Clinical trial of a DIOS Trivalent Haemorrhagic Fever Vaccine (DIOS-HFVac3)

汇集了尖端技术，我们已经产生了一种新的候选疫苗，可以预防3种高度传染性的非洲出血热病毒（HFV），这些病毒具有显著的全球流行潜力。有了这项技术，我们可以大大提高疫苗对新出现和重新出现的病原体的保护范围。我们的DIOS（数字化设计、免疫优化和选择）技术提供了最广泛的病毒变异保护，以限制未来高度可变病原体的爆发。在我们的Innovate Stage 1项目中，我们实现了该平台的明确概念验证，从展示DIOS平台免疫原性快速发展到生成独特的三价候选疫苗。在第二阶段1项目中，接种了三种不同病毒-拉沙病毒、埃博拉病毒和马尔堡病毒疫苗的动物免受致命感染。我们的最佳候选下一代DIOS抗原，靶向这3个不同的HFV家族，产生了最广泛的免疫应答，并证明在MVA疫苗载体中稳定。在Innovate Stage 2项目中，我们建议将其带入下一阶段，进行DIOS疫苗插入物的“首次人体”临床试验，以证明DIOS-HFVac 3候选物的安全性及其在人类志愿者中改善的免疫应答广度。 我们已经证明，基于DNA疫苗载体pEVAC和高免疫原性痘病毒疫苗载体修饰的安卡拉牛痘（MVA）的DIOS插入物提供了免受感染的保护。MVA是一种安全的载体，用于成功地免疫天花。它被很好地表征，并被进一步修饰为用于许多病原体的多功能疫苗载体。此外，MVA还提供针对猴痘的100%疫苗功效，猴痘是一种目前在DIOS-HFVac 3将作为疫苗部署的同一地区引起人类爆发的疾病。已经证明可以生产不依赖冷链的MVA疫苗批次，我们的目标是使用pEVAC和MVA DIOS插入物实现这一目标，以便在可能发生疫情的任何地方快速部署。 我们的人类临床试验设计将有两个组，一个组单独使用MVA/DIOS-HFVac 3，另一个组与表达在非洲发现的第四种HFV，即克里米亚-刚果出血热病毒（CCHFV）的MVA共同给药。与MVA-CCHF Innovate临床试验联盟合作，按照与MVA-DIOS-HFVac 3相同的标准生产的MVA-CCHF GMP批次将用于联合给药。这代表了一个独特的机会来评价四价人VHF疫苗是否将提供等效的免疫原性，并可能保护人类免受4种VHF病原体（拉沙、埃博拉、马尔堡、CCHF）以及猴痘的侵害。 5.建议的想法/技术描述

Bringing together cutting edge technologies, we have generated a new vaccine candidate that protects against 3 highly contagious African Haemorrhagic Fever Viruses (HFV), which have significant global epidemic potential. With this technology, we can achieve dramatic improvements to the breadth of protection conferred by vaccines against emerging and re-emerging pathogens. Our DIOS (Digitally designed, Immune Optimised and Selected) technology provides the broadest possible protection against viral variants to limit future outbreaks of highly variable pathogens. In our Innovate Stage 1 project, we achieved clear proof-of-concept for this platform, moving quickly from demonstrating DIOS platform immunogenicity to generate a unique trivalent vaccine candidate. In a second Stage 1 project, animals vaccinated against three diverse viruses - Lassa, Ebola and Marburg were protected from lethal infection. Our top candidate next generation DIOS antigens, targeting these 3 diverse families of HFVs, gave the broadest immune responses and proved stable in the MVA vaccine vector. In the Innovate Stage 2 project we propose to take this to next stage, performing a “first-in-human” clinical trial of DIOS vaccine inserts to demonstrate the safety profile of the DIOS-HFVac3 candidate and its improved breadth of the immune responses in human volunteers. We have proven that DIOS inserts based on both the DNA vaccine vector pEVAC and the highly immunogenic poxvirus vaccine vector, Modified Vaccinia Ankara (MVA), provide protection from infection. MVA is a safe vector that was used to successfully immunise against smallpox. It is well characterised and has further been modified as a versatile vaccine vector for many pathogens. MVA additionally provides 100% vaccine efficacy against Monkeypox, a disease which is currently causing outbreaks in humans in the same regions where DIOS-HFVac3 would be deployed as a vaccine. It has been demonstrated that cold chain independent vaccine lots of MVA can be produced and we would aim to achieve this with both the pEVAC and MVA DIOS inserts for rapid deployment wherever outbreaks may occur. Our human clinical trial design will have two arms, one with MVA/DIOS-HFVac3 alone, and the other with co-administration of MVA expressing a fourth HFV found in Africa, namely Crimean-Congo Haemorrhagic fever virus (CCHFV). In collaboration with the MVA-CCHF Innovate clinical trial consortium, GMP lots of MVA-CCHF, made to the same standards as MVA-DIOS-HFVac3, will be used for co-administration. This represents a unique opportunity to evaluate if a tetravalent human VHF vaccine will provide equivalent immunogenicity, and potentially protect humans against 4 VHF pathogens (Lassa, Ebola, Marburg, CCHF) as well as Monkeypox. 5. Description of Proposed Idea/Technology