SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION

选择预防丙型肝炎病毒感染的疫苗抗原

基本信息

批准号：
10608965
负责人：
Ranjit Ray
金额：
$ 34.09万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608965
关键词：
Active immunity Adjuvant Antigen-Presenting Cells Antigens B-Lymphocytes Binding Sites CD4 Positive T Lymphocytes CD81 gene Cell Culture Techniques Cell physiology Cells Chronic Hepatitis C Country Development Encapsulated Environment Evaluation Generations Genomic Segment Genotype Glycoproteins Health Health Benefit Helper-Inducer T-Lymphocyte Hepatitis C Hepatitis C Incidence Hepatitis C Vaccine Hepatitis C Viremia Hepatitis C virus Human Immune Immune response Immunization Immunize Immunocompetent Impairment Infection Interruption Literature Liver diseases MF59 Macrophage Macrophage Activation Messenger RNA Mus Mutate Natural Killer Cells Nature Nucleosides Patients Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phenotype Point Mutation Populations at Risk Preventive vaccine Proteins Public Health Recombinants Regimen Research Resistance Resource-limited setting Risk Role Safety T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Vaccinated Vaccine Adjuvant Vaccine Antigen Vaccines Vaccinia virus Viral Viral Antigens Viral Proteins Virus Diseases Work anti-hepatitis C comparative cost effective cross reactivity end stage liver disease experimental study global health healthy volunteer immune function immunogenicity immunoregulation improved lipid nanoparticle low socioeconomic status mouse model mutant nanoparticle neutralizing antibody novel vaccines pathogen preclinical study progression risk protective efficacy rational design response stem transmission process vaccine candidate vaccine delivery vaccine development vaccine efficacy vaccine evaluation vaccine platform vaccine strategy viral RNA virus envelope volunteer

项目摘要

Abstract Chronic hepatitis C virus (HCV) infection often causes end stage liver disease. Although current anti-HCV drugs are successful in eliminating viral RNA load, they do not prevent reinfection. In addition, eliminating HCV RNA load does not reduce the risk for progression to end stage liver disease. Therefore, the urgent need for the development of a comprehensive strategy to control HCV infection must include a vaccine. HCV envelope glycoproteins are the key components for the initiation of viral infection. Our phase I safety and immunogenicity trial of a recombinant HCV envelope glycoprotein candidate vaccine did not induce a strong immune response in most vaccinated volunteers. Subsequent studies indicated that purified HCV E2 has an immunoregulatory role and biases primary macrophage activation toward the M2 phenotype (via E2-CD81 interactions), impairs DC/CD4+T cell functions, and leads to an environment for a muted response to antigen. Nevertheless, HCV E2 still contains strong cross-genotype specific B- and T-cell epitopes vital to an active immunity. We hypothesize that modifying E2 by discrete point mutations to inhibit interaction with CD81 will improve immune functions and induce robust protective responses in combination with other HCV regions as candidate vaccine, and will generate stronger protective efficacy. Outstanding abilities of nucleoside modified mRNA-lipid nanoparticle (LNP) to elicit potent immune responses against pathogens makes it a viable new cost-effective platform for vaccine development. The incorporation of modified nucleosides in the mRNA will offer advantages for generation of modified antigens to induce a broad effective immune response. The premise and rigor of the study stems from our own work, and information in the literature. Thus, the use of nanoparticle encapsulated mRNA of modified E2 for stronger immunogenicity together with other viral antigens (E1 and non-structural (NS) genomic regions) for prime and boost with proteins/peptides as a candidate vaccine for HCV cross protective efficacy will generate robust B- and T- cell responses for protection against HCV. The results from our study will advance vaccine development against persistent HCV infection.

抽象的慢性丙型肝炎病毒（HCV）感染通常会引起终末期肝病。虽然当前的抗HCV 药物成功地消除了病毒RNA负荷，不会防止再感染。另外，消除 HCV RNA负荷不会降低进展终止肝病的风险。因此，紧急制定控制HCV感染的综合策略的需求必须包括疫苗。 HCV 包膜糖蛋白是启动病毒感染的关键成分。我们的第一阶段安全和重组HCV包膜糖蛋白候选疫苗的免疫原性试验不会引起强大多数接种志愿者的免疫反应。随后的研究表明，纯化的HCV E2具有免疫调节作用并偏向于M2表型的原发性巨噬细胞激活（通过E2-CD81 相互作用），损害直流/CD4+T细胞功能，并导致环境，以使其对抗原。然而，HCV E2仍然包含强大的跨基因型特异性B-和T细胞表位对主动免疫。我们假设通过离散点突变来修改E2以抑制与 CD81将改善免疫功能并诱导强大的保护反应与其他HCV 地区作为候选疫苗，将产生更强的保护功效。出色的能力核苷修饰的mRNA-脂质纳米颗粒（LNP）引发针对病原体的有效免疫反应使其成为疫苗开发的可行的新成本效益平台。修改后的融合 mRNA中的核苷将为生成改性抗原提供优势，以诱导广泛的有效性免疫反应。研究的前提和严格源于我们自己的工作，以及文学。因此，使用纳米颗粒封装了改性E2的mRNA，以实现更强的免疫原性与其他病毒抗原（E1和非结构性（NS）基因组区域）一起用于素数，并与蛋白质/肽作为HCV交叉保护功效的候选疫苗将产生强大的B-和T细胞为防止HCV提供的响应。我们研究的结果将推进疫苗开发持续的HCV感染。