Immune Response and Vaccine Efficacy in a Rodent Model

本研究的长期目标是研制一种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)在非人类灵长类动物研究中被证明是有效的hPIV-1疫苗，反向基因工程的发展现在允许将更多的基因作为乘客插入仙台病毒基因组。重组哨兵病毒(RSV)整合了其他呼吸道病毒病原体膜蛋白的乘客基因，因此可以对hPIV-1和其他病毒提供保护性免疫。为信心十足的疫苗配方提供基础，以便在 针对灵长类动物和人类，这一部分提出了一个广泛的实验过程，以在实验室啮齿动物模型--棉花鼠(Sigmodon Hispidus)--中建立安全性和有效性，在该模型中，人类呼吸道病毒在鼻腔接种后生长良好。 该项目最初的具体目标包括测试和比较携带RSV或hPIV-3附着和融合蛋白基因的单个RSV毒株。实验旨在评估RSV接种产生的体液和细胞免疫反应的活力，并评估相关的保护性免疫和免疫病理反应。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鸡尾酒，该鸡尾酒将安全有效地发挥作用，提供对RSV、hPIV-1和hPIV-3的保护。 本项目(项目2)中提出的研究将与项目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，这反过来将支持项目3中的非人类灵长类动物和临床研究。最终，我们建议该互动项目的研究将为儿童生产安全、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.