Novel Therapeutic Vaccines for Chronic HBV

慢性乙型肝炎的新型治疗疫苗

• 批准号: 8394626
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394626
• 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. PUBLIC HEALTH RELEVANCE: Hepatitis B virus infection can cause chronic disease in certain people, particularly newborns. This is a major health issue affecting over 350 million individuals worldwide resulting in 0.5-1.2 million deaths per year, often from liver cancer. We wil develop a vaccine to treat this chronic infection and potentially cure the disease.

描述（由申请人提供）：丙型肝炎病毒（HBV）是一种非肿瘤性的肝DNA病毒，在大多数健康的个体中会导致自限性急性感染，但也可能引起慢性感染，尤其是在新生儿中受到垂直传播感染的新生儿。慢性丙型肝炎感染是一个重大的全球健康问题，直接影响全球3.5亿人，每年导致0.5-120万人死亡。在围产期获得的慢性HBV感染的成年人以每十年约5％的速度发展出肝细胞癌，比未感染的个体高约100倍。抗病毒药可以抑制病毒复制，并有助于降低发病率和 死亡率，但它们并不代表治愈。长期感染HBV的黑猩猩的概念概念研究表明，编码HBV表面抗原（HBSAG）的DNA疫苗随后重组CanaryPox的增强可以使HBV DNA水平大幅下降几年。尽管这是唯一的非人类模型的令人鼓舞的结果，但治疗疫苗的临床试验尚未提供足够强烈的反应来抑制病毒复制。我们假设含有异构性肝病毒tepistopes的变体HBSAG蛋白的混合物将使辅助助手T细胞和CTL启用，以识别慢性感染个体中病毒蛋白的识别，否则这些病毒蛋白对病毒蛋白的反应不佳。嵌合序列混合物的使用是创新的。通过结合几种独特的变体，可以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。该假设是新颖的，并间接地由我们的初步研究中获得的数据支持。但是，这显然需要更广泛的实验支持，特别是直接有关T细胞响应的数据，这将由该阶段I SBIR的可行性螺柱提供。我们建议开发一种通过电穿孔传递并表达HBSAG变体混合物的治疗性DNA疫苗产品。已经使用定向的分子进化方法鉴定了许多具有新型T表位异体序列的免疫原性HBSAG变体。混合几种变体将通过包括许多不同的异构表位来增加联合疫苗的免疫治疗潜力。从七个单独的变体开始，将使用分层策略筛选所有可能的3变化组合，以识别正常和HBSAG-转基因小鼠中最免疫原性的混合物。该提案的主要目的是确定可以诱导强烈T细胞反应并安全且耐受性良好的混合物。这项工作的一个重要特征是在开发的各个阶段都存在潜在的备份候选人。在铅优化的早期阶段提高多个候选人会增加成功结果的可能性。开发这种创新的基于DNA的治疗疫苗用于慢性HBV感染将填补这种疾病的巨大需求，这代表了主要的公共卫生负担。 公共卫生相关性：丙型肝炎病毒感染会导致某些人，尤其是新生儿的慢性疾病。这是一个主要的健康问题，影响了全球超过3.5亿个人，每年通常因肝癌而导致0.5-120万人死亡。我们将开发一种疫苗来治疗这种慢性感染并可能治愈该疾病。