Harnessing the power of T-cell responses to control future pandemics

Several virus families are capable of causing sudden outbreaks, and by definition, for newly emerging viruses, vaccines are not available. Unlike antibodies, T-cell responses are often cross-reactive between pathogens. Therefore, choosing conserved regions of viruses as target vaccine antigens offers a strategy for making vaccines that have some efficacy before a virus has emerged. However, before this can be done, these conserved regions must be identified, and evidence for their protective capacity must be provided. This project will focus on two RNA virus families that are medically relevant: flaviviruses and coronaviruses, specifically SARS-CoV-2. Flaviviruses include dengue, Zika, West Nile and others. The project will aim to develop novel approaches to selecting vaccine antigens for diseases relevant to global health, with the ultimate aim of prevention of future outbreaks. Flaviviruses have caused notable outbreaks such as the 2015 Zika epidemic. SARS-CoV-2 continues to cause many infections despite the availability of vaccines and antivirals. Using samples from several local and national studies, including a phase I clinical trial of a Zika vaccine developed by our team, this project will investigate the phenotype of CD8+ T-cells that develop after both natural infection and vaccination. The student will learn techniques in T-cell epitope mapping, several methods for assessing the T-cell functions (primary supervisor), and bioinformatics (secondary supervisor) to identify T-cell epitope conservation between viruses. They will work on published and experimentally determined epitopes. Bioinformatic analyses will examine where these epitopes are found in relation to protein function, and conservation across different viruses within a family. Next, variant epitopes will be synthesised and tested experimentally to examine this relationship between protein function, conservation, and cross-reactivity of the T-cell response. The avidity and function of responses against cross-reactive epitopes will be tested to ensure they are high quality and expected to provide protection. Antigen specific cells will be sorted for single cell RNA-seq using tetramers/pentamers, to address whether receptor usage or transcriptional profile drives cross-reactivity. The student will then use samples from human experimental medicine studies testing heterologous flavivirus exposure, and directly test (for flaviviruses) which eptiopes cross-react between priming and subsequent heterologous infection in humans, using infectious vaccines. There will also be the opportunity to test real-world responses against a vaccine designed in Liverpool to target both SARS-CoV-2 and MERS-CoV. The above work will uncover the underpinning principles of epitope selection. Finally, these epitopes will be tested by synthesising enveloped mRNAs for antigen presentation assays, to ensure that they can be processed, presented and recognised by human T-cells, using antigen expanded short term T-cell cultures (a well-established method in our lab). The student will benefit from a broad range of training in human immunology and bioinformatics, allowing them to develop good interdisciplinary skills. They will also benefit from working on samples from human studies, so they will learn how to work in a laboratory at GCP, and the governance and regulatory aspects of early phase product development. There will be opportunities to learn programming in R, and to apply both these and other newly acquired bioinformatics skills to the processing of immunological data using pipelines under development in the lab of the primary supervisor.