F plus G RSV VLP Vaccine for Improved Safety and Efficacy

项目摘要 呼吸道合胞病毒（RSV）是婴儿严重下呼吸道疾病的主要原因， 全世界的孩子。由于感染只诱导部分保护，它会导致重复感染和疾病 在生活中。虽然疫苗开发是一个高度优先事项，但目前还没有疫苗。缺乏成功 这表明需要新的策略才能取得成功。RSV的大部分焦点 亚单位疫苗已经对RSV F蛋白。RSV的G蛋白：1）引起炎症， RSV疾病和2）提供与原代人气道上皮细胞的结合以感染原代人气道上皮细胞。 人体感染部位。用抗体阻断G可以防止小鼠的这些作用。因此，诱导抗- G抗体与疫苗中的G免疫原一起使用，应该可以提高安全性和有效性。这项建议是 设计用于鉴定与RSV中融合前稳定的F蛋白一起使用的最佳G蛋白构建体 成人疫苗这种方法利用了融合前F诱导高水平的广泛表达的能力。 中和抗体和G蛋白的能力，以诱导抗体，既中和病毒和阻断 RSV引起的宿主反应导致疾病。本提案基于主要研究者（PI）的工作 1）有助于阐明G引起的疾病，特别是G的中央保守结构域（CCD-G），和 2)开发了用于RSV疫苗的基于RSV的病毒样颗粒（VLP）平台。RSV VLP平台应该 - 维持F和G的天然结构以诱导最佳免疫应答。我们建议， 评价具有融合前稳定的F加上A组、G蛋白或G蛋白的不同构建体的RSV VLP 肽和B G组蛋白或具有不同佐剂的肽。我们使用PI的RSV小鼠模型 疾病以确定哪种VLP/佐剂在诱导F和G中和抗体方面最有效， 在RSV攻击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加G疫苗走向许可证。这种疫苗保证更安全 并且比现有的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.