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蜱传病毒性疾病。该病在30多个国家流行，几乎所有这些国家都是非洲、巴尔干、中东和中亚的中低收入国家，估计有30亿人面临风险。蜱的地理范围不断扩大，加上受感染但无症状牲畜的交易，正在助长CCHFv的传播。病毒暴发发生在农业地区与动物密切接触的工人中，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或负担不起疫苗开发的地区和国家。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- 1.5万例；八分之一的人患上严重疾病，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，并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高质量的蛋白质，包括病毒糖蛋白，开发一种安全、负担得起和有效的CCHFv疫苗。该项目将建立在我们目前英国疫苗网络项目的成果和成就的基础上，并确保我们做好充分准备，准备在未来进入I/II期临床试验。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。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设施中使用动物模型来评估对病毒的保护作用。我们将开发一种替代方法，该方法不含动物，并利用在低密闭实验室进行的基于细胞培养的方法。这将有助于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负担得起的评估。我们还将优化疫苗的稳定性，目前该疫苗可在冰箱中保存1个月。根据在同一系统中生产的COVID-19原型疫苗的工作，我们认为这可以缩短到3至6个月。这将减轻中低收入国家冷链供应的负担。最后，我们将创建一个监管包，并制定进行I/ II期试验的详细计划，以便在资金到位后尽快启动未来的临床工作包。

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.