VAccine deveLopment for complex Intracellular neglecteD pAThogEns (VALIDATE)

对于几种复杂的病原体，我们对我们需要一种有效的疫苗来诱导什么样的免疫反应还没有完全的了解。这在一定程度上是因为这些病原体生活在细胞内，可以躲避宿主的免疫反应。这使得开发针对这些病原体的疫苗变得非常困难。由这些病原体引起的疾病，包括结核病、麻风病、利什曼病和类鼻疽病，对低收入和中等收入国家的人民的影响不成比例，由于预测的商业回报不佳和受影响人口的边缘化，往往被忽视。目前的疫苗开发方法是识别可能重要的免疫反应的一部分，开发能够诱导这种免疫反应的疫苗，然后测试疫苗是否有效，首先在动物模型中，然后在人类临床试验中。这种方法对这些复杂的病原体不起作用，而且速度慢，效率低。在这个网络中，我们将采用迭代方法，通过反复整合来自不同病原体的人类临床研究和动物模型的数据，开发更准确的免疫反应工作模型。纳入在大型动物模型中工作的兽医将意味着所获得的结果也将与动物疫苗的开发相关。纳入这些疾病流行的LMIC的合作伙伴，以及来自行业的合作伙伴，将有助于确保现实世界的相关性。此外，较小的动物模型将使我们能够轻松地观察免疫系统的单个组件。对免疫机制的洞察将使我们能够更有效地设计和开发疫苗。这个网络将提供一个独特的机会，将研究四种样本复杂细胞内病原体(结核分枝杆菌、麻风杆菌、利什曼原虫)的个人聚集在一起。和假鼻疽杆菌)，它们与生活在被称为巨噬细胞的特定宿主细胞中的病原体有着共同的生活方式，在人类中引起类似的终末期病理，并已知影响宿主的免疫和代谢反应。在整个网络中建立的横向合作，以及为早期数据共享提供一个受保护的环境，将利用这些病原体之间的生物协同效应。积极和消极的结果可以迅速传播，研究每一种复杂疾病的合作伙伴可以从研究其他疾病的人的成功和失败中吸取教训。通过了解从感染到疾病的机制，我们计划发现共同的方法，为这些和其他复杂的细胞内病原体的疫苗开发战略提供信息。网络的主要活动和交付成果包括：知识共享年度会议；为实时数据共享创建一个虚拟网络；为填补知识空白提供启动资金，并提供数据以提高较大赠款申请的竞争力；建立一个网站和其他通讯，以加强协作和研究传播；以及通过资助、培训和指导早期博士后和新的PI研究人员进行职业发展。所有活动都致力于为这些重要疾病更有效地开发疫苗，并提高我们的伙伴LMICs的研究能力。

For several complex pathogens, we have an incomplete understanding of the kind of immune response we need an effective vaccine to induce. In part this is because these pathogens live inside cells and can hide from the host immune response. This makes it very difficult to develop vaccines against these pathogens. The diseases caused by these pathogens, including tuberculosis (TB), leprosy, leishmaniasis and melioidosis, disproportionately affect people in low and middle-income countries (LMICs) and are often neglected due to the poor predicted commercial return and marginalisation of affected populations. The current approach to vaccine development is to identify a part of the immune response that might be important, develop vaccines that induce that kind of immune response and then test that vaccine to see if it works, first in animal models and then in human clinical trials. This approach does not work for these complex pathogens and is slow and inefficient. In this Network we will adopt an iterative approach and develop more accurate working models of the immune response by cycles of repeated integration of data from human clinical studies and animal models across the different pathogens. The inclusion of vets working in large animal models will mean the results obtained are relevant for the development of animal vaccines as well. The inclusion of partners from LMIC where these diseases are endemic, together with partners from industry will help ensure real world relevance. Furthermore, the smaller animal models will allow us to easily look at single components of the immune system. The insight gained into immune mechanisms will allow us to design and develop vaccines more efficiently and more effectively. This Network will provide a unique opportunity to bring together individuals working on four exemplar complex intracellular pathogens (M.tb, M.leprae, Leishmania spp. and B.pseudomallei), which share a common lifestyle as pathogens that live in a particular host cell called macrophages, induce similar end-stage pathologies in humans and are known to affect host immune and metabolic responses. The horizontal collaborations established throughout this network, together with the provision of a protected environment for early data sharing, will exploit the biological synergies between these pathogens. Positive and negative results can be disseminated rapidly, and partners working on each of the complex diseases can learn from the successes and failures of those working on the other diseases. By understanding mechanisms that lead from infection to disease, we plan to uncover common approaches to inform vaccine development strategies for these and other complex intracellular pathogens. Key Network activities and deliverables include annual meetings for knowledge sharing; creation of a virtual network for real-time data sharing; pump-priming funding to fill knowledge gaps, and provide data to enhance the competitiveness of larger grant applications; a website and other communications to enhance collaborations and research dissemination; and career development by funding, training and mentoring of early post-doctoral and new PI researchers. All activities work towards more effective vaccine development for these important diseases, and the improvement of research capabilities in our partner LMICs.