A One Health approach to pan-valent morbillivirus vaccines

副粘病毒是对人类和动物都构成重大威胁的病毒家族。例如，澳大利亚的亨德拉病毒疫情针对赛马及其驯马师，而马来西亚的尼帕病毒疫情通过养猪场传播，导致105人死亡，约110万头猪被扑杀。虽然这种跨物种传播事件可能相对较少发生，但一旦发生，其后果对人类和动物都可能是毁灭性的。副粘病毒科还包括麻疹病毒属的病毒，其中最著名的可能是人类的麻疹病毒和牛的牛瘟病毒。动物的麻疹病毒具有很高的跨物种传播的可能性，或称为“人畜共患病”。犬瘟热病毒（CDV）虽然最初被描述为狗的病原体，但它已经跨越物种进入极度濒危的狮子、老虎、海豹和大熊猫种群。小反刍兽疫病毒（PPRV）是绵羊和山羊的一种密切相关的麻疹病毒，已在蒙古的赛加羚羊、印度的布法罗以及埃塞俄比亚和苏丹的骆驼中引起严重的疾病暴发。如果我们要对抗这种人畜共患麻疹病毒的未来传播，我们需要更好地了解跨物种传播的过程，以及如何通过接种疫苗来预防这种传播。针对一种麻疹病毒的疫苗可以提供对其他物种麻疹病毒感染的免疫力;牛瘟疫苗可以保护牛免受牛瘟，山羊免受PPRV感染，狗免受CDV感染。疫苗接种触发靶向病毒表面糖蛋白的中和抗体（nAb）的产生，因此，这些抗体中的一些必须识别在不同麻疹病毒中保守的决定簇。在这个项目中，我们着手确定病毒表面糖蛋白上被中和抗体识别的决定簇。如果这些结合位点能够被识别，我们将能够设计出更好的泛麻疹病毒疫苗，疫苗将保护免受新出现的麻疹病毒的跨物种感染。为了实现这一目标，我们设计了体外系统，我们可以重建易感宿主物种的细胞环境。麻疹病毒通过与细胞表面表达的两种蛋白质分子（CD 150或nectin-4）结合而附着于靶细胞。这些分子的氨基酸序列的变化是病毒靶向哪个物种的关键决定因素，因此CDV能够结合来自许多物种的CD 150，因此具有非常广泛的物种嗜性。CDV和PPRV都不能很好地结合人CD 150，因此感染人细胞的效率非常低。然而，随着对病毒糖蛋白的氨基酸序列的小的适应，结合大大增强，并且病毒显示出增强的感染人类细胞的能力。我们已经开发出了可以研究麻疹病毒发生这种突变的倾向的检测方法。此外，我们可以评估通过接种疫苗在宿主中产生的抗体在预防此类病毒感染方面的有效性。实际上，我们已经开发出了一套系统，可以确定人畜共患病传播发生的可能性，以及如何通过接种疫苗来预防。该项目将指导下一代泛麻疹病毒疫苗的设计，并将开发检测系统，用于体外评估其预防人畜共患病的可能功效。通过定义中和抗体的病毒靶点并评估其对潜在人畜共患病病毒的功能，该项目提供了一个独特的机会，以保护人类和动物免受新型麻疹病毒带来的新威胁。

Paramyxoviruses are a family of viruses that pose a significant threat to humans and animals alike. For example, Hendra virus outbreaks in Australia have targeted both racehorses and their trainers, while Nipah virus outbreaks in Malaysia spread through pig farms, resulting in 105 human fatalities and the culling of approximately 1.1 million pigs. While such cross-species transmission events may occur relatively infrequently, when they do occur, the consequences can be devastating for humans and animals alike. The Paramyxovirus family also includes the morbillivirus genus of viruses, possibly the most notable of which are measles virus in humans and rinderpest virus in cattle. Morbilliviruses of animals have a very high potential for cross-species transmission, or "zoonosis". Although originally described as a pathogen of dogs, canine distemper virus (CDV) has jumped species into critically endangered lion, tiger, seal and giant panda populations. A closely related morbillivirus of sheep and goats, peste des petits ruminants virus (PPRV) has caused severe disease outbreaks in saiga antelope in Mongolia, buffalo in India and camels in Ethiopia and Sudan. If we are to combat the future spread of such zoonotic morbilliviruses, we need to develop a better understanding of the process of cross-species transmission and how this can be prevented by vaccination.Vaccination against one species of morbillivirus can provide immunity to infection with morbilliviruses from other species; a rinderpest vaccine can protect cattle from rinderpest, a goat from PPRV and a dog from CDV. Vaccination triggers the production of neutralising antibodies (nAbs) targeting the surface glycoproteins of the virus, hence, some of these antibodies must recognize determinants that are conserved across diverse morbilliviruses. In this project, we set out to identify the determinants on the viral surface glycoproteins that are recognised by neutralising antibodies. If these binding sites can be identified, we will be able to design better pan-morbilliviral vaccines, vaccines that will protect against cross-species infection with emerging morbilliviruses.To achieve this goal, we have designed in vitro systems with which we can recreate the cellular environment of the susceptible host species. Morbilliviruses attach to target cells by binding to either of two protein molecules expressed on the cell surface, CD150 or nectin-4. Variations in the amino acid sequences of these molecules are key determinants of which species the viruses target, hence CDV is able to bind to CD150 from many species and thus has a very broad species tropism. Neither CDV nor PPRV bind human CD150 well and hence infect human cells very inefficiently. However, with a small adaptation to the amino acid sequence of the viral glycoproteins, binding is enhanced greatly and the viruses display an enhanced ability to infect human cells. We have developed assays with which we can study the propensity for morbilliviruses to develop such mutations. Moreover, we can assess how efficient antibodies generated in the host by vaccination are at preventing infection with such viruses. In effect, we have developed systems with which we can determine the likelihood of zoonotic transmission occurring and how to prevent it by vaccination. This project will guide the design of the next generation of pan-morbilliviral vaccines and will develop assays systems with which their likely efficacy in preventing zoonoses can be assessed in vitro. By defining the viral targets for neutralising antibodies and by assessing their function against potentially zoonotic viruses, this project offers a unique opportunity to protect both humans and animals alike against the emerging threat posed by novel morbilliviruses.