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

一种基于免疫优势的泛肺炎病毒疫苗，用于预防 RSV 和 hMPV

• 批准号: 10735979
• 负责人: Jarrod Mousa
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10735979
• 关键词: 2019-nCoV; Acute; Advanced Development; African Green Monkey; Animal Model; Animals; Antibodies; Antigens; COVID-19 pandemic; Cell surface; Cessation of life; Child; Childhood; Chimeric Proteins; Clinical Trials; Complex; Cotton Rats; Development; Dose; Ensure; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Glycoproteins; Goals; Hospitalization; Human Metapneumovirus; Immune; Immune response; Immunity; Immunodominant Epitopes; Immunologics; Individual; Infection; Interferometry; Lower Respiratory Tract Infection; Messenger RNA; Modeling; Monkeys; Monoclonal Antibodies; Mus; Pneumovirus; Pre-Clinical Model; Protein Subunits; Proteins; Rapid screening; Recombinant Proteins; Research; Research Personnel; Research Project Grants; Respiratory syncytial virus; Respiratory syncytial virus RSV proteins; Rodent; Safety; Serology; Structure; Technology; Testing; Vaccinated; Vaccination; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; design; evidence base; immunogenicity; improved; in vivo; innovation; lipid nanoparticle; mRNA Stability; manufacture; mouse model; neutralizing antibody; nonhuman primate; novel vaccines; permissiveness; pre-clinical; protective efficacy; protein structure; respiratory pathogen; screening; success; synergism; vaccine candidate; vaccine development

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.

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疫苗 假设嵌合肺病毒融合（F）蛋白疫苗显示出免疫显性表位 呼吸道合胞病毒 (RSV) 和人类偏肺病毒 (hMPV) 将针对这两种病毒产生广泛的保护 病毒。 RSV 和 hMPV 是广泛流行的儿童病毒性呼吸道感染病原体，导致数千人死亡 每年有数十万人死亡和数十万人住院。目前尚无批准的疫苗 来引发针对这两种病毒的保护性抗体，并且没有特定的治疗选择。 F RSV 和 hMPV 的糖蛋白作为中和抗体的靶标已得到充分研究，并且有一些 RSV 候选疫苗正在进行临床试验。我们开发了一种新型候选疫苗（RHMS-1） 涵盖 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。寻求嵌合候选疫苗的理由是基于 取决于几个因素，包括将免疫反应仅集中于那些引发有效中和的表位 抗体而不是效力较弱或非中和的表位来改善保护，减少疫苗逃逸 与之前包含单一表位的嵌合疫苗相比，以及对第一个嵌合疫苗的评估 小鼠模型之外的候选疫苗。此外，我们将确定保护的免疫相关性 非人类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知识 高度相关的临床前模型中的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。我们的研究将通过以下方式极大地推进该领域的发展 开发疫苗来预防急性下呼吸道感染的两个主要原因 孩子们。由于融合前的 RSV F 蛋白已被证明是安全的并且能够引发有效的 免疫反应，我们将在这一成功的基础上扩展这种疫苗以预防 hMPV。在目标 1 中， 我们将通过计算稳定并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，最佳候选者将在小鼠中快速筛选为这两种蛋白亚基 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 上表位的候选疫苗与 RSV F 和 hMPV F 蛋白相似。在目标 3 中，我们将 确定最佳候选 RHMS 疫苗对棉鼠和非洲绿猴的保护功效 RSV 和 hMPV 感染模型。我们的建议在概念上和实践上都具有创新性 设计和测试新型候选疫苗以预防两种重要的呼吸道病原体，以及 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当前的范例。 此外，该团队的创新性非常高，因为该提案汇集了不同的研究人员和 多项最先进的技术。