A novel vaccine to prevent HCV infection and hence liver cancer

一种预防丙型肝炎病毒感染进而预防肝癌的新型疫苗

基本信息

批准号：
7943947
负责人：
ELLEN S VITETTA
金额：
$ 62万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943947
关键词：
Accounting Acute Affinity American Amines Amino Acids Animals Anti-Idiotypic Antibodies Antibodies Avidity B-Lymphocyte Epitopes Binding Biological Models Carbohydrates Carrier Proteins Cells Chronic Disease Chronic Hepatitis C Consensus Sequence Coupled Development Disease E protein Enzyme-Linked Immunosorbent Assay Epitopes FLAG peptide G-substrate Genotype Glycine Grant HCV Liver Cancer HCV Vaccine HCV screening HIV Hand Haplotypes Haptens Hemorrhage Hepatitis C Hepatitis C Antibodies Hepatitis C virus Human Human Development Hybrids Immunoglobulin G Incidence Individual Infection International Keyhole Limpet Hemocyanin Libraries Liver Cirrhosis Malignant neoplasm of liver Methods Monoclonal Antibodies Mus N-substituted Glycines Oligonucleotides Peptide Hydrolases Peptide Vaccines Peptides Peptoids Phagocytosis Primary carcinoma of the liver cells Proteins Receptors, Antigen, B-Cell Regimen Reporting Resistance Risk Factors Screening procedure Serum Shapes Side Structure Students T-Lymphocyte T-Lymphocyte Epitopes Techniques Testing Vaccinated Vaccination Vaccines Viral Viral Proteins Virus West Nile virus Work aluminum sulfate anti-hepatitis C base immunogenic killings magnetic beads meetings mimetics neutralizing antibody neutralizing monoclonal antibodies novel vaccines particle pathogen prevent public health relevance response success

项目摘要

DESCRIPTION (provided by applicant): An estimated170 million people worldwide and 20 million Americans are infected with hepatitis C virus HCV). Although some individuals clear the infection, many progress to chronic disease and years later can get liver cancer. Since 85% of liver cancers are HCV-associated, if infection could be avoided by vaccination, this would have a major impact on the incidence of liver cancer. My hypothesis is that new vaccines against HCV can be generated based entirely on selecting synthetic B cell epitopes recognized by already-existing neutralizing monoclonal anti-HCV antibodies that we are fortunate to have. I believe that the best choice for a library of B cell epitopes is peptoid rather than peptide-based. Peptoids are oligomers of N-substituted glycines not restricted to the 20 natural amino. The side chains are simple primary amine derivatives, hundreds of which can be purchased inexpensively as compared to peptides. Peptoids are protease resistant, can use D amino acid side chains (peptoid-hybrids), and can also be cyclic. Peptoids are structurally similar to peptides but are protease resistant, can be created in more diverse shapes to fit into the binding pocket of B cell receptors, and are easily and inexpensively synthesized in large amounts. They can be generated with a theoretical diversity of 107 or greater and a "working diversity" of a million. They are haptens and need not contain T cell epitopes. Finally, while conserved neutralizing epitopes on HCV might not be immunodominant, or might be sparse, in our platform, epitope mimetics should be immunodominant since they are haptens and many copies will be attached to a carrier protein. The carrier protein will provide T cell help to induce robust, high affinity IgG responses against the peptoid. Hence, T cell help will not be restricted to individuals with certain HLA haplotypes. We have already shown that peptoids conjugated to carrier proteins are highly immunogenic and that, in a model system, they can induce antibodies that also react with the native peptide. In this proposal we plan to use a panel of neutralizing monoclonal antibodies (MAbs) against HCV for screening. Those peptoids that are positive in the screen will then be sequenced, synthesized in bulk, and tested for their ability to block the binding of the native E2 protein of HCV to the screening MAb Those that block at the lowest concentration will be conjugated (together or separately) to a carrier protein, mixed with alum (an adjuvant approved for humans), and used to immunize mice. The mouse sera will be tested for reactivity against E2. Those that react will be further tested for their ability to neutralize a panel of HCV genotypes. Although other mimetic platforms have not met with great success, we believe that the peptoid platform overcomes many of the problems associated with other mimetics such as peptides, carbohydrates and anti- idiotypic antibodies, and that it holds great promise as a vaccine platform for HCV and other pathogens. PUBLIC HEALTH RELEVANCE: The objective of this grant is to generate an effective vaccine against Hepatitis C virus, the major cause of liver cancer. Our vaccine platform is based on synthetic structures called peptoids that are selected by existing monoclonal antibodies that are already known neutralize the virus. These peptoids will be screened with these antibodies, and those that react will be coupled to carrier proteins and used to immunize mice. The mice should make antibodies that then both recognize both the peptoid and the virus.

