An immunodominance-based Pan-Pneumovirus vaccine for protection against RSV and hMPV

该研究项目的目标是进一步开发泛肺炎病毒疫苗，并测试我们的 假设展示以下免疫显性表位的嵌合肺炎病毒融合（F）蛋白疫苗 呼吸道合胞病毒（RSV）和人偏肺病毒（hMPV）将诱导广泛的保护， 病毒RSV和hMPV是儿童病毒性呼吸道感染的广泛流行因子， 死亡和成千上万的住院治疗。目前还没有批准的疫苗 以引发针对任何一种病毒的保护性抗体，并且没有特定的治疗选择。的F RSV和hMPV的糖蛋白作为中和抗体的靶标已经被充分研究，并且几种 RSV的候选疫苗正在进行临床试验。我们已经开发了一种新的候选疫苗（RHMS-1） 包括RSV和hMPV F蛋白的免疫显性表位，并验证了其保护性 在小鼠和棉鼠模型中的功效。寻求嵌合疫苗候选物的基本原理是基于 取决于几个因素，包括将免疫反应仅集中在那些引起有效中和的表位上 抗体，而不是效力较低或非中和表位，以提高保护，减少疫苗逃逸 与先前的包含单一表位的嵌合疫苗相比， 小鼠模型之外的候选疫苗。此外，我们将确定免疫相关的保护， 非人灵长类动物模型中的hMPV感染。这些重要的研究将提供丰富的免疫学 高度相关的临床前模型中的信息，这些信息将指导基于证据的优化路径 安全有效的泛肺炎病毒疫苗我们的研究将大大推进该领域， 研制一种疫苗，预防急性下呼吸道感染的两种主要原因， 孩子由于融合前RSV F蛋白已经证明了安全性和引发有效免疫应答的能力， 免疫应答，我们将在此成功的基础上扩展该疫苗以保护免受hMPV。在目标1中， 我们将使用Rosetta增强蛋白质， 稳定性和免疫原性，并且最佳候选物将在小鼠中快速筛选为两种蛋白亚基 和mRNA-脂质纳米颗粒疫苗。在目标2中，我们将对我们的顶部进行结构和表位分析。 用于验证RHMS上的表位的候选疫苗与RSV F和hMPV F蛋白相似。在目标3中，我们 确定最佳候选RHMS疫苗在棉鼠和非洲绿色猴中的保护效力 RSV和hMPV感染模型。我们的建议在概念上和实际上都是创新的， 设计和测试新的候选疫苗，以预防两种重要的呼吸道病原体， 我们通过提供用于双重病毒保护的单一抗原来挑战该领域中的当前范例。 此外，该团队的创新性非常高，因为该提案汇集了不同的调查人员， 几种最先进的技术。

The goal of this research project is to further the development of a pan-Pneumovirus vaccine and to test our hypothesis that a chimeric Pneumovirus fusion (F) protein vaccine displaying immunodominant epitopes of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) will induce broad protection against both viruses. RSV and hMPV are widely prevalent agents of childhood viral respiratory infection, causing thousands of deaths and hundreds of thousands of hospitalizations each year. There are currently no approved vaccines to elicit protective antibodies against either virus, and no specific treatment options are available. The F glycoproteins of RSV and hMPV have been well-studied as targets of neutralizing antibodies, and several vaccine candidates for RSV are in clinical trials. We have developed a novel vaccine candidate (RHMS-1) encompassing immunodominant epitopes of both RSV and hMPV F proteins and verified its protective efficacy in mouse and cotton rat models. The rationale for pursuing a chimeric vaccine candidate is based on several factors, including focusing the immune response to only those epitopes that elicit potent neutralizing antibodies rather than less potent or non-neutralizing epitopes to improve protection, reducing vaccine escape compared to previous chimeric vaccines incorporating a single epitope, and the assessment of the first chimeric vaccine candidate beyond the mouse model. Additionally, we will determine immune correlates of protection for hMPV infection in a nonhuman primate model. These critical studies will provide a wealth of immunologic information in highly relevant, pre-clinical models that will guide an evidence-based path toward the optimization of a safe and effective pan-Pneumovirus vaccine. Our research will substantially advance the field by developing a vaccine for protection against the two leading causes of acute lower respiratory tract infection in children. As the pre-fusion RSV F protein has already demonstrated safety and the ability to elicit an effective immune response, we will build upon this success to extend this vaccine for protection against hMPV. In Aim 1, we will computationally stabilize and redesign our vaccine candidate, RHMS-1, using Rosetta to enhance protein stability and immunogenicity, and the best candidates will be rapidly screened in mice as both protein subunit and mRNA-lipid nanoparticle vaccines. In Aim 2, we will conduct structural and epitope analysis of our top vaccine candidate to verify the epitopes on RHMS are similar to RSV F and hMPV F proteins. In Aim 3, we will determine the protective efficacy of the top candidate RHMS vaccine in cotton rat and African Green Monkey models of RSV and hMPV infection. Our proposal is both conceptually and practically innovative as we are designing and testing novel vaccine candidates for protection against two important respiratory pathogens, and we are challenging current paradigms in the field by providing a single antigen for dual-virus protection. Furthermore, the innovation of the team is very high, as this proposal brings together diverse investigators and several state of the art technologies.