Susceptibility and Protective Immunity to Noroviruses

描述(申请人提供)：诺瓦克样病毒(NLV)是杯状病毒科中的一个属，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。由于其低感染剂量、高传播性和经济影响，NLV已被美国疾病控制和预防中心和美国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。这项建议的长期目标是阐明人类对NLV感染的易感性的分子机制。在这个能力中，我们将使用人类挑战模型来检验各种假设，即特定的人类易感等位基因和获得性免疫因素决定NLV感染结果和致病性。预计对影响NLV致病的宿主因素和反应的识别将揭示对这些病毒分子生物学的基本见解，同时使NLV疫苗和治疗策略的开发成为可能。第二个目标是开发使用甲型病毒作为异源疫苗载体的NLV疫苗。委内瑞拉基于马脑炎病毒(VEE)的疫苗可诱导针对NLV的高水平粘膜和系统免疫。我们将验证各种假设，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)可诱导针对同源和异种NLV的强烈系统、细胞和粘膜免疫反应，并优于目前NLV疫苗开发的标准(NLV重组病毒样颗粒和可食性疫苗)。

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).