A human cytomegalovirus-based immunotherapy for HIV-1

基于人类巨细胞病毒的 HIV-1 免疫疗法

基本信息

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
项目类别：
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

项目摘要

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基于扩散缺陷的巨细胞病毒（CMV）衍生的疫苗，开发人类免疫缺陷病毒（HIV）-1的免疫疗法，该疫苗表达了“量身定制的”抗原，该抗原旨在最大程度地覆盖进化枝B的覆盖范围。在非人类灵长类动物模型中，恒河神CMV载体的疫苗表现出对高毒性邻近免疫缺陷病毒（SIV）的前所未有的保护。最初感染后，最终从受保护的动物中清除了SI，这表明CMV媒介可以在感染的个体中提供治疗作用。 CMV矢量在多个方面都是独特的：即使在体内矢量不足，它们也可以诱导和维持高水平的循环和组织效应的记忆T细胞。此外，在没有控制T细胞启动的病毒基因产物的情况下，CMV载体会诱导T细胞对包括MHC-II受限的CD8+ T细胞在内的非常规的表位。重要的是，CMV载体可以反复使用，并且可以在CMV阳性宿主中使用，而不会丧失免疫原性。 HIV序列多样性对HIV疫苗设计构成了挑战。但是，与努力达到最广泛的HIV亚种覆盖率的预防性疫苗不同，可以将治疗性疫苗定制为受感染者中存在的实际菌株。因此，我们将测试以下假设：从一个针对给定HIV枝的T细胞表位覆盖中优化的含有HIV抗原的小型疫苗鸡尾酒，相对于诱导“相关”的T细胞反应，与非计算方法相比，它优越。我们将使用新颖的算法来设计量身定制的抗原，以最大化表位匹配，并将这些抗原插入本提案的I期在Tomegavax上开发的新的人类CMV-vector骨架。我们将使用最近开发的HCMV的NHP模型来监视针对特定的HIV - 结构的表位特异性T细胞反应。基于这些结果，我们将设计最终的疫苗鸡尾酒。为了促进在良好的制造实践（GMP）下制造HCMV载体（GMP），我们将基于初步数据生成互补的细胞库，这是先前用于制造无关病毒疫苗的细胞类型的HCMV增长。该项目完成后，我们将采用设计，表征和制定制造策略，以生成临床级HCMV/HIV矢量产品。