An authentic RSV virus-like particle vaccine to achieve broad and long-lasting protection

真正的 RSV 病毒样颗粒疫苗，可实现广泛而持久的保护

• 批准号: 10078596
• 负责人: Antonius G Oomens
• 金额: $ 18.48万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078596
• 关键词: Adjuvant; Affect; Age; Animal Model; Antibodies; Antibody Formation; Antigens; Benchmarking; CCR; CD8-Positive T-Lymphocytes; Cessation of life; Child; Chimeric Proteins; Collaborations; Cotton Rats; Data; Dependence; Development; Elderly; Exposure to; Formaldehyde; Funding; Future; GTP-Binding Proteins; Glycoproteins; Goals; Health; Human; Immune; Immune response; Immunity; Immunologist; Individual; Lung diseases; Memory; Modeling; Molecular Conformation; Morbidity - disease rate; Morphology; Mus; Nucleocapsid Proteins; Palivizumab; Pathology; Population; Preparation; Protein Subunits; Proteins; Pulmonary Pathology; Reporting; Resistance; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV proteins; Route; Specificity; Subgroup; Surface; Symptoms; System; T cell response; Target Populations; Testing; Traction; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Viral Antigens; Virion; Virus; Virus-like particle; attachment protein G; base; immunogenicity; improved; in vivo; mortality; neutralizing antibody; novel; preclinical trial; receptor binding; response; success; vaccination strategy; vaccine trial

SUMMARY RSV is responsible for >100,000 deaths in children worldwide, and significant morbidity and mortality in the elderly and immune-compromised. A past vaccine trial using inactivated virus failed to protect and caused virus-enhanced lung disease (VED) upon exposure to RSV. Since then, achieving an efficaceous vaccine that is also safe has proven enormously challenging. Absent of an approved vaccine, both live and non-live vaccine approaches are pursued, with each approach presenting unique qualities and hurdles. Among non-live approaches, virus-like-particles (VLPs) are gaining traction, due to successes with commercial VLP vaccines and recent reports showing protective anti-RSV immunity without VED and with improved memory in animal models using VLPs without adjuvants. In part because little is known about RSV particle assembly, all VLP approaches currently in preclinical trials are based on heterologous VLP systems, with most expressing the RSV fusion (F) protein, one of two major RSV glycoproteins. It is by now well recognized that the F protein is unstable and shifts to a post-fusion (non-functional) conformation during vaccine preparation. In recent developments, a pre-fusion stabilized F form (preF) was formulated, and was shown to induce a higher proportion of RSV-neutralizing antibodies than wildtype F, making preF a critical vaccine antigen. A large body of work however shows that other RSV antigens can significantly contribute to, and will likely enhance, preF-based protection across strains. Furthermore, even a successful single-antigen vaccine can induce resistant viruses in the population, as demonstrated with Palivizumab studies in cotton rats and in humans. One avenue to broaden efficacy and simultaneously avoid dependence on a singular antigen is to use a homologous RSV VLP platform including multiple RSV antigens. In the past years, we have learned to generate RSV-based VLPs that are morphologically indistinguishable from wildtype RSV. Recently, we have been able to generate two unique RSV-based VLPs, one displaying on its surface the preF protein, the other a conserved region of the attachment protein G. G is an important antigen as anti-G antibodies can neutralize virus and reduce lung pathology. G is quite variable between strains, except for the central conserved region (G-CCR). We have developed VLPs that exclusively, and recognizably, display the G-CCR on their surface, to augment the immune response to this important region, which also contains a receptor binding domain. Here, we propose a vaccine consisting of combinations of authentic RSV VLPs, separately displaying the preF protein or the G-CCR. By using distinct RSV-based VLPs, an optimal ratio of F to G antigenicity can be determined. Additionally, these VLPs include conserved core RSV antigens for which antibodies and/or CD8 T cell responses were observed in humans. Our hypothesis is that the induced response should be more efficaceous, better protective against divergent strains, better avoid escape viruses than an F-alone based approach, and be devoid of the immune dysregulation observed with live virus and hence be more durable.

摘要 呼吸道合胞病毒导致全球100,000名儿童死亡，并导致世界各地严重的发病率和死亡率。 年事已高，免疫力受损。过去使用灭活病毒的疫苗试验未能起到保护作用，并导致 暴露在RSV环境中的病毒增强型肺部疾病(VED)。从那时起，实现了一种有效的疫苗 也是安全的已经被证明是巨大的挑战。没有批准的疫苗，无论是活疫苗还是非活疫苗 我们追求各种方法，每种方法都有独特的品质和障碍。 在非活方法中，由于商业上的成功，病毒样颗粒(VLP)正在获得吸引力 VLP疫苗和最近显示无VED和改进的保护性抗RSV免疫的报告 使用无佐剂VLP的动物模型的记忆。部分原因是对RSV颗粒知之甚少 组装，目前处于临床前试验的所有VLP方法都基于异种VLP系统，大多数 表达RSV融合(F)蛋白，这是RSV的两种主要糖蛋白之一。到目前为止，人们已经充分认识到 F蛋白是不稳定的，在疫苗制备过程中转变为融合后(非功能性)构象。在……里面 最近的发展，一种融合前稳定的F型(PREF)被制定，并被证明诱导更高的 RSV中和抗体的比例高于野生型F，使Pref成为关键的疫苗抗原。 然而，大量工作表明，其他RSV抗原可以显著地促进并很可能 加强基于首选的跨菌株保护。此外，即使是成功的单一抗原疫苗也可以 在人群中诱导耐药病毒，如Palivizumab在棉鼠和 人类。扩大疗效并同时避免依赖单一抗原的一种方法是 使用包含多种RSV抗原的同源RSV VLP平台。在过去的几年里，我们已经学会了 产生基于RSV的VLP，这些VLP在形态上与野生型RSV没有区别。最近，我们有 能够产生两个独特的基于RSV的VLP，一个在其表面显示pref蛋白，另一个在其表面显示 G蛋白的保守区是一种重要的抗原，因为抗G抗体可以中和 病毒和减少肺部病理。G在不同菌株之间有很大的差异，除了中心保守区 (G-CCR)。我们已经开发出了VLP，这种VLP只在它们的表面上可识别地显示G-CCR，以 增强对这一重要区域的免疫反应，该区域还包含一个受体结合域。 在这里，我们提出了一种由正品RSV VLP的组合组成的疫苗，分别显示了偏好 蛋白质或G-CCR。通过使用不同的基于RSV的VLP，F和G抗原性的最佳比率可以是 下定决心。此外，这些VLP包括保守的核心RSV抗原，其抗体和/或CD8T 在人类身上观察到了细胞反应。我们的假设是，诱导的反应应该比 有效，更好地保护不同的菌株，更好地避免逃逸病毒，而不是单独使用F- 方法，并且不存在活病毒观察到的免疫失调，因此更耐用。