Intrinsically-enhanced Ebola and Marburg virus like particles for increased potency and immune memory

本质上增强的埃博拉和马尔堡病毒样颗粒，可增强效力和免疫记忆

• 批准号: 10596359
• 负责人: JOANN M TUFARIELLO
• 金额: $ 23.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596359
• 关键词: Intrinsically; enhanced; Ebola; Marburg; virus

Summary This developmental project seeks to develop methods to dramatically boost immunogenicity of virus-like particle (VLP) vaccines. Ebola virus (EBOV) and Marburg virus (MARV) are members of the filovirus family of enveloped, negative-sense RNA viruses that causes outbreaks of severe human disease. Due to their lethality, filoviruses are among the handful of emerging viruses for which biosafety level 4 (BSL4) containment is required for their study. Although progress has been made toward EBOV vaccines, there remains a need for development of vaccines for other filoviruses, particularly MARV. VLPs are an often-explored vaccine platform for a variety of viruses, including for EBOV and MARV. Advantages of VLPs include their relative safety, as they cannot replicate and cause viral disease; their close resemblance to authentic virus, such that they present antigens in their native state; their capacity to elicit both B and T cell responses and their proven efficacy for a variety of systems. Potential challenges of VLPs as vaccines include relatively lower immunogenicity, as compared to live virus. Filovirus VLPs can be produced by co-expression of the viral matrix protein VP40, the viral glycoprotein (GP), with or without expression of the viral nucleoprotein (NP). Such VLPs have been demonstrated to stimulate dendritic cell (DC) responses, to elicit B and T cell mediated immunity and to protect mice, guinea pigs and non- human primates (NHPs) from lethal challenge. Therefore, filovirus VLPs are viable vaccine candidates. However, filovirus VLP immunogenicity is weak with protection requiring coadministration with an adjuvant and multiple doses. This is not ideal for vaccines that are mainly deployed in response to outbreaks. This application seeks to dramatically improve immunogenicity of EBOV and MARV VLPs by the rational incorporation of type I interferon (IFN) signaling domains from the cellular pattern recognition receptors RIG-I or TRIF into the particles. This enables delivery into cells of the IFN inducing domain by the VLPs, triggering robust innate immune responses reminiscent of live virus infection, to boost adaptive immune responses. To further pursue this direction, we will explore approaches to optimize the incorporation of IFN-inducing signaling domains into EBOV and MARV VLPs. We will then evaluate the capacity of the different enhanced VLP strategies to elicit B and T cell immune responses in vivo, and finally, test the most promising enhanced VLPs for the capacity to elicit rapid protection against EBOV and MARV challenge in mice. Successful completion of these studies will provide a novel platform for the development of filovirus vaccines and an approach that can likely be applied to other emerging viral pathogens.

总结 该开发项目旨在开发方法，以显着提高病毒样颗粒的免疫原性 (VLP)疫苗。埃博拉病毒（EBOV）和马尔堡病毒（MARV）是有包膜的丝状病毒家族的成员， 导致严重人类疾病爆发的反义RNA病毒。由于其致命性，丝状病毒 是少数需要生物安全4级（BSL 4）控制的新兴病毒之一， study.尽管已经在EBOV疫苗方面取得了进展，但仍然需要开发 其他丝状病毒的疫苗，特别是MARV。VLP是一种经常探索的疫苗平台，用于各种疫苗。 病毒，包括EBOV和MARV。VLP的优点包括它们的相对安全性，因为它们不能复制 并引起病毒性疾病;它们与真正的病毒非常相似，因此它们在其天然抗原中呈现抗原。 陈述;它们引发B和T细胞应答的能力以及它们对各种系统的经证实的功效。 与活病毒相比，VLP作为疫苗的潜在挑战包括相对较低的免疫原性。 丝状病毒VLP可以通过共表达病毒基质蛋白VP 40、病毒糖蛋白（GP） 表达或不表达病毒核蛋白（NP）。已经证明这种VLP刺激 树突状细胞（DC）应答，以引发B和T细胞介导的免疫，并保护小鼠、豚鼠和非 人类灵长类动物（NHP）的致死性攻击。因此，丝状病毒VLP是可行的候选疫苗。然而，在这方面， 丝状病毒VLP免疫原性较弱，需要与佐剂和多药联合给药 剂量这对于主要用于应对疫情的疫苗来说并不理想。本申请寻求 通过合理掺入I型病毒，显着提高EBOV和MARV VLP的免疫原性 在一些实施方案中，所述方法包括将来自细胞模式识别受体RIG-I或TRIF的干扰素（IFN）信号传导结构域引入颗粒中。 这使得能够通过VLP将IFN诱导结构域递送到细胞中，从而触发强大的先天性免疫应答。 这让人联想到活病毒感染的反应，以增强适应性免疫反应。为了进一步追求这一点， 方向，我们将探索优化IFN诱导信号结构域并入EBOV的方法 MARV VLP然后，我们将评估不同的增强VLP策略引起B和T的能力 细胞免疫应答，最后，测试最有希望的增强VLP引起快速免疫应答的能力。 在小鼠中针对EBOV和MARV攻击的保护。成功完成这些研究将提供一个 开发丝状病毒疫苗的新平台和可能应用于其他疫苗的方法 新出现的病毒病原体。