Defining mechani1sms of CD8+ T-cell mediated immunity - using an integrated longitudinal model to achieve an elusive goal.

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Vaccines have been amongst the most successful and cost-effective health intervention strategies implemented and have played a critical role in reducing the incidence of many human and animal diseases. However, for a number of diseases (e.g. HIV, malaria, African Swine Fever) for which CD8+ T-cell mediated immunity is thought to make a substantial contribution to immunity, there are currently no available vaccines that elicit protective CD8+ T-cell responses. Viral-vectored vaccines are the delivery system that has shown most promise, especially in model species. However, in target human or animal species these vaccines, although usually highly immunogenic (induce T-cell responses), have demonstrated only a limited ability to generate protective CD8+ T-cells. The discrepancy between immunogenicity and protection indicates that qualitative, rather than quantitative, parameters of the vaccine-induced T-cell responses are deficient. As yet our understanding of what these parameters are is limited and this 'knowledge-gap' prevents a fully rational approach to design of novel, efficacious vaccine delivery platforms. Theileria parva, a tick-borne protozoan parasite of cattle, causes major economic losses in livestock farming in sub-Saharan Africa of ~$600M/yr. This loss is largely borne by small-holder farmers and can be devastating for some of the most vulnerable people in low/middle income countries. Natural immunity to T. parva is associated with CD8+ T-cell responses, which can be mimicked under experimental conditions using either an 'infection-and-treatment method' (ITM) or autologous T. parva-infected cell line (ACL) immunisation which have been used to study and characterise protective immunity. A major aim of T. parva research has been the development of a subunit vaccine that could be deployed as part of sustainable T. parva control programme. Trials using a variety of viral vectors (canarypox, Ad, MVA) to deliver known T. parva CD8+ T-cell antigens have demonstrated immunogenicity but only limited protection from in vivo challenge. Recent data has implicated defects in Ad/MVA-induced CD4+ T-cell responses as contributing to deficient CD8+ T-cell functionality.Development and trialling of novel viral vectors requires substantial investments of time and resources and is limited by the availability of suitable candidates. Although disappointing, failure of current viral vectors to induce protective CD8+ T-cell responses can be exploited to understand how the induced T-cell responses differ from equivalent but protective T-cell responses.In this project we propose to use a 'longitudinal' model of T. parva immunisation in which the T-cell responses of individuals are intensively analysed following sequential administration of a non-protective (Ad/MVA) and protective (ITM) immunisation to enable the parameters that influence the transition of phenotypes to be analysed and so define the immunological parameters that determine protective efficacy of CD8+ T-cells. By facilitating intra-animal comparisons this model has a number of advantages over conventional cohort studies. The objectives of the project are to define: 1. How does the function and transcriptome of non-protective CD8+ T-cells induced by Ad/MVA heterologous prime-boost differ from protective T. parva-specific CD8+ T-cells? 2. How does the function and transcriptome of CD4+ T-cells induced by Ad/MVA heterologous prime-boost differ from those associated with protection from T. parva infection? 3. How dependent on CD4+ T-cells is the functional competency of CD8+ T-cells? This information will provide the data to understand the fundamental immunological mechanisms that dictate CD8+ T-cell vaccine success or failure and can be used to inform the design/engineering of improved novel vaccine vectors for T. parva and other human and veterinary pathogens.