Novel generic vaccine approaches applied for the prevention of hepatitis C and influenza virus infections.

为了诱导良好的免疫反应，抗原应该在一个特定的颗粒上以几个副本的形式递送。乙肝病毒编码的小分子包膜蛋白(HBs-Ag)具有与宿主来源的脂质自组装成VLP的能力。乙肝表面抗原VLP是最成功的疫苗之一的唯一成分，临床试验表明，它们是一种成功的外源表位或蛋白结构域的输送系统。丙型肝炎病毒和流感病毒是人类的主要病原体。全球有2亿人感染了丙型肝炎病毒，目前还没有有效的疫苗可用。流感每年继续影响数以千计的人，造成严重发病率和相当高的死亡率的流行病。目前的流感疫苗大多是灭活制剂，对儿童和老年人等免疫幼稚的人表现出较差的免疫原性。流感疫苗在刺激细胞免疫方面并不是最理想的。我们建议使用颗粒抗原作为流感和丙型肝炎病毒特异性表位的传递平台，重点开发针对各种丙型肝炎病毒和流感病毒株的方法，包括H5N1禽流感。我们已经成功地生产出含有丙型肝炎病毒特异性序列的修饰的VLP，它能够诱导具有中和能力的抗丙型肝炎病毒抗体。我们假设，用适当的一组丙型肝炎病毒特异性抗原设计的VLP将增强抗丙型肝炎病毒血清的中和能力，这可能克服毒株特异性。这一应用将利用原型递送系统来诱导抗体以及针对各种丙型肝炎病毒和流感病毒特异性靶序列(表位)的细胞反应。这项研究的结果将是针对一系列丙型肝炎病毒和流感特异性表位的多价疫苗原型。作为一种输送系统，这将是针对高度可变的制剂的疫苗接种的理想选择。

For the induction of good immune responses, antigens should be delivered in several copies on a defined particle. The small envelope protein (HBsAg) encoded by the hepatitis B virus (HBV) has the capacity to self-assemble with host derived lipids into VLPs. HBsAg VLPs are the sole component of one of the most successful vaccines, and clinical trials have shown that they are a successful delivery system for foreign epitopes or protein domains. Hepatitis C virus (HCV) and Influenza viruses are major human pathogens. HCV has infected 200 million people worldwide, and there is no effective vaccine available. Influenza continues to affect thousands of people each year causing epidemics with severe morbidity and considerable mortality. Current influenza vaccines are mostly inactivated formulations and they exhibit poor immunogenicity in immunological naive persons such as children and in the elderly. The influenza vaccines are not optimal for stimulation of cell-mediated immunity. We propose to use particulate antigens as a delivery platform for influenza and HCV-specific epitopes with the focus to develop approaches to target various HCV and influenza strains, including H5N1 bird influenza. We have successfully produced modified VLPs containing HCV-specific sequences, which are able to induce anti-HCV antibodies with neutralising capacity. We hypothesise that the design of VLPs with an appropriate set of HCV-specific antigens will enhance the neutralising capacity of anti-HCV sera and this may overcome strain specificity. This application will exploit a prototype delivery system to induce antibody and also cellular responses against a variety of HCV- and influenza specific target sequences (epitopes). The outcome of this study will be a prototype multivalent vaccine to a range of HCV- and influenza-specific epitopes. As a delivery system this will be ideal for vaccination against agents that are highly variable.