Novel Therapeutic Vaccines for Chronic HBV

慢性乙型肝炎的新型治疗疫苗

• 批准号: 8550764
• 负责人: Robert G. Whalen
• 金额: $ 30万
• 依托单位: ALTRAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550764
• 关键词: Acute; Address; Adjuvant; Adult; Affect; Animals; Antigens; Antiviral Agents; Biological Assay; CD4 Positive T Lymphocytes; Cancer Vaccines; Capsid; Cell Culture Techniques; Cells; Cessation of life; Chronic; Chronic Disease; Chronic Hepatitis B; Clinical Trials; Combined Vaccines; Communicable Diseases; Coupled; DNA; DNA Vaccines; DNA Viruses; Data; Development; Directed Molecular Evolution; Disease; Electroporation; Epitopes; Evaluation; Gene Expression; Health; Helper-Inducer T-Lymphocyte; Hepadnaviridae; Hepatitis B; Hepatitis B Virus; Histology; Human; Immune response; Immunization; Immunotherapeutic agent; Individual; Infection; Interferons; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Methods; Modality; Modeling; Monophenol Monooxygenase; Morbidity - disease rate; Mus; Newborn Infant; Outcome; Pan Genus; Pathology; Peptides; Perinatal; Phase; Plasmids; Polymerase; Primary carcinoma of the liver cells; Property; Proteins; Public Health; Recombinants; Small Business Innovation Research Grant; Spleen; Splenocyte; Staging; Surface Antigens; T cell response; T-Lymphocyte; Therapeutic; Transgenic Mice; Transgenic Model; Vaccination; Vaccines; Variant; Vertical Disease Transmission; Viral; Viral Proteins; Viral Vector; Virus Diseases; Work; base; cost; cytokine; enzyme linked immunospot assay; global health; immunogenic; immunogenicity; improved; innovation; melanoma; mortality; novel; novel therapeutics; novel vaccines; overexpression; response; success; therapeutic vaccine; vaccine candidate; vaccine development; viral DNA

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus that results in a self-limited acute infection in a majority of otherwise healthy individuals but can also cause chronic infection, particularly in newborns infected by vertical transmission. Chronic hepatitis B infection is a significant global health issue directly affecting 350 million people worldwide and resulting in 0.5-1.2 million deaths per year. Adults with chronic HBV infection acquired in the perinatal period develop hepatocellular carcinoma at a rate of about 5% per decade, approximately 100-fold higher than the rate among uninfected individuals. Antiviral drugs can inhibit viral replication and contribute to reducing morbidity and mortality, but they do not represent a cure. Proof-of-concept studies with chimpanzees chronically infected with HBV have shown that a DNA vaccine encoding the HBV surface antigen (HBsAg) followed by a recombinant canarypox boost can produce a large decline in HBV DNA levels for several years. Despite this encouraging result in the only non-human model, clinical trials of therapeutic vaccines have not provided a strong enough response to suppress viral replication. We hypothesize that mixtures of variant HBsAg proteins containing xenogeneic hepadnavirus T epitopes will prime helper T cells and CTLs to recognize the viral protein in chronically infected individuals, which otherwise respond poorly to the viral protein. The use of mixtures of chimeric sequences is innovative; by combining several unique variants it is possible to cover most or all wild-type epitopes while maximizing the content of immunostimulatory sequences. This hypothesis is novel and indirectly supported by data obtained in our Preliminary Studies. However, it clearly requires more extensive experimental support, notably direct data on T-cell responses, and this will be provided by the feasibility stud of this Phase I SBIR. We propose to develop a therapeutic DNA vaccine product delivered by electroporation and expressing a mixture of HBsAg variants. A number of immunogenic HBsAg variants containing xenogeneic sequences with novel T epitopes have been identified using a directed molecular evolution approach. Mixing several variants will increase the immunotherapeutic potential of the combined vaccine by including many different xenogeneic epitopes. Beginning with seven individual variants, all possible 3-variant combinations will be screened using a tiered strategy to identify the most immunogenic mixtures in normal and HBsAg-transgenic mice. The main objective of this Proposal is to identify mixtures that can induce strong T-cell responses and that are safe and well tolerated. An important feature of this work is the existence of potential backup candidates at all stages of development. Advancing multiple candidates at the early stages of lead optimization increases the likelihood of a successful outcome. Success in developing this innovative DNA-based therapeutic vaccine for chronic HBV infection would fill a considerable unmet need in the treatment of this disease, which represents a major public health burden.

描述(申请人提供)：乙肝病毒(乙肝)是一种非细胞病变的嗜肝DNA病毒，在大多数其他健康的人中会导致自限性急性感染，但也可以导致慢性感染，特别是在通过垂直传播感染的新生儿中。慢性乙肝感染是一个重大的全球健康问题，直接影响全世界3.5亿人，每年导致50万至120万人死亡。在围产期获得慢性乙肝病毒感染的成年人以每十年约5%的速度患上肝细胞癌，比未感染的人的发病率高出约100倍。抗病毒药物可以抑制病毒复制，有助于降低发病率和 死亡，但它们并不代表治愈。对长期感染乙肝病毒的黑猩猩进行的概念验证研究表明，编码乙肝表面抗原(HBs)的DNA疫苗在随后的重组金丝雀痘免疫接种后，可以在几年内使HBVDNA水平大幅下降。尽管在唯一的非人类模型中取得了这一令人鼓舞的结果，但治疗性疫苗的临床试验尚未提供足够强的反应来抑制病毒复制。我们假设，含有异种庚型肝炎病毒T表位的不同HBs Ag蛋白的混合物将启动辅助T细胞和CTL识别慢性感染患者的病毒蛋白，否则这些患者对病毒蛋白的反应很差。嵌合序列混合物的使用是创新的；通过组合几个独特的变体，有可能覆盖大多数或所有野生型表位，同时最大化免疫刺激序列的含量。这一假设是新颖的，并间接地得到了我们初步研究中获得的数据的支持。然而，它显然需要更广泛的实验支持，特别是关于T细胞反应的直接数据，这将由这一阶段SBIR的可行性研究提供。我们建议开发一种治疗性DNA疫苗产品，通过电穿孔和表达HBs Ag变异体的混合物来传递。用定向分子进化的方法已经鉴定了一些含有带有新T表位的异种序列的免疫原性乙肝表面抗原变异体。混合几种变异体将包括许多不同的异种表位，从而增加联合疫苗的免疫治疗潜力。从7个单独的变种开始，将使用分级策略筛选所有可能的3个变种组合，以确定正常小鼠和乙肝表面抗原转基因小鼠中免疫原性最强的混合物。这项建议的主要目标是确定能够诱导强烈T细胞反应的混合物，以及安全和耐受性良好的混合物。这项工作的一个重要特点是，在发展的所有阶段都存在潜在的后备候选者。在销售线索优化的早期阶段提拔多名候选人会增加成功结果的可能性。成功开发这种基于DNA的慢性乙肝治疗性疫苗将填补治疗这种疾病的相当大的未得到满足的需求，这是一种主要的公共卫生负担。