A human cytomegalovirus-based immunotherapy for HIV-1

产品说明：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，设计用于最大覆盖进化枝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。在初始感染后，SI最终从受保护动物中清除，表明CMV载体可以在感染个体中提供治疗效果。CMV载体在多个方面是独特的：它们可以诱导和维持高水平的循环和组织驻留效应记忆T细胞，即使当载体在体内扩散缺陷时。此外，在不存在控制T细胞引发的病毒基因产物的情况下，CMV载体将T细胞诱导至非常规表位，包括MHC-II限制性CD 8 + T细胞。重要的是，CMV载体可以重复使用，并在CMV阳性宿主中使用，而不会损失免疫原性。HIV序列的多样性对HIV疫苗的设计提出了挑战。然而，与努力实现最广泛的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菌株进行定制。因此，在该提议中，我们将测试以下假设：与非定制方法相比，从含有针对给定HIV进化枝的T细胞表位覆盖而优化的HIV抗原的小疫苗组中选择的定制疫苗鸡尾酒在诱导“相关”T细胞应答方面是上级的。我们将使用新的算法来设计定制的抗原，最大限度地提高表位匹配，我们将把这些抗原插入到一个新的人CMV载体骨架开发的TomegaVax在第一阶段的建议。我们将使用最近开发的HCMV NHP模型监测针对特定HIV株的表位特异性T细胞应答。根据这些结果，我们将设计最终的疫苗鸡尾酒。为了促进按照药品生产质量管理规范（GMP）生产HCMV载体，我们将根据初步数据生成补充主细胞库，初步数据首次显示先前用于生产不相关病毒疫苗的细胞类型中的HCMV生长。完成本项目后，我们将设计、表征和开发生产策略，以生产临床级HCMV/HIV载体产品。

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.