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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的虽然乙型肝炎病毒 (HBV) 有有效的预防疫苗，但慢性乙型肝炎 (CHB) 全世界多达 3.5 亿人受到影响，尽管取得了进展，但对于成年人来说，这种疾病大多是无法治愈的。 95% 的病例可通过 CD8+ T 细胞介导的机制清除 HBV 感染，但慢性、终生感染其余个体也会发生这种情况，这可能导致肝硬化和癌症。通过传统疫苗方法维持感染者肝脏中的 HBV 特异性 T 细胞免疫耐受带来的挑战是慢性乙型肝炎的标志之一，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递，从而能够招募更多的抗原新的 HBV 特异性 T 细胞群有望解决这一问题。疫苗有几个独特的特征 1) 它们可以被编程以引发常规（MHC-I 限制）。和识别大量表位的非常规（MHC-II 和 MHC-E 限制性）CD8+ T 细胞 2) CMV载体将引发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载体通过逃避来克服预先存在的抗CMV免疫载体特异性免疫反应；4) 使用确定的衰减维持免疫诱导谱； 5) 我们基于“铭文”算法的抗原设计通过整合数据来解释全球基因型变异我们从全球 3000 多个 HBV 序列中寻找基于 CMV 的 HBV 免疫疗法。通过招募新型 HBV 特异性 CD8+ T 细胞来控制和免疫治愈 CHB。在慢性感染的人类中检验这一假设，我们预计接种一种或两种注射将导致乙型肝炎病毒的终生免疫控制。在该快速通道计划的第一阶段，我们将首先。设计、构建和表征表达 HBV 抗原的传播缺陷型 HCMV 载体，具有全局性表位覆盖。我们将在安全性增强的 HCMV 中插入两种互补的 HBV“episensus”抗原。载体通过 BAC 重组工程产生最终的 HCMV/HBV 构建体，可用于在第二阶段计划中，我们将生成预主病毒种子库，为 GMP 做好准备。我们将表征 HCMV/HBV 载体的生产和制造工艺。 HCMV/HBV 疫苗在多次传代后的稳定性、抗原表达的维持和然后我们将表征疫苗和非人类体内的 HBV 特异性 T 细胞反应。我们将用 HCMV/HBV 对灵长类动物 (NHP) 进行免疫，以确定有效剂量、时机和免疫接种。我们将进一步确定抗原特异性 T 细胞反应的广度和菌株特异性。使用代表不同 HBV 基因型的肽进行尸检后的外周血和肝脏 T 细胞。完成这些目标后，我们将开发并表征一种新型乙型肝炎免疫疗法，即为 GMP 生产和人体安全性和功效研究做好准备。