Susceptibility and Protective Immunity to Noroviruses

对诺如病毒的易感性和保护性免疫

• 批准号: 7064828
• 负责人: Ralph S Baric
• 金额: $ 37.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064828
• 关键词: Calicivirus; Norwalk virus; Venezuelan equine encephalitis virus; bioterrorism /chemical warfare; blood group antigens; clinical research; drug administration routes; feces analysis; genetic polymorphism; genetic susceptibility; hexosyltransferase; human subject; immunity; laboratory mouse; leukocyte count; longitudinal human study; patient oriented research; polymerase chain reaction; saliva; serology /serodiagnosis; transfection /expression vector; vaccine development; vector vaccine; virulence; virus cytopathogenic effect; virus diseases

DESCRIPTION (provided by applicant): Norwalk-like viruses (NLV), a genus within the Caliciviridae, are the major cause of epidemic gastroenteritis in the US and a significant cause of severe diarrhea in young children. Based on their low infectious dose, high transmissibility and economic impact, NLVs have been classified as Bioterrorism Category B Priority Pathogens by the U.S. Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases. The long-term goals of this proposal are to elucidate the molecular mechanisms governing human susceptibility to NLV infection. In this capacity, we will use human challenge models to test various hypotheses that specific human susceptibility alleles and acquired immune factors determine NLV infection outcomes and pathogenicity. It is anticipated that the identification of host factors and responses that influence NLV pathogenesis will reveal fundamental insights into the molecular biology of these viruses, simultaneously allowing for the development of NLV vaccine and therapeutic strategies. A second goal is to develop NLV vaccines using alphaviruses as heterologous vaccine vectors. Venezuelan equine encephalitis virus (VEE)-based vaccines elicit high levels of mucosal and systemic immunity against NLVs. We will test various hypotheses that VEE replicon particles (VRPs) encoding different genogroup I and II (GI and GII) NLV capsid genes elicit strong systemic, cellular and mucosal immune responses against homologous and heterologous NLVs and are superior to the current standards for NLV vaccine development (NLV recombinant virus-like particles (VLPs) and edible vaccines).

描述（由申请人提供）：诺沃克样病毒（NLV）是杯状病毒科的一个属，是美国流行性胃肠炎的主要原因，也是幼儿严重腹泻的重要原因。基于其低感染剂量、高传播性和经济影响，NLV 已被美国疾病控制与预防中心和国家过敏和传染病研究所列为生物恐怖主义 B 类优先病原体。 该提案的长期目标是阐明控制人类对 NLV 感染易感性的分子机制。以此能力，我们将使用人类挑战模型来测试特定人类易感性等位基因和获得性免疫因素决定 NLV 感染结果和致病性的各种假设。预计影响 NLV 发病机制的宿主因素和反应的识别将揭示这些病毒分子生物学的基本见解，同时允许开发 NLV 疫苗和治疗策略。第二个目标是开发使用甲病毒作为异源疫苗载体的 NLV 疫苗。基于委内瑞拉马脑炎病毒 (VEE) 的疫苗可引发针对 NLV 的高水平粘膜和全身免疫力。 我们将测试各种假设，即编码不同基因组 I 和 II（GI 和 GII）NLV 衣壳基因的 VEE 复制子颗粒（VRP）可引发针对同源和异源 NLV 的强烈全身、细胞和粘膜免疫反应，并且优于 NLV 疫苗开发的现行标准（NLV 重组病毒样颗粒（VLP）和食用 疫苗）。