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: 9767007
• 负责人: ERIC BRUENING
• 金额: $ 100万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767007
• 关键词: Acute Hepatitis; Adult; Affect; Algorithms; Antibodies; Antibody Response; Antigen Presentation; Antigens; Antiviral Agents; Antiviral Therapy; Autopsy; Bacterial Artificial Chromosomes; 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; Hepatitis B Virus; Hepatocyte; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunize; Immunocompromised Host; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Injections; 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; 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; antigen-specific T cells; attenuation; base; chronic infection; 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; recruit; safety study; seroconversion; side effect; therapeutic vaccine; 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.

摘要 尽管有一种有效的预防性疫苗可用于治疗乙肝病毒(乙肝)、慢性乙肝(CHB) 全球多达3.5亿人受到影响，尽管取得了进展，但大多数人仍然无法治愈。成人中，急性 95%的病例通过CD8+T细胞介导的机制清除了乙肝病毒感染，但慢性终身感染 随后在剩下的个体中发生，这可能会导致肝硬化和癌症。归纳法和 通过传统疫苗方法维持感染者肝脏中的乙肝病毒特异性T细胞 由于免疫耐受性的挑战，这是慢性乙肝的标志之一。为了克服这些挑战，我们 将使用CMV载体平台提供持久的抗原呈现，能够招募更多的人 新的乙肝病毒特异性T细胞群体有望绕过这一问题。巨细胞病毒载体乙肝病毒 疫苗有几个独特的特点。1)它们可以被编程以引发常规(MHC-I受限) 以及识别更多表位的非传统(MHC-II和MHC-E受限)CD8+T细胞 2)CMV载体将诱导并维持高频率的未耗尽效应器 血液和肝脏中的记忆T细胞；3)CMV载体通过逃避先前存在的抗CMV免疫来克服 媒介特异性免疫反应；4)使用限定的减毒作用维持免疫诱导特性； 5)我们的基于“警句”算法的抗原设计通过整合数据来解释全球的基因变异。 来自全球3000多个乙肝病毒序列。我们假设，基于巨细胞病毒的乙肝免疫疗法将导致 慢性乙型肝炎的控制和免疫治疗是由于新的乙肝病毒特异性CD8+T细胞的招募。我们的目标是 在慢性感染者身上测试这一假设，在这种情况下，我们预计接种一或两种疫苗 注射将导致对乙肝病毒的终身免疫控制。在此Fast Track计划的第一阶段，我们将首先 人巨细胞病毒传播缺陷表达载体的设计、构建及鉴定 表位覆盖率。我们将把两个互补的乙肝病毒“普查”抗原插入到安全增强的HCMV中- 载体通过BAC重组工程产生最终的HCMV/乙肝病毒构建物，可用于 临床发展。在第二阶段计划中，我们将生成一个可用于GMP的预主病毒种子库 生产和优化人巨细胞病毒/乙肝病毒载体的生产工艺。我们将描述 人巨细胞病毒/乙肝疫苗在多代传代中的稳定性、抗原表达的维持和 基因组的完整性。然后，我们将对疫苗和非人类体内的乙肝病毒特异性T细胞反应进行表征 灵长类(NHP)。我们将用人巨细胞病毒/乙肝病毒免疫NHP，以确定有效剂量、时间和 抗原特异性T细胞反应的大小。我们将进一步确定广度和菌株特异性 使用代表不同HBV型的多肽在尸检时检测外周血和肝脏T细胞。vt.在.的基础上 完成这些目标后，我们将产生并表征一种针对乙肝病毒的新型免疫疗法，即 为GMP生产和人体安全性和有效性研究做好准备。