Development of a subunit vaccine against CCHF virus for use in low-middle income countries; completion of pre-clinical studies

克里米亚刚果出血热病毒(CCHFv)是影响人类的最广泛的硬虱传播的病毒性疾病。它在30个国家流行，几乎所有这些国家都是非洲、巴尔干、中东和中亚的LMIC，估计有30亿人处于危险之中。扁虱地理范围的扩大以及受感染但没有症状的牲畜的贸易正在助长CCHFV的传播。病毒暴发发生在农业地区与动物有密切接触的工人中，并传播给家庭成员和卫生工作者。因此，CCHFV影响到最没有能力应对CCHFV或承担疫苗开发费用的地区和国家。没有疫苗，也没有有效的治疗方法；早期重症监护、补液和支持性药物治疗是主要的护理途径。每年有10-15,000例；每8人中就有1人患上严重疾病，死亡率在10%至40%之间(世卫组织)。幸存者通常会经历长期的衰弱症状，这些症状会产生额外的社会经济影响。我们的项目旨在利用我们的平台技术在昆虫细胞中生产包括病毒糖蛋白在内的高质量蛋白质，开发一种安全、负担得起和有效的CCHFV疫苗。这个项目将建立在我们目前英国疫苗网络项目的结果和成就的基础上，并确保我们做好充分的准备，并为未来进入I/II阶段临床试验做好准备。在这个为期一年的项目中，我们将最终确定与疫苗一起使用的佐剂，以确保良好的免疫反应和保护。其目的是在初始剂量和一次加强剂量后实现保护。目前对疫苗性能的测试依赖于在高度封闭的设施中使用动物模型来评估对病毒的保护。我们将开发一种不含动物的替代方法，并利用在较低围堵实验室进行的基于细胞培养的方法。这将使在疫苗开发的未来临床阶段对疫苗效力/免疫反应进行有效但更负担得起的评估成为可能。我们还将优化疫苗的稳定性，目前疫苗可以在冰箱中保存1个月。基于对同一系统生产的新冠肺炎疫苗原型的研究，我们认为这一期限可以改进到3到6个月。这将减轻LMIC的冷链供应负担。最后，我们将创建一套监管方案，并制定进行第一阶段/第二阶段试验的详细计划，以便一旦获得资金，未来的临床工作方案就可以开始。

Crimean Congo Haemorrhagic Fever virus (CCHFv) is the most widespread tick-borne viral disease affecting people. It is endemic in \>30 countries, almost all of which are LMICs in Africa, the Balkans, Middle East and Central Asia with an estimated 3 billion people at risk. The expanding geographic range of the tick along with trade in infected but asymptomatic livestock is fuelling the spread of CCHFv. Virus outbreaks occur in agricultural areas in workers with close contact with animals, spreading to family members and health workers. Thus CCHFv affects regions and countries least able to deal with CCHFv or afford vaccine development. There is no vaccine, nor effective treatment; early intensive care, rehydration and supportive drug therapy are the main care pathways. There are 10-15,000 cases annually; 1 in 8 develop severe disease with mortality rates between 10 and 40% (WHO). Survivors typically experience long term debilitating symptoms that have additional socio-economic impacts.Our project aims to develop a safe, affordable and effective vaccine for CCHFv using our platform technologies for producing high quality proteins, including viral glycoproteins, in insect cells. This project will build on the results and achievements of our current UK Vaccine Network project and ensure we are well prepared and ready to move to Phase I/II Clinical Trials in future.In this 1 year project, we will finalise the adjuvant to be used with the vaccine, which ensures a good immune response and protection. The aim is to achieve protection after an initial and one booster dose. Current tests of vaccine performance depend on the use of an animal model in high containment facilities to assess protection from the virus. We will develop an alternative approach that is animal-free and utilizes a cell culture-based method performed in lower containment laboratories. This will enable effective but more affordable assessment of vaccine efficacy/immune response in future Clinical Phases of vaccine development. We will also optimize stability of the vaccine, which currently can be preserved for 1 month in a refrigerator. Based on work with a prototype COVID-19 vaccine produced in the same system we think this can be improved to 3 to 6 months. This will reduce the burden of cold chain supply in LMICs. Finally, we will create a regulatory package and develop a detailed plan to undertake Phase I/Phase II Trials to allow future Clinical work packages to start as soon as funding is available.