One Health and accelerating Vaccines for Ebola and Lassa (OVEL)

埃博拉和拉沙的One Health和加速疫苗（OVEL）是一个重点比较的One Health疫苗项目，基于了解人畜共患病病毒从其天然动物宿主溢出到人类的未来威胁的需要。这些信息对于开发最有效的保护性疫苗以防止未来的人类疫情非常重要。相当多的新发和再发疾病是由RNA病毒引起的，并且许多是由动物自然携带的（Heeney，J Internal Med，2006）。它们的基因组是众所周知的可变的，因为在复制过程中发生的高突变率。这些病毒随着时间的推移而积累，并导致病毒在其天然动物宿主种群中传播时的进化。因此，这些由动物携带的变异病毒对人类健康构成风险，并可能蔓延到共享同一环境的人。如果病毒变异体出现并能够适应人体细胞受体，并且能够逃脱免疫防御，它们可能会变得具有高度传染性并导致大规模疾病爆发。疫苗的效果取决于它们设计的病原体的免疫靶点（疫苗所呈递的病毒蛋白（抗原））。如果抗原发生变化，疫苗就不能起到保护作用。在大多数情况下，目前针对RNA病毒的候选疫苗来自过去的人类疫情，很少或没有关于动物宿主中携带的病毒变体未来风险的信息，特别是那些具有动物到人（人畜共患病）传播潜力的病毒变体。我们建议建立一个扩展的病毒序列数据库来自动物水库的两个病毒家族，导致病毒性出血性疾病在西非的地理重叠地区。通过从动物宿主中获得新的分子/基因组和抗体数据，我们将了解感染动力学和病毒在其天然宿主中的持久性，同时提供储存库中重要的病毒多样性数据，以发现新的疫苗抗原并加速真正保护性疫苗的设计。我们将从对天然啮齿动物宿主的全面调查中获得拉沙病毒/沙粒病毒序列多样性数据，（Mastomys natalensis和其他啮齿动物储库物种），在尼日利亚，有记录的拉沙疫情发生在拉沙热病毒不同同种型引起病例的州。第二个储存库病毒序列数据库可能来自英国GCRF奖给J Wood教授的一项补充研究，该研究基于加纳的蝙蝠群落样本，这些蝙蝠群落发现了埃博拉病毒抗体和抗原阳性动物。配备了这些关于动物储存库中病毒序列多样性的信息，这些病毒有可能溢出到人类，我们将能够设计出更好的疫苗抗原，以获得更有效和更广泛的保护性疫苗。我们将通过一个新的加速疫苗开发平台来实现这一目标，该平台采用尖端技术，以大幅提高疫苗效力和疫苗开发速度。我们将使用新的EVAC（新兴病毒疫苗抗原构建）平台疫苗技术，我们以前开发的创新英国的资金。EVAC平台大大加速了疫苗开发，它合并了（i）西非爆发病原体及其宿主的序列，（ii）来自病毒性出血热幸存者的广泛抗病毒中和单克隆抗体，（iii）计算建模方法，（iv）合成基因技术，以及（v）体内免疫选择和疫苗效力读数。最终产品是新型疫苗抗原，使用数字设计，免疫优化和选择（DIOS）疫苗抗原，针对重新出现的RNA病毒拉沙热和埃博拉病毒，引发最广泛的保护性免疫反应。

The One Health and accelerating Vaccines for Ebola and Lassa (OVEL) is a focused comparative One Health vaccine project based on the need to understand future threats of zoonotic virus spill-overs from their natural animal reservoirs to humans. This information is important to develop the most effective protective vaccines to prevent future human outbreaks. A disproportionally high number of emerging and re-emerging diseases are caused by RNA viruses and many are carried naturally by animals (Heeney, J Internal Med, 2006). Their genomes are notoriously variable due to the high mutation rate that occurs during replication. These accumulate over time and results in evolvolution of the viruses as they circulate in their natural animal reservoir populations. Thus, these variant viruses carried by animals are a risk to human health and may spill-over to people who share the same environment. If some viral variants arise and are able to adapt to use human cell receptors and if they are able to escape immune defences, they may become highly infectious and cause large disease outbreaks.Vaccines are only as good as the immune targets (the viral protein (antigen) presented by vaccines) of the pathogen that they are designed for. If the antigen changes, vaccines fail to protect. In most cases current vaccine candidates against RNA viruses are from past human outbreaks with little or no information of future risks from viral variants carried in animal reservoirs, especially those with the potential for animal to human (zoonotic) transmission. We propose to establish an extended viral sequence database derived from animal reservoirs for two virus families which cause viral haemorrhagic diseases in geographically overlapping regions of West Africa. By gaining new molecular/genomic and antibody data from animal hosts, we will acquire an understanding of the infection dynamics and viral persistence in their natural reservoirs, while providing essential viral diversity data in reservoirs to discover new vaccine antigens and accelerate truly protective vaccine design.We will acquire Lassa/Arenavirus sequence diversity data from a comprehensive survey of the natural rodent hosts (Mastomys natalensis and other rodent reservoir species) in Nigeria where documented Lassa outbreaks occur in states with cases caused by diverse isoaltes of Lassa fever virus. A second reservoir viral sequence database is likely to arise from a complementary study funded by the UK GCRF award to Prof J Wood based from sampled bat colonies in Ghana which Ebolavirus antibody and antigen positive animals have been found.Equipped with this information on the sequence diversity of viruses in animal reservoirs which threaten to spill-over to humans, we will be able to design better vaccine antigens for more effective and broadly protective vaccines. We will achieve this using a new accelerated vaccine development platform using cutting edge technologies to achieve dramatic improvements in vaccine efficacy and the speed of vaccine development. We will use the new EVAC (Emerging viral Vaccine Antigen Construct) platform vaccine technology we previously developed with Innovate-UK funding. The EVAC platform, which significantly accelerates vaccine development, merges (i) sequences of outbreak pathogens and their reservoirs in West Africa, (ii) broadly anti-viral neutralising monoclonal antibodies derived from viral haemorrhagic fever survivors, (iii) computational modelling methodologies, (iv) synthetic gene technology, and (v) in vivo immune selection and vaccine efficacy readouts. The end products are novel vaccine antigens to trigger the broadest spectrum of protective immune responses using Digitally Designed, Immune Optimised and Selected (DIOS) vaccine antigens against re-emerging RNA viruses Lassa Fever and Ebola viruses.