A human cytomegalovirus-based immunotherapy for HIV-1

基于人类巨细胞病毒的 HIV-1 免疫疗法

• 批准号: 8852050
• 负责人: ERIC BRUENING
• 金额: $ 98.65万
• 依托单位: TOMEGAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852050
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Algorithms; Animal Model; Animals; Anti-Retroviral Agents; Antigens; Antiviral Agents; CD8B1 gene; Cell Line; Cells; Clinical; Clinical Trials; Complement; Computational algorithm; Congenital Abnormality; Cytomegalovirus; Data; Development; Disease; Engineering; Epitopes; Escape Mutant; Exposure to; Fetus; Frequencies; Goals; Growth; HIV; HIV vaccine; HIV-1; Health; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunotherapy; In Vitro; Individual; Infection; Life; Light; Macaca mulatta; Mediating; Modeling; Molecular Cloning; Monitor; Patients; Peripheral; Pharmacotherapy; Phase; Preparation; Proteins; Publications; Research; SIV; Safety; Series; Site; Small Business Innovation Research Grant; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; Target Populations; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Tropism; Vaccinated; Vaccine Design; Vaccines; Variant; Vertebral column; Viral; Viral Antigens; Viral Proteins; Viral Vaccines; Virulent; Virus; Work; base; cell bank; cell type; design; dosage; effective therapy; fight against; immunogenic; immunogenicity; immunosuppressed; improved; in vivo; innovation; nonhuman primate; novel; pandemic disease; prevent; programs; prophylactic; research clinical testing; response; secondary infection; standard of care; therapeutic vaccine; vaccine development; vector; vector vaccine; vector-based vaccine; vector-induced

DESCRIPTION: The ultimate goal of this project is to develop an immunotherapy for human immunodeficiency virus (HIV)-1 based on a spread-deficient cytomegalovirus (CMV)-derived vaccine expressing "tailored" antigens designed for maximal coverage of clade B epitopes. In non-human primate models, rhesus CMV-vectored vaccines demonstrated unprecedented protection against highly virulent simian immunodeficiency virus (SIV). After initial infection, SI was ultimately cleared from protected animals suggesting that CMV-vectors can provide a therapeutic effect in infected individuals. CMV vectors are unique in multiple aspects: they can induce and maintain high levels of circulating and tissue-resident effector memory T cells even when vectors are spread-deficient in vivo. Moreover, in the absence of viral gene products that control T cell priming, CMV vectors induce T cells to unconventional epitopes including MHC-II restricted CD8+ T cells. Importantly, CMV vectors can be used repeatedly and in CMV-positive hosts without loss of immunogenicity. HIV sequence diversity poses a challenge to HIV vaccine design. However, unlike prophylactic vaccines which strive to achieve the broadest possible coverage of HIV sub-species, therapeutic vaccines can be tailored towards the actual strains present in an infected individual. In this proposal, we will therefore test the hypothesis that a tailored vaccine cocktail selected from a small vaccine panel containing HIV antigens optimized for T cell epitope coverage of a given HIV clade are superior with respect to inducing "relevant" T cell responses as compared to non-tailored approaches. We will use novel algorithms to design tailored antigens that maximize epitope-matches and we will insert these antigens into a new human CMV-vector backbone developed at TomegaVax during phase I of this proposal. We will monitor epitope specific T cell responses against specific HIV-strains using a recently developed NHP model for HCMV. Based on these results, we will design our final vaccine cocktail. To facilitate manufacturing of HCMV vectors under good manufacturing practices (GMP) we will generate a complementing master cell bank based on preliminary data showing, for the first time, HCMV growth in a cell type previously used for the manufacturing of unrelated viral vaccines. Upon completion of this project, we will have a designed, characterized, and developed a manufacturing strategy to generate clinical grade HCMV/HIV vector products.

描述：该项目的最终目标是开发一种基于传播缺陷型巨细胞病毒 (CMV) 衍生疫苗的人类免疫缺陷病毒 (HIV)-1 免疫疗法，该疫苗表达“定制”抗原，旨在最大限度地覆盖进化枝 B 表位。在非人灵长类动物模型中，恒河猴 CMV 载体疫苗表现出前所未有的针对高毒力猿猴免疫缺陷病毒 (SIV) 的保护作用。初次感染后，SI 最终从受保护动物中清除，表明 CMV 载体可以为感染个体提供治疗效果。 CMV 载体在多个方面都是独特的：即使载体在体内传播缺陷，它们也可以诱导并维持高水平的循环和组织驻留效应记忆 T 细胞。此外，在缺乏控制 T 细胞启动的病毒基因产物的情况下，CMV 载体会诱导 T 细胞进入非常规表位，包括 MHC-II 限制性 CD8+ T 细胞。重要的是，CMV 载体可以在 CMV 阳性宿主中重复使用，而不会丧失免疫原性。 HIV序列多样性对HIV疫苗设计提出了挑战。然而，与努力实现尽可能广泛的 HIV 亚种覆盖的预防性疫苗不同，治疗性疫苗可以针对感染个体中存在的实际毒株进行定制。因此，在本提案中，我们将测试以下假设：与非定制方法相比，从包含针对给定 HIV 进化枝的 T 细胞表位覆盖而优化的 HIV 抗原的小型疫苗组中选择的定制疫苗混合物在诱导“相关”T 细胞反应方面更优越。我们将使用新颖的算法来设计定制抗原，以最大限度地实现表位匹配，并将这些抗原插入到 TomegaVax 在本提案第一阶段开发的新人类 CMV 载体主干中。我们将使用最近开发的 HCMV NHP 模型来监测针对特定 HIV 毒株的表位特异性 T 细胞反应。根据这些结果，我们将设计最终的疫苗混合物。为了促进在良好生产规范 (GMP) 下制造 HCMV 载体，我们将根据初步数据生成一个补充主细胞库，该数据首次显示 HCMV 在先前用于制造不相关病毒疫苗的细胞类型中生长。该项目完成后，我们将设计、表征和开发生产策略，以生成临床级 HCMV/HIV 载体产品。