Trivalent Lassa, Ebola and Marburg viral vaccine (Tri-LEMvac)

三价拉沙、埃博拉和马尔堡病毒疫苗 (Tri-LEMvac)

• 批准号: 971511
• 金额: $ 88.64万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 英国
• 项目类别: Small Business Research Initiative
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=971511
• 关键词: Trivalent; Lassa; Ebola; Marburg; viral

African haemorrhagic fever viruses have a significant impact on human health in low income countries and developing economies (Heeney, J Internal Med, 2006). Lassa fever is endemic to Western Africa with estimates ranging between 300,000 to a million infections, with 5,000 deaths per year. It’s overlapping geographic distribution with other Viral Haemorrhagic Fevers (VHFs) caused by Filoviruses such as Ebola virus (EBOV), complicated the early clinical diagnosis of Ebola virus disease in the 2014/2015 West African outbreak. A combined Old World Arenavirus and Filovirus vaccine eliciting protection against Lassa Fever virus (LASV), Ebola (EBOV) and Marburg (MARV) viruses, the most important haemorrhagic fevers in West and Central Africa, would be of great benefit in the control of spread of these notorious pathogens. Currently there are no licensed vaccines for these infections. A single vaccine to protect against all three of these regionally important VHFs that was economic, easy to produce, readily deployable and temperature stable in the absence of continuous cold chain storage would be highly desirable. The Modified Vaccinia Ankara (MVA) vaccine platform is a non-replicating strain third generation smallpox vaccine and one of the most advanced recombinant poxviral vaccine vectors in human clinical trials (Cottingham & Carroll, Vaccine, 2013). MVA is a robust vector system capable of co-expressing up to four transgenes facilitating potent promoters and stable insertion sites (Orubu et al, Pone, 2012). We will bring synergistic new platform technologies together from EVAC and LassaVacc (Innovate UK). Using EVAC’s DIOS synthetic immune optimised vaccine inserts to give the broadest possible vaccine protection, together with LassaVacc's MVA based LASV (NP/GPC T & B-cell antigens) we will develop a single trivalent vaccine (Tri-LEMvac) that will generate combined vaccine efficacy against future outbreaks of variants of the haemorrhagic fever Lassa, Ebola and Marburg viruses.Towards this goal we propose two stages: Stage 1) Proof of concept (this application). Within 12 months, we will demonstrate proof of concept by constructing trivalent MVAs expressing conserved Lassa, Ebola and Marburg antigen inserts in a single MVA, confirming optimal expression, demonstrating immunogenicity in small animals and efficacy by live virus challenges with these pathogens. MVA is a clinically trialled vaccine vector which we will use to compare improvements in immune responses, the breadth of protection, durability and efficacy. This new trivalent LEMvac MVA vaccine will allow direct comparison in head to head clinical trials in stage 2. Stage 2) follow-up proposal; refine preclinical work, including GLP manufacturing toxicology/manufacturing. To perform first in human phase I trials of Tri-LEMvac to establish dose, durability of one shot versus prime boost and safety.

非洲出血热病毒对低收入国家和发展中经济体的人类健康具有重大影响（Heeney，J Internal Med，2006）。拉沙热是西非的地方病，估计感染人数在 30 万到 100 万人之间，每年有 5,000 人死亡。它与埃博拉病毒 (EBOV) 等丝状病毒引起的其他病毒性出血热 (VHF) 的地理分布重叠，使得 2014/2015 年西非疫情中埃博拉病毒病的早期临床诊断变得复杂。旧世界沙粒病毒和丝状病毒联合疫苗可针对拉沙热病毒（LASV）、埃博拉病毒（EBOV）和马尔堡病毒（MARV）（西非和中非最重要的出血热）提供保护，对于控制这些臭名昭著的病原体的传播将大有裨益。目前还没有针对这些感染的许可疫苗。非常需要一种经济、易于生产、易于部署且在缺乏连续冷链储存的情况下温度稳定的单一疫苗来预防所有这三种区域性重要的甚高频。改良安卡拉牛痘 (MVA) 疫苗平台是一种非复制株第三代天花疫苗，也是人体临床试验中最先进的重组痘病毒疫苗载体之一（Cottingham & Carroll，疫苗，2013）。 MVA 是一个强大的载体系统，能够共表达多达四个转基因，促进有效的启动子和稳定的插入位点（Orubu 等人，Pone，2012）。我们将把 EVAC 和 LassaVacc（Innovate UK）的协同新平台技术结合在一起。利用 EVAC 的 DIOS 合成免疫优化疫苗插入物提供尽可能广泛的疫苗保护，结合 LassaVacc 的基于 MVA 的 LASV（NP/GPC T 和 B 细胞抗原），我们将开发一种单一三价疫苗 (Tri-LEMvac)，该疫苗将产生针对未来出血热拉沙热、埃博拉和埃博拉病毒变种爆发的联合疫苗功效。 马尔堡病毒。为了实现这一目标，我们提出两个阶段：第 1 阶段）概念验证（本应用）。在 12 个月内，我们将通过构建在单个 MVA 中表达保守的拉沙病毒、埃博拉病毒和马尔堡抗原插入物的三价 MVA 来证明概念，确认最佳表达，证明小动物的免疫原性以及用这些病原体进行活病毒攻击的功效。 MVA 是一种经过临床试验的疫苗载体，我们将用它来比较免疫反应、保护范围、持久性和功效的改善情况。这种新的三价 LEMvac MVA 疫苗将允许在第 2 阶段的头对头临床试验中进行直接比较。第 2 阶段）后续提案；完善临床前工作，包括 GLP 制造毒理学/制造。首先进行 Tri-LEMvac 的人体 I 期试验，以确定单次注射的剂量、持久性与初免增强和安全性。