Generation of Novel Recombinant Rabies Virus Vaccines

新型重组狂犬病病毒疫苗的产生

• 批准号: 7574388
• 负责人: Bernhard F Dietzschold
• 金额: $ 25.39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574388
• 关键词: Affect; Americas; Animals; Apoptosis; Attenuated Vaccines; Cells; Chiroptera; Coyotes; Data; Dendritic Cells; Development; Economic Burden; Engineering; Europe; Foundations; Foxes; Future; GTP-Binding Proteins; Generations; Genes; Goals; Human; Immune response; Immunity; Immunization; In Vitro; Infection; Interleukin-4; Life; Mediator of activation protein; Mephitidae; Methods; Neurons; Oral; Pathogenicity; Production; Proteins; Rabies; Rabies Vaccines; Rabies virus; Raccoons; Recombinant Cytokines; Recombinant Vaccines; Recombinants; Rhabdoviridae; Risk; Safety; Testing; Vaccines; Variant; Viral Pathogenesis; Virus; Wild Animals; base; cost; cytochrome c; cytokine; experience; immunogenicity; in vivo; interest; macrophage; novel; positional cloning; recombinant virus; thermostability; vaccine delivery; vaccine development; vaccine safety; vector

DESCRIPTION (provided by applicant): In the US, extensive reservoirs of the rabies virus exist in many diverse wild animal species that continue to pose a serious risk of lethal infection of humans and cause an economic burden exceeding $1 billion annually. Previous experience with rabies control in foxes in Europe has clearly demonstrated that oral immunization with live vaccines is the only practical approach to eradicating rabies in free-ranging animals. However, unlike Europe where vulpine rabies was the only major reservoir, the Americas harbor a variety of species including raccoons, skunks, coyotes, and bats that serve as the primary reservoirs of rabies. Each of these animal reservoirs carries an antigenically distinct virus variant. Because the currently available modified-live rabies virus vaccines have either safety problems or do not induce sufficient protective immunity, particularly in wildlife species, die overall goal of this proposal is the development of recombinant rabies virus vaccines that are very safe and highly effective in particular wildlife species. Based on preliminary data indicating that the potency of a vaccine is significantly increased if the G protein of the vaccine strain is identical to that of the target virus, we propose to use a reverse genetics approach to engineer viruses that contain G proteins from virus strains associated with relevant wildlife species. Our preliminary data also indicate that an increased ability of rabies virus to induce apoptosis leads to enhanced immunogenicity of the virus and to reduced pathogenicity. Moreover, our recent evidence indicates that the immunogenicity can also be enhanced by immunostimulatory cytokines. Thus, we will construct recombinant viruses that express genes encoding proapoptotic proteins and cytokines in order to stimulate immunity or otherwise interfere with viral pathogenesis in order to enhance their efficacy and safety. In addition to the practical implications of this approach for vaccine development, information derived from studying these viruses will provide a better understanding of factors that stimulate immunity against rabies and may provide a strategy based on co-expression of immunostimulatory proteins that finds broad application to other vaccines.

描述（由申请人提供）：在美国，狂犬病病毒的广泛水库存在于许多多样化的野生动物物种中，这些物种继续构成严重的人类致死感染的严重风险，并每年造成超过10亿美元的经济负担。以前在欧洲狐狸控制的狂犬病控制经验清楚地表明，用实时疫苗的口服免疫是消除自由行动动物中狂犬病的唯一实际方法。但是，与欧洲不同的是，vulpine狂犬病是唯一的主要水库，美洲藏有各种物种，包括浣熊，臭鼬，土狼和蝙蝠，这些物种是狂犬病的主要水库。这些动物储层中的每一个都带有一种抗原不同的病毒变体。由于当前可用的改良活着的狂犬病病毒疫苗要么有安全问题，要么没有诱导足够的保护性免疫，尤其是在野生动植物物种中，该提案的总体目标是开发重组狂犬病病毒疫苗，这些病毒疫苗在特定的野生动植物中非常安全且非常有效。基于初步数据，表明如果疫苗菌株的G蛋白与靶病毒相同，则疫苗的效力会显着提高，我们建议使用反向遗传学方法来对含有与相关野生生物物种相关的病毒菌株的G蛋白进行工程病毒。我们的初步数据还表明，狂犬病病毒诱导凋亡的能力提高导致病毒的免疫原性增强并降低致病性。此外，我们最近的证据表明，免疫刺激性细胞因子也可以增强免疫原性。因此，我们将构建重组病毒，以表达编码促凋亡蛋白和细胞因子的基因，以刺激免疫或以其他方式干扰病毒发病机理，以增强其功效和安全性。除了这种方法对疫苗开发的实际含义外，研究这些病毒所获得的信息还将更好地理解刺激对狂犬病免疫力的因素，并可能基于对免疫刺激蛋白的共表达提供策略，从而发现了对其他疫苗的广泛应用。