A Novel Approach to RSV Vaccination

RSV 疫苗接种的新方法

• 批准号: 8056668
• 负责人: Joan E. Durbin
• 金额: $ 60.01万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056668
• 关键词: Animal Model; Animals; Antiviral Agents; Avulavirus; B-Lymphocytes; Bovine Respiratory Syncytial Virus; Bronchiolitis; CD8B1 gene; Cattle; Cells; Child; Chimeric Proteins; Chinchilla (genus); Clinical Trials; Cotton Rats; Dendritic Cells; Disease; Dose; Effectiveness; Elderly; Generations; Genes; Histopathology; Human; Human respiratory syncytial virus; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunologic Memory; Individual; Infant; Infection; Interferons; Laboratories; Life; Link; Lower Respiratory Tract Infection; Lung; Lymphocyte; Mediating; Memory; Mus; Newcastle disease virus; Nose; Paramyxovirus; Patients; Persons; Phase; Pneumonia; Population; Process; Production; Prophylactic treatment; Proteins; Recombinants; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Rodent; Rodent Model; Safety; Sigmodon; T-Lymphocyte; Testing; Time; Translating; Vaccination; Vaccine Design; Vaccines; Viral Antigens; Viral Vector; Virus; Virus Activation; Virus Diseases; Virus Shedding; Work; base; cytokine; experience; human subject; humanized monoclonal antibodies; immunogenicity; in vivo; large scale production; novel strategies; pathogen; prevent; respiratory virus; response; safety testing; vaccine candidate; vaccine safety; vector; vector vaccine

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is a paramyxovirus that infects essentially all persons by their second birthday. Infants experiencing their first infection are most susceptible to lower airway infection in the form of bronchiolitis and pneumonia, but older adults and immunocompromised patients also experience severe RSV disease. In addition, this virus frequently reinfects healthy, immunocompetent individuals throughout life. Disease in seropositive adults and older children is usually limited to the upper airway, but significant virus shedding has been observed at each reinfection thus maintaining the virus within an immune population. The reason for this relatively ineffective immune response to RSV infection is not well understood, but the poor immunogenicity of this pathogen has so far confounded attempts to develop a safe and effective RSV vaccine. Currently there is no treatment for RSV, only transient prophylaxis in the form of a humanized monoclonal antibody targeting the RSV F protein. In a new approach to RSV vaccine design we made use of a viral vector derived from an avian paramyxovirus, Newcastle disease virus (NDV), chosen because it is known to be a very strong trigger for IFN-¿/¿ production in mammalian species As expected, intranasal instillation of recombinant NDV encoding the RSV F gene (NDV-F) into mice induced 1000 times more IFN-¿/¿ than did an equivalent dose of RSV, and 3 weeks after NDV-F priming mice were protected from live virus challenge. In addition, as we had hoped, NDV-F priming elicited significantly more RSV F protein-specific memory CD8+ T cells than did RSV itself. This result has now been reproduced in two additional rodent species (chinchillas and cotton rats).To test the NDV-F vaccine candidate for safety, efficacy, and establishment of long-lived protection we propose the following aims: 1) Generation of an optimized NDV-F vaccine candidate. 2) Assessment of T and B cell responses to the HRSV F protein following NDV-F priming, protection from live virus challenge, histopathology, and immunological memory in the cotton rat. 3) Assessment of T and B cell responses to the BRSV F protein following NDV-FB priming, protection from live virus challenge, histopathology, and immunological memory in the cow. 4) Large scale production of genetically stable NDV-F under GMP conditions. There is a large body of evidence to suggest that vaccinations placed in the nose may be the most effective means of protection against respiratory viruses. Our laboratory is working to develop an intranasal vaccine against respiratory syncytial virus, a virus responsible for the majority of nose and lung infections in children. The approach involves using Newcastle disease virus (NDV), which is not harmful to humans, to deliver pieces of RSV for processing by the immune system. This idea has worked very well in mice; one dose of the vaccine protects the animals from being infected later with RSV. In this proposal we will test this vaccine for safety and effectiveness in cotton rats and cattle, the animals who suffer a similar disease with this virus. If it appears safe and effective, we can move this into human trials.

描述（由申请人提供）： 呼吸道合胞病毒（RSV）是一种副粘病毒，基本上感染所有人的第二个生日。经历首次感染的婴儿最容易发生细支气管炎和肺炎形式的下呼吸道感染，但老年人和免疫功能低下的患者也会经历严重的RSV疾病。此外，这种病毒经常重新感染健康，免疫功能正常的人一生。血清阳性成人和年龄较大的儿童的疾病通常限于上呼吸道，但在每次再感染时观察到显著的病毒脱落，从而将病毒维持在免疫群体中。对RSV感染的这种相对无效的免疫应答的原因尚不清楚，但这种病原体的不良免疫原性迄今为止混淆了开发安全有效的RSV疫苗的尝试。目前没有RSV的治疗方法，只有靶向RSV F蛋白的人源化单克隆抗体形式的短暂预防。在RSV疫苗设计的一种新方法中，我们使用了一种来源于禽副粘病毒纽卡斯尔病病毒（NDV）的病毒载体，选择该病毒载体是因为已知其是哺乳动物物种中IFN-γ产生的非常强的触发剂。在NDV-F致敏后3周，保护小鼠免受活病毒攻击。此外，正如我们所希望的那样，NDV-F引发比RSV本身引起显著更多的RSV F蛋白特异性记忆CD 8 + T细胞。为了测试NDV-F疫苗候选物的安全性、有效性和建立长期保护，我们提出以下目标：1）产生优化的NDV-F疫苗候选物。2)评估NDV-F致敏后棉鼠中T和B细胞对HRSV F蛋白的应答、对活病毒攻击的保护、组织病理学和免疫记忆。3)评估NDV-FB初免后T和B细胞对牛呼吸道合胞病毒F蛋白的应答、对活病毒攻毒的保护、组织病理学和免疫记忆。4)在GMP条件下大规模生产遗传稳定的NDV-F。大量证据表明，鼻内接种疫苗可能是预防呼吸道病毒的最有效方法。我们的实验室正在努力开发一种针对呼吸道合胞病毒的鼻内疫苗，这种病毒是导致儿童鼻和肺部感染的主要原因。该方法涉及使用对人类无害的纽卡斯尔病病毒（NDV）来传递RSV片段，以供免疫系统处理。这个想法在小鼠身上效果很好;一剂疫苗可以保护动物免受RSV感染。在这项提议中，我们将在棉鼠和牛身上测试这种疫苗的安全性和有效性，这些动物患有与这种病毒类似的疾病。如果它看起来安全有效，我们可以将其用于人体试验。