SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION

摘要 慢性丙型肝炎病毒感染常导致终末期肝病。尽管目前的抗-丙型肝炎病毒 药物可以成功地消除病毒的RNA载量，但它们不能防止再感染。此外，消除 丙型肝炎病毒RNA负荷并不能降低进展为终末期肝病的风险。因此，当务之急 制定控制丙型肝炎病毒感染的全面战略的需要必须包括疫苗。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 重组丙型肝炎病毒包膜糖蛋白候选疫苗的免疫原性试验没有诱导出强的 大多数接种疫苗的志愿者的免疫反应。后续研究表明，纯化的丙型肝炎病毒E2具有 免疫调节作用和原始巨噬细胞激活偏向M2表型(通过E2-CD81 相互作用)，损害DC/CD4T细胞功能，并导致对 抗原。尽管如此，丙型肝炎病毒E2仍然包含强烈的跨基因特异性B细胞和T细胞表位，对 主动豁免权。我们假设，通过离散的点突变来修改E2以抑制与 CD81将改善免疫功能，并与其他丙型肝炎病毒一起诱导强大的保护性反应 地区作为候选疫苗，并将产生更强的保护效果。杰出的能力 核苷修饰的mRNA-脂质纳米粒(LNP)诱导抗病原体免疫应答 使其成为疫苗开发的一个可行的、成本效益高的新平台。改良剂的加入 RNA中的核苷将为修饰抗原的产生提供有利条件，诱导产生广泛有效的 免疫反应。研究的前提和严谨源于我们自己的工作，而信息在 文学。因此，使用纳米颗粒包裹修饰的E2的mRNA具有更强的免疫原性 与其他病毒抗原(E1和非结构(NS)基因组区)一起用于启动和增强 蛋白质/多肽作为丙型肝炎病毒交叉保护的候选疫苗将产生强大的B细胞和T细胞 对丙型肝炎病毒的保护反应。我们的研究结果将推动疫苗的开发 持续的丙型肝炎病毒感染。

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.