Immune Response and Vaccine Efficacy in a Rodent Model

本研究的长期目标是生产针对呼吸道合胞病毒（RSV）、人副流感病毒1型（hPIV-1）和人副流感病毒3型（hPIV-3）的有效疫苗。仙台病毒（小鼠PIV-1）已被证明是一种有效的疫苗，hPIV-1在非人类灵长类动物的研究，和发展，现在允许在反向基因工程额外的基因插入作为乘客在仙台病毒基因组。重组仙台病毒（rSV），纳入乘客基因的其他呼吸道病毒病原体的膜蛋白，因此可以提供保护性免疫hPIV-1和其他病毒。为确定待测试疫苗的配方奠定基础， 本节提出了一个广泛的实验过程，以确定在实验室啮齿动物模型，棉鼠（Sigmodon hispidus），其中人类呼吸道病毒在鼻内接种后生长良好的安全性和有效性。 本项目的初始特定目的包括检测和比较携带RSV或hPIV-3附着和融合蛋白基因的rSV单个毒株。设计实验以评估由rSV接种产生的体液和细胞免疫应答的活力，并评价相关的保护性免疫和免疫病理学反应。我们的最后一个目标是测试日益复杂的rSV毒株组合，最终目标是配制一种优化的rSV混合物，该混合物将安全有效地提供对RSV、hPIV-1和hPIV-3的保护。 本项目（项目2）中建议的研究将与项目1和项目3高度互动。项目1的产品和概念将支持每个特定目标，这反过来又将支持项目3中的非人灵长类动物和临床研究。最终，我们建议这项互动计划项目的研究将为儿童提供安全，有效和负担得起的呼吸道病毒疫苗。

The long term objective of this research is to produce an effective vaccine against respiratory syncytial virus (RSV), human parainfluenza virus-type 1 (hPIV-1) and human parainfluenza virus-type 3 (hPIV-3). Sendai virus (mouse PIV-1) has proven effective as a vaccine for hPIV-1 in non-human primate studies, and developments in reverse genetic engineering now permit additional genes to be inserted as passengers in the Sendal virus genome. The recombinant Sendal viruses (rSV) that incorporate passenger genes for membrane proteins of other respiratory viral pathogens may thus provide protective immunity both to hPIV-1 and to the other viruses. To provide a foundation for the confident formulation of vaccines to be tested in primates and humans, this section proposes an extensive course of experimentation to establish safety and efficacy in a laboratory rodent model, the cotton rat (Sigmodon hispidus), in which human respiratory viruses grow well after intranasal inoculation. Initial Specific Aims in this project involve testing and comparing individual strains of rSV that carry genes for the attachment and fusion proteins of RSV or hPIV-3. Experiments are designed to assess the vigor of the humoral and cellular immune responses generated by rSV inoculations, and to evaluate associated protective immunity and immunopathological reactions. Our last Aim is to test increasingly complex combinations of rSV strains, with the final objective of formulating an optimized rSV cocktail that will function safely and effectively to provide protection from RSV, hPIV-1 and hPIV-3. Studies proposed in this Project (Project 2) will be highly interactive with Projects 1 and 3. Products and concepts from Project 1 will support each of the Specific Aims, which will, in turn, support the non-human primate and clinical studies in Project 3. Ultimately, we propose that the research from this interactive Program Project will yield a safe, effective and affordable respiratory virus vaccine for children.