A rationally-designed, live-attenuated RSV vaccine for the elderly

设计合理的老年人RSV减毒活疫苗

• 批准号: 10208694
• 负责人: Steffen Mueller
• 金额: $ 66.55万
• 依托单位: CODAGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208694
• 关键词: 1 year old; Adult; Age; Age-Years; Animal Model; Animals; Antibody Response; Antibody titer measurement; Antigens; Attenuated; Attenuated Vaccines; Books; Bronchiolitis; Buffers; CD8-Positive T-Lymphocytes; Cellular Immunity; Cessation of life; Child; Clinical; Clinical Research; Clinical Trials; Collaborations; Computer Assisted; Cotton Rats; Cyclic GMP; Data; Development; Devices; Disease; Documentation; Dose; Drug Formulations; Elderly; Engineering; Excipients; Exhibits; Formulation; Freezing; Genes; Genetic; Histopathology; Hospitalization; Human; Human poliovirus; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunological Models; Inactivated Vaccines; Infant; Infection; Influenza; Intranasal Administration; Investigation; Lead; Life; Lung; Mediating; Modeling; Mus; Mutation; Open Reading Frames; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Pneumonia; Polymerase; Population; Populations at Risk; Preclinical Testing; Preparation; Proteins; Regimen; Research Contracts; Resistance; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Safety; Schedule; Services; Small Business Innovation Research Grant; Sucrose; Symptoms; T cell response; T-Lymphocyte; Target Populations; Technology; Testing; Time; United States Food and Drug Administration; United States National Institutes of Health; Vaccines; Vero Cells; Vial device; Viral; Virus; Virus Diseases; Work; aged; base; cell mediated immune response; chemical synthesis; cytotoxic CD8 T cells; design; efficacy testing; human disease; human old age (65+); immunogenicity; immunosenescence; influenza virus vaccine; lead candidate; meetings; nonhuman primate; novel; patient population; preclinical safety; respiratory pathogen; respiratory virus; safety testing; stability testing; vaccination schedule; vaccine candidate; vaccine development; vaccine trial; years of life lost

PROJECT SUMMARY/ABSTRACT Respiratory syncytial virus (RSV) is a common respiratory virus that usually causes mild, cold-like symptoms. Most people recover within two weeks, but RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age, and leads to hospitalization of ~177,000 adults aged 65 and older of which ~14,000 die annually. Despite many attempts, a vaccine to protect these at-risk populations from RSV infection remains elusive. To remediate this critical unmet need, Codagenix has applied its core technology, Synthetic Attenuated Virus Engineering (SAVE) to the development of an RSV vaccine. SAVE is based on rational, computer-aided gene design and chemical synthesis to produce live attenuated viruses through gene “deoptimization.” SAVE generates live-attenuated viruses that are 100% antigenically identical to wild type virus in all their proteins. MinL4.0, our lead RSV vaccine candidate contains 1,378 synonymous mutations in the polymerase L open reading frame. It grows well at 32°C, is highly attenuated, displays wt-like immunogenicity, and is genetically stable for at least 8 passages at 32°C in Vero cells. In this Phase IIb SBIR, we will build on our successful Phase II SBIR and subsequent studies to further develop MinL4.0. Our initial target patient population will be adults aged 50-75, a population that is at-risk for severe RSV disease. In this Phase IIb work, we will reformulate MinL4.0 to make it commercially suitable for intranasal administration and storage and then perform FDA-required stability and release testing of the re-formulated vaccine. We will also perform preclinical safety and efficacy testing in cotton rats. No animal model of RSV recapitulates all of the aspects of human RSV disease, but the cotton rat is probably the best small animal model. The cotton rat is relatively permissive, can be infected throughout its life, exhibits immuno-senescence, including T-cell loss as is found in older humans, and, like humans, is less resistant to RSV infection with age. Even though most adults have some immunity to RSV and elderly adults are at risk for severe RSV infections, vaccine studies are typically performed in young RSV naïve animals. Here, we will develop a new model of RSV pre-immunity in aged cotton rats to more accurately model conditions found in older adults and serve as a more relevant and stringent pre-clinical test of safety and efficacy that can be used by others. We will then test the safety and efficacy of MinL4.0 in this new pre-immune aged cotton rat model of RSV disease. Our animal studies will be conducted in partnership with Sigmovir, a contract research organization whose sole focus is the study of infectious human diseases in the cotton rat model. Finally, based on these and other data, we will complete all required documentation and submit an Investigational New Device (IND) application to the US Food and Drug Administration (FDA) in order to conduct Phase I clinical trials in adults 50-75 years of age.

项目总结/摘要 呼吸道合胞病毒（RSV）是一种常见的呼吸道病毒，通常会导致轻微的感冒样症状。 大多数人在两周内康复，但RSV是细支气管炎和肺炎的最常见原因， 1岁以下儿童，导致约177，000名65岁及以上的成年人住院， 每年约有14，000人死亡。尽管进行了许多尝试，但保护这些高危人群免受RSV感染的疫苗 仍然难以捉摸为了弥补这一关键的未满足的需求，Codagelet应用了其核心技术，合成 减毒病毒工程（SAVE）用于RSV疫苗的开发。SAVE基于理性， 计算机辅助基因设计和化学合成， “去优化”SAVE产生与野生型100%抗原相同的减毒活病毒 病毒在所有的蛋白质中。MinL4.0是我们的主要RSV候选疫苗，包含1，378个同义突变， 聚合酶L开放阅读框。它在32°C下生长良好，高度衰减，显示WT样 在某些实施方案中，该化合物具有免疫原性，并且在32°C下在Vero细胞中遗传稳定至少8次传代。在本阶段IIb SBIR中，我们 我们将在成功的第二阶段SBIR和后续研究的基础上进一步开发MinL4.0。我们最初 目标患者群体将是50-75岁成人，这是处于严重RSV疾病风险中的群体。在这 IIb期工作，我们将重新配制MinL4.0，使其适合鼻内给药 和储存，然后进行FDA要求的重新配制疫苗的稳定性和放行测试。我们将 还在棉鼠中进行临床前安全性和有效性测试。没有RSV的动物模型能概括所有的 在人类RSV疾病方面，但棉鼠可能是最好的小动物模型。棉鼠是 相对允许的，可以在其整个生命中被感染，表现出免疫衰老，包括T细胞损失， 在老年人中发现，并且与人类一样，随着年龄的增长，对RSV感染的抵抗力降低。尽管大多数 成年人对RSV有一定的免疫力，老年人有严重RSV感染的风险，疫苗研究 通常在未感染RSV的幼年动物中进行。在这里，我们将开发一种新的RSV预免疫模型， 老年棉鼠更准确地模拟老年人的情况，并作为一个更相关的， 对安全性和有效性进行严格的临床前测试，可供他人使用。然后我们将测试安全性， MinL4.0在这种新的RSV疾病的免疫前老龄棉鼠模型中的功效。我们的动物研究将是 与Sigmovir合作进行，Sigmovir是一家合同研究组织，其唯一的重点是研究 棉花鼠模型中的人类传染病。最后，根据这些数据和其他数据，我们将完成所有 要求的文件，并向美国食品和药物管理局提交研究性新器械（IND）申请， 美国药品监督管理局（FDA）的一项研究，以便在50-75岁的成年人中进行I期临床试验。