Immunization strategies to elicit broadly neutralizing antibodies against HCV

引发针对 HCV 的广泛中和抗体的免疫策略

• 批准号: 10681384
• 负责人: Andrew I Flyak
• 金额: $ 24.9万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681384
• 关键词: Animal Model; Animals; Antibodies; Antibody Avidity; Antibody Response; Antigens; Antiviral Agents; Area; Automobile Driving; Award; B-Lymphocytes; Binding; Binding Sites; Biological Models; Biology; CD81 gene; Chronic; Collaborations; Complex; Development; Epidemic; Epitopes; Exhibits; Future; Genes; Genetic Variation; Glycoproteins; Goals; HIV-1; Hepatitis C Vaccination; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune response; Immunization; Immunology; Individual; Infection; Laboratories; Learning; Length; Liver Cirrhosis; Macaca; Malignant neoplasm of liver; Mediating; Mentors; Mentorship; Methods; Modeling; Molecular Conformation; Mus; Mutate; Orthologous Gene; Persons; Phase; Preventive vaccine; Production; Proteins; Protocols documentation; Public Health; Research; Site; Sorting; Specificity; Structure; Testing; Training; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Variant; Virus; Virus Diseases; Virus-like particle; Wild Type Mouse; cost; design; efficacy study; env Gene Products; epidemic response; epidemic virus; experimental study; hepatitis C virus envelope 2 protein; in vivo; interdisciplinary approach; neutralizing antibody; nonhuman primate; novel vaccines; preservation; receptor; response; structural biology; structural determinants; success; vaccination strategy; vaccine candidate; vaccine development; vaccine-induced antibodies; viral detection

PROJECT SUMMARY Hepatitis C virus (HCV) infects over 70 million people worldwide and is a leading cause of chronic liver cirrhosis and liver cancer. Despite the success of direct-acting antivirals, control of the HCV epidemic remains challenging due to difficulties in early virus detection, the high cost of therapy, and possible reinfection after the successful treatment. An effective prophylactic vaccine would help to control the epidemic, but the enormous genetic diversity of the HCV hampers its development. Despite the high variability of the virus, 30% of HCV-infected individuals clear the viral infection by developing broadly neutralizing antibodies (bNAbs) that bind to conserved neutralizing epitopes of HCV glycoprotein E2. By stimulating the development of bNAbs by vaccination, the HCV epidemic might be stopped. We recently identified several E2 proteins from different HCV isolates that bind to germline precursors of human bNAbs, raising the possibility of vaccine development using these variants. In this proposal, we aim to use naturally-occurring E2 proteins to design immunogens that will elicit HCV-specific bNAbs in animal models. To accomplish this goal, E2 protein or virus-like particle-based immunogens will be tested in wild-type mice and non-human primates. Next, the structures of HCV-specific antibodies induced by immunization will be determined. For this, we will sort and sequence epitope-specific B cells from vaccinated animals and express antibodies from these sequences. Then, we will determine the structures of HCV-specific bNAbs alone or in complex with immunogens to elucidate the determinants of broad neutralization of HCV by vaccine-induced antibodies. The detailed analysis of the elicited antibody response will facilitate the optimization of immunogens by enhancing their specificity and selectivity. Together, the results of these aims will lead to the identification and characterization of novel vaccine candidates that elicit HCV-specific bNAbs, facilitating the development of an effective HCV vaccine. The mentoring phase of this proposal will take place in Dr. Pamela Bjorkman's laboratory at Caltech. Since there are several critical areas of the proposed project that require additional training, Dr. Andrew Flyak has assembled a mentorship committee comprising experts in structural biology (Dr. Pamela Bjorkman), B cell immunology (Dr. Michel Nussenzweig), and HCV biology (Dr. Justin Bailey). By using an interdisciplinary approach developed throughout this project and support from the mentoring committee, Dr. Flyak will begin the independent phase of this award, answering fundamental questions that hinder the development of effective vaccines against HCV, or other rapidly mutating viruses. !

项目总结 丙型肝炎病毒(丙型肝炎病毒)感染全球超过7000万人，是慢性肝硬变的主要原因 和肝癌。尽管直接作用的抗病毒药物取得了成功，但控制丙型肝炎病毒流行仍然具有挑战性。 由于早期病毒检测困难，治疗费用高昂，以及成功治疗后可能再次感染 治疗。一种有效的预防性疫苗将有助于控制疫情，但巨大的基因 丙型肝炎病毒的多样性阻碍了其发展。尽管病毒的变异性很高，但30%的丙型肝炎病毒感染者 个人通过产生广泛的中和抗体(BNAbs)来清除病毒感染，这些抗体与保守的 丙型肝炎病毒糖蛋白E2的中和表位。通过接种疫苗刺激bNAbs的发展，丙型肝炎病毒 流行病可能会被遏制住。 我们最近从不同的丙型肝炎病毒分离株中鉴定出几种与人类生殖系前体结合的E2蛋白 BNAbs，增加了使用这些变体开发疫苗的可能性。在这项提案中，我们的目标是使用 自然产生的E2蛋白设计将在动物中诱导丙型肝炎病毒特异性bNAb的免疫原 模特们。为了实现这一目标，将在野生型中测试基于E2蛋白或病毒样颗粒的免疫原 老鼠和非人灵长类动物。接下来，免疫诱导的丙型肝炎病毒特异性抗体的结构将是 下定决心。为此，我们将对来自免疫动物的表位特异性B细胞进行分类和测序，并表达 来自这些序列的抗体。然后，我们将确定丙型肝炎病毒特异性bNAb的结构 用免疫原复合体阐明疫苗诱导的丙型肝炎病毒广泛中和的决定因素 抗体。对所激发的抗体反应的详细分析将有助于优化免疫原。 通过提高它们的特异性和选择性。总而言之，这些目标的结果将导致确定和 诱导丙型肝炎病毒特异性bNAb的新型候选疫苗的特征，促进了丙型肝炎病毒的发展 有效的丙型肝炎疫苗。 这项提案的指导阶段将在加州理工大学帕梅拉·比约克曼博士的实验室进行。因为在那里 安德鲁·弗莱亚克博士召集了拟议项目的几个关键领域，需要额外的培训 由结构生物学(Pamela Bjorkman博士)、B细胞免疫学(Dr. 和丙型肝炎病毒生物学(贾斯汀·贝利博士)。通过使用开发的跨学科方法 在整个项目中，在指导委员会的支持下，Flyak博士将开始独立阶段 回答了阻碍开发有效的丙型肝炎疫苗的根本问题， 或其他快速变异的病毒。 好了！