Novel VLP vaccines for pandemic influenza virus

野生水产动物体内存在大量人类感染的禽流感病毒。 禽类和高致病性H5N1禽流感毒株目前在东南部几个国家流行 在亚洲，它们已经造成了数十人死亡。这些菌株特别令人担忧，因为 他们对最具成本效益的抗病毒药物金刚烷胺和金刚乙胺具有抗药性。新技术的出现 一种新的可传播的流感病毒，对人群几乎没有免疫力，将导致 全球大流行，目前还没有疫苗可用。目前的流感疫苗是由病毒生产的 适合在胚胎母鸡的鸡蛋中生长良好的病毒，而高致病性禽流感病毒 对鸡蛋是致命的，这使得目前的疫苗生产方法存在问题。备择 因此，迫切需要开发有效流感疫苗的方法。为了努力发展 流感疫苗生产的替代品和应对大流行的威胁，我们在这个项目中的目标是 确定以流感病毒样颗粒为基础的疫苗是否会对甲流提供保护性免疫 高致病性禽流感病毒。其他目标是解决当前 流感疫苗：效力有限，不能预防粘膜表面的感染，以及 观察到的免疫是高度菌株特异性的，持续时间很短。因此，我们将开发方法来 增强流感疫苗的免疫原性，增强对疫苗的记忆反应，以及 在粘膜表面诱导有效的免疫反应，这可能对更广泛的 病毒株。除了一组监测体液和细胞免疫反应的检测外，我们还将 利用已构建的新型转基因小鼠直接检测B细胞数量 免疫后产生的记忆。该项目的具体目标是：1.生产类似病毒的 含有流感病毒糖蛋白和基质(M1)蛋白的颗粒(VLP)；2.鉴定 流感病毒疫苗免疫后的体液和细胞免疫反应及其保护效果； 和3.通过引入针对目标的配体来开发更有效的流感VLP疫苗 VLP到抗原提呈细胞。

A large spectrum of avian influenza virus to which the human population is naTve is present in wild aquatic birds, and highly pathogenic H5N1 avian strains are currently circulating in several countries in southeast Asia where they have caused dozens of human fatalities. These strains are of particular concern because they are resistant to the most cost-effective antiviral drugs, amantadine and rimantadine. The emergence of a novel transmissible influenza virus against which the population has little or no immunity would cause a global pandemic, for which no vaccine is available. Current influenza vaccines are produced from viruses that are adapted to grow well in embryonated hens' eggs, whereas highly pathogenic avian influenza viruses are lethal for hens' eggs, making the current methods of vaccine production problematic. Alternative approaches to develop effective influenza vaccines are therefore urgently needed. In an effort to develop alternatives for influenza vaccine production and in response to a pandemic threat, our goal in this project is to determine whether influenza virus-like particle based vaccines will provide protective immunity against a highly pathogenic avian influenza virus. Additional goals are to address other shortcomings of current influenza vaccines: they exhibit limited efficacy, they fail to protect against infection at mucosal surfaces, and the observed immunity is highly strain-specific and of short duration. Thus, we will develop approaches to enhance the immunogenicity of influenza vaccines, to enhance memory responses to the vaccine, and to induce effective immune responses at mucosal surfaces which may be protective against a broader range of viral strains. In addition to a panel of assays to monitor humoral and cellular immune responses, we will make use of novel transgenic mice which have been constructed to directly measure the magnitude of B cell memory generated in response to immunization. The specific aims of the project are:1. to produce virus-like particles (VLPs) incorporating influenza viral glycoproteins and matrix (M1) protein; 2. to characterize humoral and cellular immune responses after immunization with influenza VLPs and their protective efficacy; and 3. to develop more effective influenza VLP-based vaccines by incorporation of ligands designed to target the VLPs to antigen-presenting cells.