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

摘要 主要目标的父母奖有关这一补充是开发和测试在体内的新疫苗 为研制通用流感疫苗提供了新的候选人。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， 优先引发针对多种流感病毒的广泛交叉反应性抗体。作为父母的一部分 获得，我们提出在体内工程和测试两个血凝素（HA）头部为基础的免疫原与 目标是引发针对HA头部三聚体界面的广泛免疫反应。该HA区域是 在许多流感亚型中是保守的，并被多种广泛交叉反应性抗体所参与。我们 已经在小鼠中测试了两种工程HA头部免疫原的免疫原性，并发现它们 引发与多种流感亚型交叉反应的抗体，不像WT HA头部模板， 基于这些结果，我们在此申请资金，以进一步优化和测试HA 用于引发HA头部三聚体界面抗体的基于头部的免疫原。该补充将提供 资源，以测试额外的免疫原比那些计划在家长奖，并将提供更多的 通过与杜克大学的合作， 区域生物防护实验室。杜克RBL已经开发出多种小鼠和雪貂病毒 挑战模型与不同的流感毒株，现在将成为我们可以通过这种补充。 因此，这项建议将通过提供资源， 开发并严格测试体内HA头部衍生的免疫原，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.