins and conserved mimotope and/or peptide boosts. Both subtype B and non-subtype B HIV-1 envelopes will be studied. The scientific cores will be: the Vaccine Technologies Core (Core B) and the Primate Models/Virology and Immunology Core (Core C). This program structure should provide for the performance of well-controlled comparative evaluations in primates of the proposed vaccines. These efforts are expected to lead to the selection of a strong candidate vaccine regimen for future clinical evaluations.

描述（由申请人提供）：拟议研究的目标是设计一种多组分 HIV-1 疫苗，其具有合理设计的包膜 (Env) 抗原，可诱导持久的保护性免疫，抵抗 SHIV/恒河猴模型。三种抗原成分，Env、Gag 和 Pol，将用于诱导一系列效应机制，以促进最广泛的保护性反应。选择这些抗原是为了涵盖有效疫苗中可能需要的靶标范围：Env，用于保护性抗体反应； Gag 和 Pol 用于针对保守病毒抗原的保护性细胞反应。这些抗原的表达、配制和递送将通过最先进的方法进行。疫苗将以佐剂（ISCOMS）或配制蛋白（在微粒上）或肽（针对Env抗原）的形式递送，或以吸附到聚丙交酯共乙交酯（PLG）微粒上或通过电穿孔递送的DNA疫苗递送，或其组合。疫苗注射的肠胃外和粘膜途径都将进行测试。该计划包括 2 个项目和 2 个科学核心。这两个项目将重点关注新型 HIV Env 免疫原的设计、生产和配制，用于诱导广泛反应性中和抗体，然后补充 Gag 和 Pol 抗原。 Env 抗原设计将基于有关 HIV-1 包膜糖蛋白及其在病毒结合、进入和融合过程中与宿主细胞受体相互作用的当前结构信息。项目1将重点关注新型免疫原，这些免疫原经过结构修饰，通过删除Env表面糖蛋白中的可变（V）区和“桥接片”结构来暴露重要的保守表位；该项目还将评估与 CD4 微型蛋白复合的 Env 蛋白。项目 2 将使用 ISCOM 配制的蛋白质和保守的模拟表位和/或肽增强来评估多价和 primeboost 策略。 B 亚型和非 B 亚型 HIV-1 包膜都将被研究。科学核心将是：疫苗技术核心（核心B）和灵长类动物模型/病毒学和免疫学核心（核心C）。该计划结构应能够在灵长类动物中对拟议疫苗进行良好控制的比较评估。预计这些努力将为未来的临床评估选择强有力的候选疫苗方案。