QUALITATIVE NATURE OF ANTIBODIES TO HCV GLYCOPROTEIN SUBUNIT VACCINE IN HUMANS

描述(由申请人提供)：持续感染丙型肝炎病毒(丙型肝炎病毒)是全球慢性肝病的重要原因。因此，开发预防丙型肝炎病毒感染的疫苗，或至少防止慢性进展，是一个主要目标。病毒进入是抑制病毒感染的一个有吸引力的靶点，因为进入机制是细胞外的，因此它可以被抗体访问。中和抗体是人类对多种病原体的有效免疫应答的主要组成部分，这些病原体与病毒包膜蛋白上的特定表位结合，使它们不能通过各种机制感染靶细胞。重组的1a型丙型肝炎病毒的E1和E2糖蛋白目前被用作正在进行的人类志愿者临床试验的候选疫苗(由DMID、NIH赞助，由圣路易斯大学疫苗和治疗评估单位赞助)，并似乎能诱导中和抗体。我们和其他人在细胞培养中培养了丙型肝炎病毒，并开发了假型病毒作为研究丙型肝炎病毒感染的模型，并检查了抗体介导的病毒中和。我们推测，丙型肝炎病毒E1E2疫苗诱导的抗体在血清补体存在的情况下具有很强的中和活性，具有基因交叉保护作用，或可能增强丙型肝炎病毒的感染性。我们计划对候选丙型肝炎病毒疫苗第一阶段临床试验期间诱导的体液免疫反应的定性性质进行深入研究，以解决以下特定目标：(1)确定补体增强疫苗诱导抗体介导的病毒中和的程度和定性性质。(2)研究疫苗诱导抗体对其他丙型肝炎病毒的交叉中和作用。(3)探讨免疫复合体的形成在调节丙型肝炎病毒感染性中的作用。我们在这一接种队列中提出的免费实验方法将有助于开发成功的疫苗战略，干预丙型肝炎病毒生命周期的第一个关键步骤。

DESCRIPTION (provided by applicant): Persistent infection with hepatitis C virus (HCV) is an important cause of chronic liver disease worldwide. Therefore, the development of vaccines to prevent HCV infection, or at least to prevent progression of chronicity, is a major goal. Virus entry is an attractive target for inhibition of virus infection because the entry machinery is extracellular and it is therefore accessible to antibody. Neutralizing antibodies are a principal component of an effective human immune response to many pathogens which bind to specific epitopes on the envelope proteins of virus, and render them incapable of infecting target cells by a variety of mechanisms. Recombinant E1 and E2 glycoproteins of HCV genotype 1a are currently in use as a candidate vaccine in an ongoing Phase I clinical trial in human volunteers (sponsored by DMID, NIH, at the Saint Louis University Vaccine and Treatment Evaluation Unit), and appear to induce neutralizing antibody. We and others have grown HCV in cell culture and developed pseudotype viruses as models for studies of HCV infection, and examined antibody-mediated virus neutralization. We hypothesize that HCV E1E2 vaccine induced antibodies can have strong neutralizing activity in the presence of serum complement, genotype cross-protective effects, or possibly enhance HCV infectivity. We plan an in-depth investigation into the qualitative nature of humoral immune responses induced during a Phase I clinical trial of the HCV candidate vaccine by addressing the following specific aims: (1) Determine the extent and qualitative nature by which complement enhances viral neutralization mediated by vaccine induced antibodies. (2) Study possible cross-neutralization of other HCV genotypes by vaccine induced antibodies. (3) Investigate the role of immune complex formation in modulation of HCV infectivity. Our proposed complimentary experimental approaches in this vaccinated cohort will help in developing successful vaccine strategies for the intervention of the first crucial step of the HCV life cycle.