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

基于重组新城疫病毒的高 pri 病原体活疫苗

• 批准号: 8230244
• 负责人: Peter Palese
• 金额: $ 44.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230244
• 关键词: Adjuvant; Alpha Cell; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Attenuated; Attenuated Vaccines; Cells; Chikungunya virus; Collaborations; DEC-205 receptor; Dendritic Cells; Disease; Emerging Communicable Diseases; Galactosylceramides; Genes; Genome; Glycolipids; Goals; Grant; H5 influenza virus; Human; Immune response; Immunocompromised Host; Inactivated Vaccines; Individual; Influenza; Influenza A Virus, H5N1 Subtype; Length; Life; Mus; Newcastle disease virus; Nipah Virus; Population; Proteins; Recombinant Vaccines; Recombinants; Regimen; Research Personnel; Rosa; Safety; Signal Transduction; Site; Subunit Vaccines; Surface; System; Testing; Vaccinated; Vaccines; Vesicular stomatitis Indiana virus; Virion; Virulent; Virus; aged; base; biodefense; chikungunya; design; immunogenicity; improved; influenzavirus; novel; pandemic influenza; pathogen; research study; vaccine candidate; vaccine development; vaccine efficacy; vaccine safety; vector; vector vaccine; viral RNA

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.

这项资助的目的是进一步开发新型重组载体，纽卡斯尔病病毒（NDV）， 它可以作为一个平台，为人类接种疫苗，以对抗生物地球主义因子和新出现的传染病。一个 这种策略的优点是，通过插入病毒的蛋白质，可以快速制备新出现疾病的疫苗。 NDV基因组中。对于这笔赠款，我们将重点开发针对三种危险病原体的疫苗： 潜在的大流行性流感病毒、尼帕病毒和基孔肯雅病毒。我们将测试几种不同的策略， 改进rNDV疫苗。虽然NDV已经安全地应用于人类，但我们将开发单周期 疫苗不会扩散到最初感染的细胞之外。由于这些疫苗不能在整个宿主中传播， 它们可以安全地施用于免疫功能低下的个体。我们将开发二节段和三节段rNDV， 能够表达两种或三种外源蛋白的疫苗。这些病毒会引发更广泛的免疫反应 与只表达外源病原体的一种蛋白质的重组疫苗相比，我们还将鉴定NDV RNA包装信号，并将这些信号掺入多节段rNDV疫苗中以增加免疫应答。 将多个片段包装到同一病毒体中的效率。疫苗开发的一个问题是， 在老年人群中通常不是很有效，需要采取策略来加强疫苗保护， 组我们将确定刺激NKT细胞的佐剂α-C-半乳糖神经酰胺是否能增强NKT细胞的增殖。 NDV疫苗在幼龄和老龄小鼠中的免疫原性。另一种增强免疫原性的策略是 rNDV疫苗包括将rNDV疫苗重新靶向树突细胞，树突细胞是免疫应答的起始位点。 适应性免疫反应这将通过表达针对树突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， 初免-加强方案，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可以增强对流感病毒HA的免疫应答， vector单独为了确定疫苗是否具有保护性，我们将在Mount 西奈和其他RCE研究人员合作，挑战接种尼帕和基孔肯雅rNDV的动物 疫苗。