Immunologic and Virologic Basis of RhCMV/SIV Vaccine-Induced Replication Arrest Efficacy

RhCMV/SIV 疫苗诱导复制抑制功效的免疫学和病毒学基础

• 批准号: 10709002
• 负责人: Louis J. Picker
• 金额: $ 503.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709002
• 关键词: AIDS prevention; Animals; Applications Grants; Autopsy; Bioinformatics; Biotechnology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cercopithecine Herpesvirus 1; Characteristics; Communicable Diseases; Cytomegalovirus; DNA; E protein; Electroporation; Epitopes; Experimental Models; Extinction; Frequencies; Future; Genetic Programming; HIV; HIV vaccine; HIV/AIDS; HIV/SIV vaccine; Haplotypes; Herpesviridae; Human; Immune; Immune response; Immunobiology; Immunologics; Immunotherapy; Infection; Interleukin-15; Macaca mulatta; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Memory; Modeling; Mucous Membrane; Myeloid Cells; Natural Killer Cells; Nature; Pathogenicity; Pattern; Phase; Phase I/II Trial; Phenotype; Population; Process; Publishing; Research; Rhesus; Role; SIV; SIV Vaccines; Signal Transduction; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Vaccinated; Vaccination; Vaccines; Viral; Viral Vector; Viremia; Virus; Virus Replication; Whole Blood; Work; adaptive immune response; clinical development; clinical efficacy; clinical translation; cost; cost effective; data management; efficacy evaluation; efficacy trial; immunogenicity; immunoregulation; in vivo; interest; novel; pandemic disease; programs; research clinical testing; response; therapeutic development; transcriptomics; transmission process; vaccine development; vaccine efficacy; vaccine evaluation; vector; vector induced; vector vaccine; vector-based vaccine

OVERALL - PROJECT SUMMARY Almost 2 decades ago our research group began development of vaccine vectors based on the persistent β- herpesvirus Cytomegalovirus (CMV) because of the ability of CMV to elicit and indefinitely maintain high frequency, effector-differentiated T cell responses in diverse tissues. Using the rhesus macaque (RM) model, we have demonstrated that not only do RhCMV/SIV vaccines provide superior efficacy against highly pathogenic SIV challenge than conventional SIV vaccines (in aggregate, 59% of RhCMV/SIV vaccinated RM with abrogation of progressive SIV infection), this efficacy is of an entirely new pattern – early SIV replication arrest followed by eventual viral clearance – and is mediated by a novel immune response – MHC-E-restricted, effector memory- differentiated CD8+ T cells (which to date can only be elicited by CMV vectors with specific genetic programming). We also know that the efficacy of MHC-E targeted CD8+ T cell responses is predicted by a whole blood transcriptomic signature featuring IL-15 signaling, but the mechanisms responsible for complete arrest and subsequent clearance of nascent SIV infection are not defined, including the questions of why MHC-E-restricted epitope recognition is required for efficacy, how these cells mediate replication arrest, and how the protective whole blood transcriptomic signature influences these unique effector responses. In this program, we seek to both answer these questions and develop detailed criteria for “replication arrest” efficacy for guiding ongoing phase I/II clinical testing of human CMV/HIV vaccines. The proposed program will include the following 3 projects: 1) Immunologic and virologic characterization of RhCMV/SIV vaccine-mediated SIV “replication arrest” efficacy, 2) Characterization of the in vivo T cell (and overall immune) interception of primary SIV infection after vaccination with differentially response programmed RhCMV/SIV vectors (MHC-E- vs. MHC-II- vs. MHC-Ia- restricted) and a conventional prime-boost SIV vaccine (MHC-Ia-restricted), and 3) Determination of the minimal MHC-E-restricted SIV epitope targeting required for RhCMV/SIV vaccine-mediated SIV “replication arrest” efficacy. These projects will be supported by 4 cores: A) Administration, B) NHP, C) Advanced Spatial Analysis, and D) `Omics, Bioinformatics, and Data Management. In addition to guiding current and future clinical testing of HMCV/HIV vaccines, the understanding the immunologic basis of “SIV replication arrest” efficacy and the role of MHC-E-restricted CD8+ T cells in this process will have broad implications for HIV cure approaches, as well as inform the use of MHC-E-restricted CD8+ T cells as universal (MHC haplotype independent) effectors for immunotherapies directed at other infectious diseases or cancer.

总体 - 项目概要 大约二十年前，我们的研究小组开始开发基于持久性β-的疫苗载体 疱疹病毒 巨细胞病毒 (CMV)，因为 CMV 能够引发并无限期维持高水平 使用恒河猴 (RM) 模型，观察不同组织中的效应分化 T 细胞反应的频率。 我们已经证明，RhCMV/SIV 疫苗不仅能够针对高致病性病原体提供卓越的功效 与传统 SIV 疫苗相比，SIV 挑战更大（总计 59% 的 RhCMV/SIV 疫苗 RM 被废除） 进行性 SIV 感染），这种功效是一种全新的模式——早期 SIV 复制停滞，随后 最终的病毒清除——由一种新型免疫反应介导——MHC-E限制性效应记忆—— 分化的 CD8+ T 细胞（迄今为止只能由具有特定遗传编程的 CMV 载体诱导）。 我们还知道，MHC-E 靶向 CD8+ T 细胞反应的功效是通过全血预测的 以 IL-15 信号传导为特征的转录组特征，但负责完全抑制和 新生 SIV 感染的后续清除尚未定义，包括为什么 MHC-E 限制的问题 表位识别是功效所必需的，这些细胞如何介导复制停滞，以及保护性细胞如何 全血转录组特征影响这些独特的效应器反应。 两者都回答了这些问题，并制定了“复制抑制”功效的详细标准，以指导正在进行的研究 人类 CMV/HIV 疫苗的 I/II 期临床测试 拟议的计划将包括以下 3 项。 项目： 1) RhCMV/SIV 疫苗介导的 SIV“复制停滞”的免疫学和病毒学特征 功效，2) 体内 T 细胞（和整体免疫）拦截原发性 SIV 感染后的表征 使用差异反应编程的 RhCMV/SIV 载体（MHC-E- vs. MHC-II- vs. MHC-Ia-）进行疫苗接种 限制）和传统的初免-加强 SIV 疫苗（MHC-Ia 限制），以及 3) 确定最小 RhCMV/SIV 疫苗介导的 SIV“复制停滞”所需的 MHC-E 限制性 SIV 表位靶向 这些项目将由 4 个核心支持：A) 管理，B) NHP，C) 高级空间分析， D) 除了指导当前和未来的临床测试之外，还包括组学、生物信息学和数据管理。 HMCV/HIV 疫苗，了解“SIV 复制抑制”功效的免疫学基础及其作用 MHC-E 限制性 CD8+ T 细胞在此过程中将对 HIV 治疗方法以及 告知使用 MHC-E 限制性 CD8+ T 细胞作为通用（MHC 单倍型独立）效应器 针对其他传染病或癌症的免疫疗法。