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.

For several complex intracellular pathogens, we have an incomplete understanding of protective immunity. These diseases, including TB, leprosy, leishmaniasis and melioidosis, disproportionately affect LMICs and are often neglected due to the poor predicted commercial return and marginalisation of affected populations. The current linear approaches, which identify a component of the immune response, induce it by vaccination and evaluate efficacy in animal models and clinical trials, are flawed and have proven inefficient for intracellular pathogens. In this Network we will adopt an iterative approach and develop accurate working models of immunity by repeated integration of data from human experimental studies and animal models across the different pathogens. Veterinary vaccinologists and large animal models will facilitate the One Health agenda, and experimental medicine studies and LMIC and industrial partners will ensure relevance and translational value. The smaller animal models will provide the tools with which to easily dissect mechanisms and immune pathways. The integrated approach incorporates in-silico and in-vitro tools to delineate mechanisms, that will feed directly into vaccine design and development.

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 of macrophages, induce similar end-stage pathologies (granulomatous inflammation, tissue remodeling) and alter 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. By interrogating 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.

There are many beneficiaries of the work carried out under this Network.

The first obvious beneficiaries of this work are basic scientists, clinicians, veterinarians, epidemiologists and clinical trial investigators working in the field of vaccinology, particularly vaccines for the exemplar pathogens that are the focus of this Network. The scientific data sharing, pump-priming funding, and support to existing and new collaborations that are all supported by this Network will lead to new scientific insights which will facilitate vaccine research and development. The networking activities are designed to maximise the impact of the Network. Furthermore, the academic community will gain from the training, mentoring and knowledge sharing that will occur as part of this network.

Industrial colleagues in vaccinology will also benefit from this work, both in SMEs and in large pharmaceutical companies. Industrial involvement in these complex pathogens is currently limited, in part because of a predicted poor return on investment. This Network aims to 'de-risk' vaccine development by providing novel insights into host immunity and in sharing across pathogens any lessons learned so the broader applicability of any novel findings can be rapidly evaluated.

Ultimately, this Network will 'de-risk' vaccine development for complex intracellular pathogens and allow the design and development of vaccine candidates that are more likely to succeed. The development of effective vaccines for any of the pathogens outlined here would have a very significant impact on global mortality and morbidity, particularly in LMIC where these diseases are endemic. The health and ultimately wealth of LMIC will improve with the development of effective vaccines against these devastating pathogens.

Policy makers, in the UK and LMIC, together with the funders of scientific research, also have the potential to benefit from the work outlined in this Network. The insights gained will allow better selection and prioritisation of vaccine candidates at an earlier stage, and a greater likelihood of success.