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

这项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 假设一种显示免疫优势表位的嵌合肺炎病毒融合(F)蛋白疫苗 呼吸道合胞病毒(Rsv)和人类偏肺病毒(Hmpv)将对这两种病毒产生广泛的保护作用。 病毒。RSV和hMPV是儿童病毒性呼吸道感染的广泛流行病原体，导致数千人 每年死亡和数十万人住院的人数。目前还没有批准的疫苗 以诱导针对这两种病毒的保护性抗体，并且没有特定的治疗方案可用。《F》 RSV和hMPV的糖蛋白作为中和抗体的靶标已经得到了很好的研究，并且有几种 RSV的候选疫苗正在进行临床试验。我们开发了一种新的候选疫苗(RHMS-1) 包含RSV和hMPV F蛋白的免疫优势表位，并验证其保护性 对小鼠和棉花大鼠模型的疗效。寻求嵌合疫苗候选疫苗的理由是 在几个因素上，包括将免疫反应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，以加强保护，减少疫苗逃逸 与以前含有单一表位的嵌合疫苗相比，以及对第一个嵌合疫苗的评估 候选疫苗超越了小鼠模型。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。这些关键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，将引导循证路径走向优化 一种安全有效的泛肺炎病毒疫苗。我们的研究将极大地推动该领域的发展 开发一种疫苗，用于预防中国人急性下呼吸道感染的两种主要原因 孩子们。由于融合前的RSV F蛋白已经证明是安全的，并且能够诱导有效的 在免疫反应方面，我们将在这一成功的基础上扩大该疫苗的范围，以保护其免受hMPV感染。在目标1中， 我们将通过计算稳定和重新设计我们的候选疫苗RHMS-1，使用Rosetta来增强蛋白质 稳定性和免疫原性，最好的候选者将在小鼠身上快速筛选出这两个蛋白质亚单位 以及信使核糖核酸-脂质纳米粒疫苗。在目标2中，我们将对我们的顶端进行结构和表位分析 疫苗候选以验证RHMS上的表位与RSV F和hMPV F蛋白相似。在《目标3》中，我们将 RHMS头号候选疫苗对棉鼠和非洲绿猴的保护效果测定 RSV和hMPV感染模型。我们的建议在概念上和实践上都是创新的。 设计和测试针对两种重要呼吸道病原体的新型候选疫苗，以及 我们正在通过为双病毒保护提供单一抗原来挑战该领域目前的范例。 此外，团队的创新力非常高，因为这项提议汇集了不同的调查人员和 几项最先进的技术。

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.