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

• 批准号: 10397662
• 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
• 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/10397662
• 关键词: Active immunity; Address; 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 Activation; Messenger RNA; Mus; Mutate; Natural Killer Cells; Nature; Nucleosides; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Point Mutation; Preventive vaccine; Proteins; Public Health; Recombinants; Regimen; Research; Resistance; Resource-limited setting; Risk; Role; Safety; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Vaccinated; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vaccinia virus; 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; macrophage; mouse model; mutant; nanoparticle; neutralizing antibody; novel vaccines; pathogen; preclinical study; 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

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）感染通常会导致终末期肝病。虽然目前抗HCV 药物可以成功消除病毒 RNA 负荷，但不能防止再次感染。此外，消除 HCV RNA 载量不会降低进展为终末期肝病的风险。因此，当务之急 需要制定控制HCV感染的综合策略，其中必须包括疫苗。丙型肝炎病毒 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并未诱导出强烈的免疫原性。 大多数接种疫苗的志愿者的免疫反应。随后的研究表明，纯化的 HCV E2 具有 免疫调节作用并使初级巨噬细胞活化偏向 M2 表型（通过 E2-CD81 相互作用），损害 DC/CD4+T 细胞功能，并导致对以下因素的反应减弱的环境 抗原。尽管如此，HCV E2 仍然含有强跨基因型特异性 B 细胞和 T 细胞表位，对于 主动免疫。我们假设通过离散点突变修饰 E2 来抑制与 CD81 与其他 HCV 结合可改善免疫功能并诱导强大的保护反应 地区作为候选疫苗，将产生更强的保护功效。杰出的能力 核苷修饰的 mRNA-脂质纳米颗粒 (LNP) 可引发针对病原体的有效免疫反应 使其成为疫苗开发可行的、具有成本效益的新平台。修改后的并入 mRNA 中的核苷将为修饰抗原的产生提供优势，以诱导广泛的有效 免疫反应。研究的前提和严谨性源于我们自己的工作和信息 文学。因此，使用纳米颗粒封装修饰的E2的mRNA以获得更强的免疫原性 与其他病毒抗原（E1 和非结构 (NS) 基因组区域）一起进行初免和加强 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 细胞和 T 细胞 预防 HCV 的反应。我们的研究结果将推动疫苗的开发 持续性丙型肝炎病毒感染。