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: 10449335
• 负责人: Steffen Mueller
• 金额: $ 80.94万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449335
• 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; Persons; 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; rational design; respiratory pathogen; respiratory virus; safety testing; stability testing; vaccination schedule; vaccine candidate; vaccine formulation; 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.

项目摘要/摘要 呼吸道合胞病毒(RSV)是一种常见的呼吸道病毒，通常会引起轻微的感冒症状。 大多数人在两周内康复，但呼吸道合胞病毒是导致毛细支气管炎和肺炎的最常见原因。 一岁以下儿童，导致约177,000名65岁及以上的成年人住院，其中 每年约有14,000人死亡。尽管多次尝试，一种保护这些高危人群免受RSV感染的疫苗 仍然难以捉摸。为了补救这一严重的未得到满足的需求，Codagenix应用了其核心技术--合成 减毒病毒工程(SAVE)对RSV疫苗的开发。储蓄是基于理性的， 计算机辅助基因设计和化学合成通过基因生产减毒活病毒 “去最优化。”SAVE产生的减毒活病毒与野生型在抗原性上100%相同 病毒存在于它们所有的蛋白质中。MinL4.0，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，显示出wt状 免疫原性，在32℃下在Vero细胞中至少8代遗传稳定。在此阶段IIb SBIR中，我们 将在我们成功的第二阶段SBIR和后续研究的基础上进一步开发MinL4.0。我们最初的 目标患者人群将是50-75岁的成年人，这一人群有患严重RSV疾病的风险。在这 第二阶段工作，我们会重新配制MinL4.0，使其在商业上适合鼻腔给药。 和储存，然后对重新配制的疫苗进行FDA要求的稳定性和释放测试。我们会 还在棉鼠身上进行临床前安全性和有效性测试。没有一种RSV的动物模型可以概括所有的 在人类呼吸道合胞病毒病方面，但棉鼠可能是最好的小动物模型。棉花鼠是 相对宽容，可在其一生中感染，表现出免疫衰老，包括T细胞损失 在老年人中发现，并且像人类一样，随着年龄的增长对RSV感染的抵抗力降低。即使大多数人 成年人对RSV有一定的免疫力，老年人有严重RSV感染的风险，疫苗研究是 通常在幼小的RSV幼稚动物身上进行。在这里，我们将开发一种新的RSV预免疫模型 以更准确地模拟在老年人中发现的情况，并作为更相关和 严格的临床前安全性和有效性测试，可供其他人使用。然后我们将测试安全性和 MinL4.0在这一新的免疫前老年棉鼠RSV病模型中的疗效。我们的动物研究将是 与Sigmovr合作进行，这是一个合同研究机构，其唯一重点是研究 棉鼠模型中的人类传染性疾病。最后，基于这些和其他数据，我们将完成所有 并向美国食品和药物管理局提交调查性新设备(IND)申请 药物管理局(FDA)，以便在50-75岁的成年人中进行I期临床试验。

项目成果

Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy.

• DOI: 10.1073/pnas.2102775118
• 发表时间: 2021-07-20
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Wang Y;Yang C;Song Y;Coleman JR;Stawowczyk M;Tafrova J;Tasker S;Boltz D;Baker R;Garcia L;Seale O;Kushnir A;Wimmer E;Mueller S
• 通讯作者: Mueller S