F plus G RSV VLP Vaccine for Improved Safety and Efficacy

项目摘要 呼吸道合胞病毒(RSV)是引起婴幼儿严重下呼吸道疾病的主要原因之一。 世界各地的儿童。由于感染只能产生部分保护作用，它会导致反复感染和疾病。 在一生中。尽管疫苗开发是高度优先的，但目前还没有疫苗可用。缺乏成功 在开发疫苗方面，表明需要新的策略才能取得成功。呼吸道合胞病毒的大部分关注点 亚基疫苗已经出现在RSV F蛋白上。RSV：1)的G蛋白引起的炎症增加 呼吸道合胞病毒病和2)提供与原代人呼吸道上皮细胞的结合，以在原代细胞感染细胞 人类感染的部位。用抗体阻断G可以阻止小鼠的这些效应。因此，诱导反 疫苗中含有G免疫原的G抗体，应该可以提高安全性和有效性。这项建议是 旨在确定在RSV中与融合前稳定的F蛋白一起使用的最佳G蛋白结构 成人疫苗。这种方法利用融合前F的能力来诱导高水平的广泛 中和抗体和G蛋白诱导中和病毒和阻断病毒的抗体的能力 呼吸道合胞病毒引起的宿主反应，导致疾病。这项建议建立在首席调查员(PI)的工作基础上 这1)有助于阐明G引起的疾病，特别是G的中央保守结构域(CD-G)，以及 2)开发了基于RSV的病毒样颗粒(VLP)平台，用于RSV疫苗。RSV VLP平台应 ~维持F和G的天然结构，以诱导最佳免疫反应。我们建议制造和制造 用稳定的F+A、G组蛋白或G蛋白的不同结构评估RSV VLP 多肽和一组B、G蛋白或具有不同佐剂的多肽。我们使用PI的RSV小鼠模型 以确定哪种VLP/佐剂在诱导F和G中和抗体方面最有效， 在RSV挑战的小鼠中防止病毒复制和疾病，并且不能引起增强的疾病。这些 研究将确定最佳的F+G疫苗，以走向许可。这种疫苗承诺会更安全 而且比现有的RSV疫苗更有效。

Project Summary Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in infants and young children worldwide. Since infection induces only partial protection, it causes repeat infection and disease throughout life. Though a high priority for vaccine development no vaccine is yet available. The lack of success in developing a vaccine suggests novel strategies are needed to achieve success. Most of the focus for RSV subunit vaccines has been on the RSV F protein. The G protein of RSV: 1) causes inflammation that increases RSV disease and 2) provides binding to primary human airway epithelial cells to infect the cells at the primary site of infection in humans. Blocking G with antibodies prevents these effects in mice. Accordingly, inducing anti- G antibodies with a G immunogen in a vaccine, should improve both safety and efficacy. This proposal is designed to identify the optimal G protein construct to use with a pre-fusion stabilized F protein in an RSV vaccine for adults. This approach takes advantage of the pre-fusion F’s ability to induce highly levels of broadly neutralizing antibodies and the G protein’s ability to induce antibodies that both neutralize the virus and block RSV-induced host responses that cause disease. This proposal is built on the principal investigator’s (PI’s) work that 1) helped elucidate the disease caused by G, especially the central conserved domain of G (CCD-G), and 2) developed an RSV-based virus-like particle (VLP) platform for RSV vaccines. The RSV VLP platform should ~maintain the native structures of F and G to induce optimal immune responses. We propose to make and evaluate RSV VLPs with prefusion stabilized F plus different constructs of a group A, G protein or G protein peptides and a group B G protein or peptides with different adjuvants. We use the PI’s mouse model of RSV disease to determine which VLP/adjuvant is most effective at inducing F and G neutralizing antibodies, preventing virus replication and disease in RSV-challenged mice, and fails to cause enhanced disease. These studies will identify the optimal F plus G vaccine to move toward licensure. This vaccine promises to be safer and more effective than existing RSV vaccines.