VAccine deveLopment for complex Intracellular neglecteD pAThogEns (VALIDATE)

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.