A Cytomegalovirus-based therapeutic vaccine for chronic hepatitis B

基于巨细胞病毒的慢性乙型肝炎治疗疫苗

• 批准号: 9253200
• 负责人: ERIC BRUENING
• 金额: $ 29.74万
• 依托单位: TOMEGAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-03 至 2018-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253200
• 关键词: Acute Hepatitis; Adult; Adverse effects; Affect; Algorithms; Antibodies; Antibody Response; Antigen Presentation; Antigens; Antiviral Agents; Antiviral Therapy; Autopsy; Biotechnology; Blood; CD8-Positive T-Lymphocytes; Cessation of life; Chronic; Chronic Hepatitis B; Cirrhosis; Clinic; Clinical; Clinical Trials; Cytomegalovirus; Cytomegalovirus Vaccines; Data; Development; Dose; Epitopes; Etiology; Fibroblasts; Frequencies; Future; Genetic; Genotype; Goals; HBV Genotype; HIV; Health Sciences; Hepatitis B; Hepatitis B Vaccines; Hepatocyte; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunize; Immunocompromised Host; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Injection of therapeutic agent; Interferons; Lead; Licensing; Liver; Liver Cirrhosis; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Methods; Nature; Oregon; Peptides; Peripheral; Phase; Population; Preventive vaccine; Primary carcinoma of the liver cells; Production; Publishing; Recruitment Activity; Recurrence; Research; Safety; Sales; Schedule; Science; Seeds; Specificity; Surface; Surface Antigens; T cell response; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Therapeutic; Therapeutic Clinical Trial; Universities; Vaccination; Vaccines; Variant; Viral Antigens; Viral Vector; Virus; Virus Diseases; Woman; attenuation; base; clinical candidate; clinical development; congenital infection; design; design and construction; disorder risk; efficacy study; genome integrity; immunological status; in vivo; latent infection; liver transplantation; manufacturing process; manufacturing process development; men; nonhuman primate; novel; programs; prototype; response; safety study; seroconversion; therapeutic vaccine; vaccine trial; vector

Abstract Although an efficient prophylactic vaccine is available for hepatitis B virus (HBV), chronic hepatitis B (CHB) affects up to 350 million people worldwide, and despite advances remains mostly incurable. In adults, acute HBV infection is cleared in 95% of cases by CD8+ T cell-mediated mechanisms, but chronic, lifelong infection ensues in the remaining individuals, which can lead to liver cirrhosis and cancer. The induction and maintenance of HBV-specific T cells in the liver of infected individuals by traditional vaccine methods has been a challenge due to immunological tolerance, one of the hallmarks of CHB. To overcome these challenges, we will use a CMV vector platform to provide persistent antigen presentation capable of recruiting an expanded set of new HBV-specific T cell populations that are expected to circumvent this problem. CMV-vectored HBV vaccines have several unique features. 1) They can be programmed to elicit conventional (MHC-I restricted) and unconventional (MHC-II and MHC-E-restricted) CD8+ T cells that recognize a larger number of epitopes than traditional vaccines; 2) CMV vectors will elicit and maintain high frequencies of non-exhausted effector memory T cells in the blood and liver; 3) CMV vectors overcome pre-existing anti-CMV-immunity by evading vector-specific immune responses; 4) Use of defined attenuations maintain the immunological induction profile; 5) Our “epigraph”-algorithm-based antigen design accounts for global genotype variations by integrating data from over 3000 worldwide HBV sequences. We hypothesize that CMV-based HBV immunotherapy will lead to control and immunologic cure of CHB due to the recruitment of novel HBV-specific CD8+ T cells. Our goal is to test this hypothesis in chronically infected humans, in which we expect that vaccination with either one or two injections will result in lifelong immune control of HBV. In the Phase 1 of this Fast Track Program we will first design, construct and characterize a spread-deficient HCMV vector expressing HBV antigens with global epitope coverage. We will insert two complementary HBV “episensus” antigens into a safety-enhanced HCMV- vector through BAC recombineering to generate the final HCMV/HBV construct that can be taken forward for clinical development. In the Phase 2 program we will generate a pre-master virus seed stock ready for GMP production and optimize the manufacturing process of HCMV/HBV vectors. We will characterize the HCMV/HBV vaccine with respect to stability upon multiple passages, maintenance of antigen expression and genomic integrity. We will then characterize the vaccine and the HBV-specific T cell responses in non-human primates (NHP). We will immunize NHP with HCMV/HBV to determine the effective dose, the timing, and the magnitude of the antigen-specific T cell response. We will further determine the breadth and strain-specificity of peripheral and liver T cells upon necropsy using peptides representative of different HBV genotypes. Upon completion of these Aims we will have generated and characterized a novel immunotherapy for HBV that is ready for GMP manufacture and for human safety and efficacy studies.

抽象的 尽管有效的预防性疫苗可用于乙型肝炎病毒（HBV），但慢性肝炎B（CHB） 全世界最多影响3.5亿人，首选进步仍然无法治愈。在成年人中，急性 CD8+ T细胞介导的机制在95％的病例中清除了HBV感染，但慢性终身感染 其余个体随之而来，这可能导致肝硬化和癌症。感应和 通过传统疫苗方法维持感染个体的HBV特异性T细胞一直是 由于免疫耐受性而引起的挑战，是CHB的标志之一。为了克服这些挑战，我们 将使用CMV矢量平台提供持续的抗原演示文稿，能够招募扩展的集合 预计将解决此问题的新型HBV特异性T细胞群体中。 CMV矢量的HBV 疫苗具有几个独特的功能。 1）它们可以被编程以引起常规（MHC-I受限） 和非常规（MHC-II和MHC-E限制）CD8+ T细胞，这些CD8+ T细胞识别大量的表位 比传统疫苗； 2）CMV矢量将引起并保持非排量效应器的高频 记忆T细胞在血液和肝脏中； 3）CMV矢量通过逃避来克服现有的抗CMV免疫性 载体特定的免疫调查； 4）使用定义的衰减保持免疫诱导概况； 5）我们的“题词” - 基于估计性的抗原设计通过整合数据来说明全球基因型变化 来自3000多个全球HBV序列。我们假设基于CMV的HBV免疫疗法将导致 由于新型HBV特异性CD8+ T细胞的募集，CHB的控制和免疫学治疗。我们的目标是 在长期感染的人类中检验这一假设，我们期望一两个 注射将导致HBV的终生免疫控制。在这个快速轨道程序的第1阶段，我们将首先 设计，构造和表征具有全球表达HBV抗原的扩展缺陷的HCMV载体 表位覆盖范围。我们将插入两个完整的HBV“ episensus”抗原中的HCMV- 通过BAC重组的向量，以生成最终的HCMV/HBV构建体，可用于前进 临床发展。在第二阶段计划中，我们将生成准备GMP的预先病毒种子量 生产并优化HCMV/HBV矢量的制造过程。我们将表征 HCMV/HBV疫苗相对于多次通过时的稳定性，抗原表达和 基因组完整性。然后，我们将表征非人类的疫苗和HBV特异性T细胞反应 素数（NHP）。我们将用HCMV/HBV免疫NHP，以确定有效剂量，时机和 抗原特异性T细胞反应的大小。我们将进一步确定广度和应变特异性 使用代表不同HBV基因型的肽在尸检后的周围和肝T细胞的外周细胞和肝脏T细胞。之上 这些目标的完成我们将产生并表征了一种新型的HBV免疫疗法 准备GMP制造以及人力安全和效率研究。