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（由申请人提供）：乙型肝炎病毒 (HBV) 是一种非细胞病变性、亲肝性 DNA 病毒，可导致大多数健康个体发生自限性急性感染，但也可引起慢性感染，特别是通过垂直传播感染的新生儿。 。慢性乙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。围产期慢性乙型肝炎病毒感染的成年人每十年患肝细胞癌的比率约为 5%，比未感染者的比率高出约 100 倍。抗病毒药物可以抑制病毒复制，有助于降低发病率和 死亡率，但它们并不代表治愈方法。对长期感染 HBV 的黑猩猩进行的概念验证研究表明，编码 HBV 表面抗原 (HBsAg) 的 DNA 疫苗随后进行重组金丝雀痘加强免疫可以使 HBV DNA 水平在数年内大幅下降。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，含有异种肝炎病毒 T 表位的变异 HBsAg 蛋白混合物将启动辅助 T 细胞和 CTL 来识别慢性感染个体中的病毒蛋白，否则这些个体对病毒蛋白的反应很差。嵌合序列混合物的使用是创新的；通过组合几种独特的变体，可以覆盖大部分或全部野生型表位，同时最大化免疫刺激序列的含量。这一假设是新颖的，并得到我们初步研究中获得的数据的间接支持。然而，它显然需要更广泛的实验支持，特别是有关 T 细胞反应的直接数据，这将由第一阶段 SBIR 的可行性研究提供。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。使用定向分子进化方法已鉴定出许多含有具有新 T 表位的异种序列的免疫原性 HBsAg 变体。混合几种变体将通过包含许多不同的异种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 变体组合，以识别正常和 HBsAg 转基因小鼠中最具免疫原性的混合物。该提案的主要目标是确定能够诱导强烈 T 细胞反应且安全且耐受性良好的混合物。这项工作的一个重要特点是在开发的各个阶段都存在潜在的后备候选者。在先导化合物优化的早期阶段推进多个候选药物可以增加取得成功结果的可能性。成功开发这种基于 DNA 的创新慢性 HBV 感染治疗疫苗将填补该疾病治疗中相当大的未满足需求，该疾病是一项重大的公共卫生负担。