Correlates of protective immunity to HCV and rational vaccine design: Project 3

HCV 保护性免疫与合理疫苗设计的相关性：项目 3

• 批准号: 10608113
• 负责人: Rama Rao Amara
• 金额: $ 95.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608113
• 关键词: Adjuvant; Antibody Response; Antigens; B-Lymphocytes; Blood; CD8-Positive T-Lymphocytes; Cellular Immunity; Combined Vaccines; Comparative Study; DNA; Development; Genotype; Glycoproteins; Goals; HIV; HIV vaccine; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C virus; Human; Humoral Immunities; Immune response; Immunity; Immunization; In Vitro; Infection; Infection prevention; Liver; Membrane; Modality; Modified Vaccinia Virus Ankara; Molecular; Nonstructural Protein; Persons; Preventive vaccine; Proteins; Recombinants; Regimen; Reporting; Role; Series; Site; Structure; T cell response; T-Lymphocyte; TNFSF5 gene; Testing; Tissues; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Proteins; Virion; Virus Diseases; Virus Replication; Virus-like particle; antiviral immunity; cross reactivity; delivery vehicle; design; experience; improved; insight; neutralizing antibody; nonhuman primate; preservation; prospective; protein expression; response; vaccination strategy; vaccine trial; virus core

Hepatitis C virus (HCV) continues to infect ~71 million people worldwide with an estimated 1.5 to 2 million new infections each year. A complete eradication of HCV infection warrants development of an effective vaccine that can rapidly induce a durable anti-viral immunity and prevent infection. Evidence from spontaneous controllers suggests that a broad and durable HCV-specific CD4 and CD8 T cell responses are critical for effective control of HCV infection. In addition, a protective role for neutralizing antibody against viral glycoproteins E1&E2 has also been implicated. Furthermore, it is critical generate anti-viral immunity in the liver (the primary site of virus replication). Thus, the primary goal of this proposal is to develop a vaccination strategy using DNA, modified vaccinia Ankara (MVA), and protein-based vaccines that will generate a robust and broad HCV specific T and B cell responses in blood and liver against multiple HCV proteins. We hypothesize that induction of a strong, broad, and persistent T cell response against HCV antigens in the blood and liver combined with induction of strong neutralizing antibody response will provide protection against HCV infection and different combinations of DNA/MVA/protein vaccination can be harnessed to achieve the desired protective immunity. We propose to achieve these objectives using 3 specific aims. In Aim 1 we will construct and characterize DNA and MVA vaccines expressing HCV core, NS3-NS5 and E1E2 proteins. In Aim 2 we will optimize the DNA/MVA vaccine modality for inducing strong T cell and antibody responses. The optimizations will include testing the E1E2 in two forms either presented on the virus-like particle (VLP) or secreted. In addition, we will test the influence of CD40L adjuvant on cellular and humoral immunity. In Aim 3 we will optimize E1E2 protein boosts for DNA/MVA vaccine for further enhancing the antibody responses. By completion of these studies we hope generate an optimal vaccine against HCV that induces strong T cell and neutralizing antibody responses.

丙型肝炎病毒 (HCV) 继续感染全球约 7100 万人，估计新增 1.5 至 200 万人 每年都有感染。彻底根除 HCV 感染需要开发一种有效的疫苗 能迅速诱导持久的抗病毒免疫力，预防感染。来自自发控制者的证据 表明广泛且持久的 HCV 特异性 CD4 和 CD8 T 细胞反应对于有效控制至关重要 HCV 感染。此外，针对病毒糖蛋白 E1 和 E2 的中和抗体具有保护作用。 也受到了牵连。此外，在肝脏（病毒的主要部位）中产生抗病毒免疫力也至关重要。 复制）。因此，该提案的主要目标是使用经过修饰的 DNA 开发疫苗接种策略 安卡拉牛痘 (MVA) 和基于蛋白质的疫苗，将产生强大且广泛的 HCV 特异性 T 和 B 血液和肝脏中的细胞对多种 HCV 蛋白的反应。我们假设归纳出一个强大的、广泛的、 和针对血液和肝脏中 HCV 抗原的持续 T 细胞反应，并结合强诱导 中和抗体反应将提供针对 HCV 感染和不同组合的保护 可以利用 DNA/MVA/蛋白质疫苗接种来实现所需的保护性免疫。我们建议 使用 3 个具体目标来实现这些目标。在目标 1 中，我们将构建并表征 DNA 和 MVA 表达 HCV 核心、NS3-NS5 和 E1E2 蛋白的疫苗。在目标 2 中，我们将优化 DNA/MVA 疫苗 诱导强烈 T 细胞和抗体反应的方式。优化将包括测试 E1E2 存在于病毒样颗粒（VLP）上或分泌的两种形式。此外，我们还将测试影响 CD40L 对细胞和体液免疫的佐剂。在目标 3 中，我们将优化 DNA/MVA 的 E1E2 蛋白增强 疫苗进一步增强抗体反应。通过完成这些研究，我们希望产生 针对 HCV 的最佳疫苗，可诱导强烈的 T 细胞和中和抗体反应。