Novel VLP vaccines for pandemic influenza virus

野生水生动物中存在人类对之免疫的大范围禽流感病毒， 禽流感和高致病性H5 N1禽流感病毒株目前在东南部的几个国家流行。 在亚洲已经造成数十人死亡。这些菌株特别值得关注，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有抗药性。的出现 一种新的传染性流感病毒，如果人们对它几乎没有免疫力， 全球大流行，没有疫苗可用。目前的流感疫苗是由病毒制成的 这些病毒适合在含胚鸡蛋中生长良好，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。替代 因此，迫切需要开发有效流感疫苗的方法。为了开发 为应对流感疫苗生产和大流行威胁，我们在该项目中的目标是 为了确定基于流感病毒样颗粒的疫苗是否会提供针对流感病毒的保护性免疫， 高致病性禽流感病毒。另外的目标是解决目前的其他缺点， 流感疫苗：它们表现出有限的效力，它们不能保护粘膜表面免受感染， 所观察到的免疫是高度菌株特异性的并且持续时间短。因此，我们将制定方法， 增强流感疫苗的免疫原性，增强对疫苗的记忆反应， 在粘膜表面诱导有效免疫应答，其可以保护免受更广泛的 病毒株除了一组检测来监测体液和细胞免疫反应，我们将 利用已构建的新型转基因小鼠直接测量B细胞的大小， 免疫后产生的记忆该项目的具体目标是：1。产生类似病毒的 掺入流感病毒糖蛋白和基质（M1）蛋白的颗粒（VLP）; 2.表征 流感病毒VLP免疫后的体液和细胞免疫应答及其保护效力; 和3.通过掺入设计用于靶向的配体来开发更有效的流感VLP疫苗 VLP到抗原呈递细胞。

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.