QUALITATIVE NATURE OF ANTIBODIES TO HCV GLYCOPROTEIN SUBUNIT VACCINE IN HUMANS

描述（由申请人提供）：丙型肝炎病毒（HCV）持续感染是全球慢性肝病的重要原因。因此，开发预防HCV感染或至少预防慢性进展的疫苗是一个主要目标。病毒进入是抑制病毒感染的有吸引力的靶标，因为进入机制是细胞外的，因此抗体可以接近。中和抗体是针对许多病原体的有效人类免疫应答的主要组分，其结合病毒包膜蛋白上的特异性表位，并使它们不能通过多种机制感染靶细胞。HCV基因型1a的重组E1和E2糖蛋白目前在人类志愿者中正在进行的I期临床试验中用作候选疫苗（由DMID，NIH，在圣刘易斯大学疫苗和治疗评价单位赞助），并且似乎诱导中和抗体。我们和其他人已经在细胞培养中培养了HCV，并开发了假型病毒作为HCV感染研究的模型，并检查了抗体介导的病毒中和。我们推测，HCV E1E2疫苗诱导的抗体可以在血清补体存在下具有强中和活性，基因型交叉保护作用，或可能增强HCV感染性。我们计划深入研究HCV候选疫苗I期临床试验期间诱导的体液免疫应答的定性性质，具体目标如下：（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)研究疫苗诱导的抗体对其他HCV基因型的可能交叉中和作用。(3)研究免疫复合物形成在HCV感染性调节中的作用。我们在这个接种疫苗的队列中提出的免费实验方法将有助于开发成功的疫苗策略，用于干预HCV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.