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: 10205769
• 负责人: Rama Rao Amara
• 金额: $ 69.27万
• 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/10205769
• 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; 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; base; cross reactivity; design; experience; improved; insight; neutralizing antibody; nonhuman primate; preservation; prospective; protein expression; response; vaccination strategy; vaccine delivery; vaccine trial; vector; 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）在全球范围内继续感染约7100万人，估计有1.5至200万人 每年感染。 HCV感染的完全根除需要开发有效的疫苗 可以快速诱导耐用的抗病毒免疫并防止感染。自发控制器的证据 表明宽阔耐用的HCV特异性CD4和CD8 T细胞反应对于有效对照至关重要 HCV感染。此外，对抗病毒糖蛋白E1和E2中和抗体的保护作用 也被牵连。此外，它是肝脏中至关重要的抗病毒免疫（病毒的主要部位 复制）。因此，该提案的主要目标是使用DNA制定疫苗接种策略，修改 Vacinia Ankara（MVA）和基于蛋白质的疫苗，将产生强大而宽的HCV特异性T和B 血液和肝脏对多种HCV蛋白的细胞反应。我们假设诱导强大，广泛， 以及对血液和肝脏中HCV抗原的持续性T细胞反应，结合诱导强 中和抗体反应将为HCV感染提供保护和不同的组合 可以利用DNA/MVA/蛋白质疫苗接种以实现所需的保护性免疫。我们建议 使用3个特定目标实现这些目标。在AIM 1中，我们将构建和表征DNA和MVA 表达HCV核，NS3-NS5和E1E2蛋白的疫苗。在AIM 2中，我们将优化DNA/MVA疫苗 诱导强T细胞和抗体反应的模态。优化将包括测试E1E2 在病毒样粒子（VLP）上或分泌的两种形式。此外，我们将测试 CD40L佐剂在细胞和体液免疫方面。在AIM 3中，我们将优化DNA/MVA的E1E2蛋白增强 疫苗以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T细胞和中和抗体反应。