Live, recombinant newcastle disease virus-based vaccine against high pri pathoge

这笔赠款的目的是进一步开发新型重组载体新城疫病毒(NDV)，因此 它可以被用作一个平台，为人类接种疫苗，以抵御生物细菌病病原体和新出现的传染病。一个 这一策略的优点是，可以通过在新出现的疾病中加入一种蛋白质来快速制造疫苗。 病原体进入新城疫病毒基因组。在这笔赠款中，我们将重点开发针对三种危险病原体的疫苗： 潜在的大流行流感病毒、尼帕病毒和基孔肯雅病毒。我们将测试几种不同的策略来 改进rNDV疫苗。虽然新城疫病毒已经安全地用于人类，但我们将开发单周期 不会扩散到最初感染细胞之外的疫苗。由于这些疫苗不能在宿主中传播， 它们可以安全地应用于免疫功能低下的人。我们将发展双节段和三节段rNDV 能够表达两到三种外源蛋白质的疫苗。这些病毒将诱导更广泛的免疫反应。 与只表达一种外来病原体的一种蛋白质的重组疫苗相比。我们还将确定新城疫病毒 RNA包装信号，并将这些信号整合到多节段rNDV疫苗中，以增加 将多个片段包装成同一病毒粒子的效率。疫苗开发的一个问题是疫苗 在老年人群中往往不是很有效，需要采取策略来加强疫苗在这方面的保护 一群人。我们将确定一种刺激NKT细胞的佐剂--α-C-半乳糖神经酰胺是否能增强 新城疫疫苗对幼龄和老年小鼠的免疫原性。另一种增强免疫原性的策略 RNDV疫苗包括将rNDV疫苗重新靶向树突状细胞，树突状细胞是启动 适应性免疫反应。这将通过表达树突状细胞受体的单链抗体来实现， DEC-205，来自rNDV基因组。我们将与NBC调查员约翰·罗斯博士合作确定 PRIME-BOOST方案，包括用表达流感病毒HA蛋白的rNDV接种小鼠，并用 表达流感病毒HA蛋白的rVSV能更好地增强对流感病毒HA的免疫应答 单独的航向。为了确定疫苗是否具有保护作用，我们将在山上挑战感染H5N1流感的小鼠 并与其他RCE调查人员合作，挑战接种尼帕和基孔肯雅rNDV疫苗的动物 疫苗。

The goal of this grant is to further develop the novel recombinant vector, Newcastle disease virus (NDV), so that it can be used as a platform to vaccinate humans against bioterrism agents and emerging infectious diseases. An advantage of this strategy is that vaccines for emerging diseases can be quickly made by inserting a protein of the pathogen into the NDV genome. For this grant we will focus on developing vaccines to three dangerous pathogens: potential pandemic influenza virus, Nipah virus, and Chikungunya virus. We will test several different strategies to improve rNDV vaccines. Though NDV has already been safely administered to humans, we will develop single-cycle vaccines that do not spread beyond the initially infected cells. Since these vaccines cannot spread throughout the host, they could be administered safely to immunocompromised individuals. We will develop bi- and triple-segmented rNDV vaccines that are able to express two or three foreign proteins. These viruses will induce a broader immune response compared to recombinant vaccines expressing just one protein of a foreign pathogen. We will also identify the NDV RNA packaging signals and incorporate these signals into the multiple-segmented rNDV vaccines to increase the efficiency of packaging multiple segments into the same virion. One problem with vaccine development is that vaccines are often not very effective in the aged population and strategies are needed to enhance vaccine protection in this group. We will determine whether an adjuvant that stimulates NKT cells, alpha-C-galactosylceramide, can enhance the immunogenicity of the NDV vaccines in both young and aged mice. Another strategy to enhance immunogenicity to rNDV vaccines includes re-targeting the rNDV vaccines to dendritic cells, which is the site of the initiation of the adaptive immune response. This will be accomplished by expressing a single-chain antibody to dendritic cell receptor, DEC-205, from the rNDV genome. We will collaborate with NBC investigator Dr. John Rose to determine whether prime-boost regimens involving vaccinating mice with rNDV expressing influenza virus HA protein and boosting with rVSV expressing influenza virus HA protein can enhance the immune response to influenza virus HA better than either vector alone. To determine whether the vaccines are protective, we will challenge mice with influenza H5N1 at Mount Sinai and collaborate with other RCE investigators to challenge animals vaccinated with Nipah and Chikungunya rNDV vaccines.