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: 10619297
• 负责人: Louis J. Picker
• 金额: $ 498.32万
• 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/10619297
• 关键词: AIDS prevention; AIDS/HIV problem; Animals; Applications Grants; Autopsy; Bioinformatics; Biotechnology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cercopithecine Herpesvirus 1; Characteristics; Communicable Diseases; Cytomegalovirus; DNA; Direct Costs; E protein; Epitopes; Experimental Models; Extinction (Psychology); Frequencies; Future; Genetic Programming; HIV; HIV vaccine; HIV/SIV vaccine; Haplotypes; Human; Immune; Immune response; Immunobiology; Immunologics; Immunotherapy; Infection; Intercept; 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; base; clinical development; clinical efficacy; clinical translation; cost; cost effective; data management; efficacy evaluation; efficacy trial; exhaustion; 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 vaccine; vector-based vaccine; vector-induced

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 - 项目摘要 大约20年前 疱疹病毒巨细胞病毒（CMV），因为CMV能够无限期地保持高 频率，效应子分化的多样性组织中的T细胞反应。使用恒河猴（RM）模型， 我们已经证明，不仅RHCMV/SIV疫苗可为高度致病性提供较高的效率 SIV挑战比常规SIV疫苗（总计，RHCMV/SIV接种RM的59％ 渐进的SIV感染），这种效率是一种全新的模式 - 早期SIV复制停滞，然后是 最终的病毒清除率 - 由新型免疫反应介导 - MHC-E限制的效应子记忆 - 分化的CD8+ T细胞（迄今为止，只能由具有特定遗传编程的CMV载体引起）。 我们还知道，MHC-E靶向CD8+ T细胞反应的效率由全血预测 带有IL-15信号传导的转录组签名，但负责完全逮捕的机制和 随后的新生SIV感染的清除率未定义，包括为什么MHC-E限制的问题 效率，这些细胞介质复制停滞以及如何受到保护需要表位识别 全血转录组签名会影响这些独特的效应子响应。在这个程序中，我们试图 两者都回答了这些问题，并为指导持续的效率制定了详细的标准 人CMV/HIV疫苗的I/II期临床测试。拟议的计划将包括以下3 项目：1）RHCMV/SIV疫苗介导的SIV“复制停滞”的免疫和病毒学特征 效率，2）表征体内T细胞（以及总体免疫）对原发性SIV感染的截止 具有不同响应编程的RHCMV/SIV载体的疫苗接种（MHC-E-vs. MHC-II-与MHC-IA-- 受限制）和常规的原始促进SIV疫苗（MHC-IA受限），以及3）确定最小的 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 这些项目将得到4个核心的支持：a）管理，b）NHP，c）高级空间分析，， 和d）``omics，生物信息学和数据管理。除了指导当前和未来的临床测试 HMCV/HIV疫苗，理解“ SIV复制停滞”效率的免疫学基础和作用 在此过程中，MHC-E限制的CD8+ T细胞将对HIV治疗方法以及 告知使用MHC-E限制的CD8+ T细胞作为通用（MHC单倍型独立）效应的使用 针对其他传染病或癌症的免疫疗法。