VACCINE: Defining signature responses at the innate-adaptive interface to inform the design of vaccines inducing cellular immunity

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Preventing and controlling infectious disease by vaccination is critical to the productivity and welfare of farmed animals worldwide, and necessary to maintain global food security. However, for many prevalent diseases, and in particular those for which immunity requires cell-mediated responses, effective deployable vaccines are not available and are proving extremely challenging to develop. Furthermore, the current approach for screening candidate vaccines involves inoculation of animals followed by disease challenge to test immunity. This is lengthy and costly, and frequently offers little insight into why a particular vaccine has failed. We aim to generate novel tools to address these problems by identifying features of the early immune response associated with initiating protective immune responses. Central to this process are specialised cells called dendritic cells (DCs). DCs reside in peripheral tissues (including skin) and, on encounter with a pathogen or vaccine, migrate via the lymphatic ducts to the lymph node. They carry with them both antigen and signals regarding the nature of the pathogen/vaccine, which together they use to initiate appropriate immune responses. The ability of the DCs to stimulate fully functional immune responses appears to be critically dependant on nature of the signals it received at the point of pathogen/vaccine encounter in the tissues. However the location of these processes makes them extremely difficult to access and study. We have established expertise in a model system (lymphatic cannulation) that allows us to collect large numbers of DCs from calves as they drain from the skin, following interactions with pathogens/vaccines. This provides a unique opportunity, not possible in other species, to investigate this pivotal early phase of the immune response in a natural setting. In this project we will collect DCs for laboratory analysis before, and immediately after, the administration of live pathogens selected on the basis that they stimulate predictable and well described immune responses. We will then use a range of techniques to investigate the response of the DCs to these pathogens, including recently developed sequencing tools that provide detailed resolution of the processes occurring, in which we have additional expertise. We will focus on defining responses to different categories of pathogen (a bacterium, parasite and virus) selected on the basis that they are expected to generate different responses in the DCs. We aim to define the processes that occur within DCs that enable them to induce immunity (as opposed to those processes which occur when immunity is not induced). This will provide us with 'signatures' that can be used as a basis for assessing vaccine-induced responses in future studies aiming to generate novel/improved vaccines. From these 'signatures' we may also be able to identify particular processes that we know are associated with immunity that could be targets for improved vaccines in the future. We will also assess whether these 'signatures' can be detected if DCs are exposed to pathogens or vaccines in the lab.This work aims to develop two novel tools1. Open-access reference data that could be exploited in future studies to design improved vaccine formulations that specifically induce defined protective signatures2. Proof-of-concept for a laboratory based screening system whereby candidate vaccines can be tested and rationally selected These tools will offer a totally novel approach to development of more efficacious vaccines applicable across a wide-range of animal diseases, and so could have far-reaching impact. They will aid the development of cheaper, more efficient research and development methods, with less reliance on animal models. Furthermore, such tools are highly relevant to human medicine where improved methods to test new vaccines are required but where traditional infection studies to test vaccines are not possible.