SUPPLEMENT TO: A Novel approach to RSV vaccination

补充：RSV 疫苗接种的新方法

• 批准号: 8846767
• 负责人: Joan E. Durbin
• 金额: $ 52.55万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2015-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846767
• 关键词: SUPPLEMENT; Novel; approach; RSV; vaccination

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，几乎所有人到两岁生日时都会受到感染。首次感染的婴儿最容易受到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，这种病毒在一生中经常会再次感染健康、免疫功能正常的个体。血清反应呈阳性的成年人和年龄较大的儿童的疾病通常仅限于上呼吸道，但每次再感染时都观察到明显的病毒脱落，从而将病毒保留在免疫群体中。这种针对 RSV 感染的相对无效的免疫反应的原因尚不清楚，但这种病原体较差的免疫原性迄今为止阻碍了开发安全有效的 RSV 疫苗的尝试。目前还没有针对 RSV 的治疗方法，只能以针对 RSV F 蛋白的人源化单克隆抗体的形式进行短暂预防。在 RSV 疫苗设计的新方法中，我们使用了源自禽类副粘病毒、新城疫病毒 (NDV) 的病毒载体，之所以选择它，是因为已知它是哺乳动物物种中 IFN-¿/¿ 产生的非常强的触发因素。正如预期的那样，将编码 RSV F 基因 (NDV-F) 的重组 NDV 鼻内滴注到小鼠体内，诱导的效果增加了 1000 倍。 IFN-¿/¿比同等剂量的RSV效果更好，NDV-F引发后3周，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 本身诱导出明显更多的 RSV F 蛋白特异性记忆 CD8+ T 细胞。这一结果现已在另外两种啮齿动物（龙猫和棉鼠）中得到重现。 为了测试 NDV-F 候选疫苗的安全性、有效性和建立长期保护作用，我们提出以下目标： 1）生成优化的 NDV-F 候选疫苗。 2)评估NDV-F引发后T细胞和B细胞对HRSV F蛋白的反应、棉鼠免受活病毒攻击的保护、组织病理学和免疫记忆。 3) 评估 NDV-FB 引发后 T 和 B 细胞对 BRSV F 蛋白的反应、对活病毒攻击的保护、组织病理学和牛的免疫记忆。 4）在GMP条件下大规模生产基因稳定的NDV-F。有大量证据表明，鼻内疫苗接种可能是预防呼吸道病毒的最有效方法。我们的实验室正在致力于开发一种针对呼吸道合胞病毒的鼻内疫苗，这种病毒是导致大多数儿童鼻子和肺部感染的病毒。该方法涉及使用对人类无害的新城疫病毒 (NDV) 来传递 RSV 片段供免疫系统处理。这个想法在老鼠身上效果很好。一剂疫苗可保护动物免于日后感染 RSV。在这项提案中，我们将在棉鼠和牛身上测试这种疫苗的安全性和有效性，这些动物患有这种病毒的类似疾病。如果它看起来安全有效，我们可以将其转移到人体试验中。