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

“同一个健康和加速埃博拉和拉沙疫苗”（OVEL）是一个重点比较的“同一个健康”疫苗项目，其基础是需要了解人畜共患病毒从其自然动物宿主向人类扩散的未来威胁。这一信息对于开发最有效的保护性疫苗以预防未来的人间疫情非常重要。大量新出现和再出现的疾病是由RNA病毒引起的，其中许多是由动物自然携带的（Heeney，内科学杂志，2006年）。由于在复制过程中发生的高突变率，它们的基因组是出了名的多变。这些因素随着时间的推移而积累，并导致病毒在其自然动物宿主种群中传播时发生进化。因此，这些由动物携带的变异病毒对人类健康构成威胁，并可能蔓延到共享同一环境的人。如果出现某些病毒变体并能够适应使用人类细胞受体，如果它们能够逃脱免疫防御，它们可能变得高度传染性并引起大规模疾病暴发。疫苗的有效性取决于它们所针对的病原体的免疫靶标（疫苗提供的病毒蛋白（抗原））。如果抗原发生变化，疫苗就无法起到保护作用。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，很少或根本没有关于动物宿主中携带的病毒变体未来风险的信息，特别是那些有可能从动物传播到人类（人畜共患）的病毒变体的信息。我们建议建立一个扩展的病毒序列数据库，该数据库来源于西非地理重叠地区导致病毒性出血性疾病的两个病毒家族的动物储存库。通过从动物宿主获得新的分子/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，同时提供宿主中必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。我们将从尼日利亚对天然啮齿动物宿主（Mastomys natalensis和其他啮齿动物宿主物种）的全面调查中获取拉沙/沙粒病毒序列多样性数据。在尼日利亚，有记录的拉沙疫情发生在由不同拉沙热病毒分离体引起病例的州。第二个库病毒序列数据库可能来自于由J Wood教授获得的英国GCRF资助的一项补充研究，该研究基于在加纳发现埃博拉病毒抗体和抗原阳性动物的蝙蝠群落样本。掌握了动物宿主中病毒序列多样性的信息，我们将能够设计出更好的疫苗抗原，以获得更有效和具有广泛保护作用的疫苗。我们将利用一个新的加速疫苗开发平台实现这一目标，该平台利用尖端技术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，我们之前在英国创新基金的资助下开发。EVAC平台显著加快了疫苗开发，它合并了(i)西非暴发病原体及其宿主的序列，（ii）从病毒性出血热幸存者身上提取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数据。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）疫苗抗原触发最广泛的保护性免疫反应，以对抗重新出现的拉沙热和埃博拉病毒RNA病毒。

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.