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

基本信息

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
项目类别：
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

项目摘要

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。