SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION

摘要 慢性丙型肝炎病毒（HCV）感染往往会导致终末期肝病。虽然目前抗HCV 药物成功地消除了病毒RNA载量，但它们不能防止再感染。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，紧急 发展控制HCV感染的综合策略的需要必须包括疫苗。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免疫原性试验未诱导强烈的 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-CD 81 相互作用），损害DC/CD 4 +T细胞功能，并导致对 抗原的尽管如此，HCV E2仍然含有强的跨基因型特异性B和T细胞表位， 主动免疫我们假设，通过离散点突变来修饰E2以抑制与E2的相互作用， CD 81将与其他HCV结合，改善免疫功能并诱导强大的保护性应答 区域作为候选疫苗，并将产生更强的保护效力。杰出的能力 核苷修饰的mRNA-脂质纳米颗粒（LNP），以引发针对病原体的有效免疫应答 使其成为疫苗开发的可行的新的成本效益平台。修改后的合并 mRNA中的核苷将为产生修饰的抗原提供优势，以诱导广泛的有效免疫应答。 免疫反应这项研究的前提和严谨性源于我们自己的工作， 文学因此，使用纳米颗粒包封的修饰的E2的mRNA用于更强的免疫原性， 与其他病毒抗原（E1和非结构（NS）基因组区域）一起用于初免和加强， 作为HCV交叉保护效力的候选疫苗的蛋白质/肽将产生稳健的B-和T-细胞 针对HCV的保护反应。我们的研究结果将促进疫苗的开发， 持续性HCV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.