In vivo Testing of Universal Influenza Vaccine Candidates at the Duke Regional Biocontainment Laboratory

摘要 与此补充相关的家长奖的主要目标是开发和测试体内新型疫苗。 这些候选人致力于开发一种通用的流感疫苗。通过使用计算蛋白质 设计和高通量文库筛选方法，我们的目标是产生新的免疫原， 优先激发针对不同流感病毒的广泛交叉反应抗体。作为父级的一部分 获奖后，我们建议设计并在体内测试两种血凝素(HA)头部免疫原用于 目标是诱导针对HA头部三聚体界面的广泛免疫反应。此HA区域是 在许多流感亚型中保守，并与多种广泛交叉反应的抗体接触。我们 已经在小鼠身上测试了两种工程HA头部免疫原的免疫原性，发现它们 诱导与多种流感亚型交叉反应的抗体，与WT HA头部模板不同，它们 都是基于。基于这些结果，我们在此应用程序中申请资金，以进一步优化和测试HA 基于头部的免疫原用于诱导HA头部三聚体界面抗体。本副刊将提供 用于测试比家长奖项中计划的免疫原更多的资源，并将提供更多 通过与公爵合作进行体内免疫原检测的生物学相关动物模型 区域生物遏制实验室(RBL)。公爵RBL已经开发出多种老鼠和雪貂病毒 挑战具有不同流感病毒株的模型，现在我们将通过本补充材料获得这些模型。 因此，这项提议将通过提供资源，进一步加强父奖项的工作。 开发并严格测试体内HA头部来源的免疫原，最终目标是发现一种通用的 流感疫苗。

Abstract The main goal of the parent award related this supplement is to develop and test in vivo novel vaccine candidates towards the development of a universal influenza vaccine. By employing computational protein design and high-throughput library screening methods, we aim to generate novel immunogens that preferentially elicit broadly cross-reactive antibodies against diverse influenza viruses. As part of the parent award, we proposed to engineer and test in vivo two hemagglutinin (HA) head-based immunogens with the goal of eliciting broadly immune responses that target the HA head trimer interface. This HA region is conserved across many influenza subtypes and is engaged by multiple broadly cross-reactive antibodies. We have already tested in mice the immunogenicity of two engineered HA head immunogens and found that they elicit antibodies that cross-react with multiple influenza subtypes, unlike the WT HA head template that they were based on. Based on these results, we request funds in this application to further optimize and test HA head-based immunogens for the elicitation of HA head trimer interface antibodies. This supplement will provide resources to test additional immunogens than those planned in the parent award, and will make available more biologically relevant animal models for in vivo immunogen testing through a collaboration with the Duke Regional Biocontainment Laboratory (RBL). The Duke RBL has developed multiple mouse and ferret viral challenge models with diverse influenza strains that will now become accessible to us through this supplement. This proposal will therefore augment the work of the parent award, by providing the resources to further develop and rigorously test in vivo HA head derived immunogens with the final goal of discovering a universal influenza vaccine.