VAccine deveLopment for complex Intracellular neglecteD pAThogEns (VALIDATE)

对于一些复杂的病原体，我们对需要一种有效疫苗来诱导的那种免疫反应还不完全了解。部分原因是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群影响尤为严重，由于预测的商业回报不佳和受影响人群被边缘化，这些疾病往往被忽视。目前开发疫苗的方法是确定免疫反应的一部分可能是重要的，开发疫苗来诱导这种免疫反应，然后测试疫苗，看看它是否有效，首先在动物模型中，然后在人体临床试验中。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。包括在大型动物模型中工作的兽医将意味着所获得的结果也与动物疫苗的开发相关。将这些疾病流行的低收入和中等收入国家的合作伙伴与工业界的合作伙伴一起纳入，将有助于确保在现实世界中发挥作用。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成部分。对免疫机制的深入了解将使我们能够更有效地设计和开发疫苗。该网络将提供一个独特的机会，将研究四种典型的复杂细胞内病原体（结核分枝杆菌、麻风分枝杆菌、利什曼原虫和假芽孢杆菌）的个人聚集在一起，这些病原体具有共同的生活方式，它们生活在称为巨噬细胞的特定宿主细胞中，在人类中引起类似的终末期病理，并且已知会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受保护的环境，将利用这些病原体之间的生物协同作用。积极和消极的结果可以迅速传播，致力于每一种复杂疾病的合作伙伴可以从致力于其他疾病的合作伙伴的成功和失败中学习。通过了解从感染到疾病的机制，我们计划发现针对这些和其他复杂细胞内病原体的疫苗开发策略的常用方法。主要网络活动和可交付成果包括知识共享的年度会议；建立实时数据共享的虚拟网络；注入资金以填补知识空白，并提供数据以提高大型资助申请的竞争力；建立网站和其他通讯工具，以加强合作和传播研究成果；通过资助、培训和指导早期博士后和新的PI研究人员来促进职业发展。所有活动都致力于为这些重要疾病开发更有效的疫苗，并提高我们的中低收入合作伙伴的研究能力。

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.