描述（由申请人提供）：估计全世界有 1.7 亿人以及 2000 万美国人感染丙型肝炎病毒（HCV）。尽管有些人清除了感染，但许多人会发展为慢性疾病，数年后可能会患上肝癌。由于85%的肝癌与HCV相关，如果可以通过疫苗接种来避免感染，这将对肝癌的发病率产生重大影响。我的假设是，可以完全基于选择合成 B 细胞表位来生产针对 HCV 的新疫苗，这些合成 B 细胞表位被我们幸运拥有的现有中和性单克隆抗 HCV 抗体所识别。我相信 B 细胞表位库的最佳选择是类肽而不是基于肽的。类肽是 N-取代甘氨酸的寡聚物，不限于 20 个天然氨基酸。侧链是简单的伯胺衍生物，与肽相比，可以便宜地购买数百种侧链。类肽具有蛋白酶抗性，可以使用 D 氨基酸侧链（类肽混合体），也可以是环状的。类肽在结构上与肽相似，但具有蛋白酶抗性，可以制成更多样化的形状以适应 B 细胞受体的结合口袋，并且可以轻松且廉价地大量合成。它们可以以 107 或更高的理论多样性和 100 万的“工作多样性”生成。它们是半抗原，不需要包含 T 细胞表位。最后，虽然 HCV 上的保守中和表位可能不是免疫显性的，或者可能是稀疏的，但在我们的平台中，表位模拟物应该是免疫显性的，因为它们是半抗原，并且许多拷贝将附着到载体蛋白上。载体蛋白将帮助 T 细胞诱导针对类肽的强大、高亲和力 IgG 反应。因此，T 细胞的帮助将不仅限于具有某些 HLA 单倍型的个体。我们已经证明，与载体蛋白缀合的类肽具有高度免疫原性，并且在模型系统中，它们可以诱导也与天然肽发生反应的抗体。在本提案中，我们计划使用一组针对 HCV 的中和单克隆抗体 (MAb) 进行筛查。然后，对筛选中呈阳性的那些拟肽进行测序、批量合成，并测试它们阻断 HCV 天然 E2 蛋白与筛选 MAb 结合的能力。那些以最低浓度阻断的拟肽将被缀合（一起或单独）到载体蛋白，与明矾（批准用于人类的佐剂）混合，并用于免疫小鼠。将测试小鼠血清针对 E2 的反应性。那些发生反应的药物将被进一步测试其中和一组 HCV 基因型的能力。尽管其他模拟平台尚未取得巨大成功，但我们相信类肽平台克服了与其他模拟物（例如肽、碳水化合物和抗独特型抗体）相关的许多问题，并且它作为 HCV 和 HCV 疫苗平台具有广阔的前景。其他病原体。公共健康相关性：这笔赠款的目的是开发一种有效的疫苗来对抗丙型肝炎病毒，丙型肝炎病毒是肝癌的主要原因。我们的疫苗平台基于称为类肽的合成结构，这些结构是由已知中和病毒的现有单克隆抗体选择的。这些类肽将用这些抗体进行筛选，那些发生反应的类肽将与载体蛋白偶联并用于免疫小鼠。小鼠应该产生能够识别类肽和病毒的抗体。