MRC DiMeN Doctoral Training Partnership: 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. The immune system can protect us through vaccination, but this works best where the infecting virus is known so that antibodies can be made which are a good match. However, the specialised cells of the immune system called T cells also respond to viruses. T cell responses can be less virus specific. T cells do not provide the same level of protection as antibodies do, but there is good evidence for COVID that they can reduce the severity of disease and keep you out of hospital, which is a major benefit. It is probably also more difficult for the virus to escape from T cell responses than antibodies.

In the Turtle lab, our approach, therefore, is to try to identify regions of viruses that are similar between different viruses (conserved regions) to act as target vaccine antigens. This strategy allows for making vaccines that have some effect before a virus has even emerged. The first step in this process is to identify these conserved regions, and establish which have the greatest protective capacity.

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. 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 CD8+ T-cell (killer T cell) response that develops after both natural infection and vaccination.

This project will offer training in techniques in the high-resolution study of T-cell responses, such as epitope mapping, and several methods for assessing the T-cell functions. Training in bioinformatics will be used to identify conserved regions between viruses that can be targeted by T cells. Bioinformatic analyses will also examine where these epitopes are found in relation to protein function, and look at conservation across different viruses within a family. This will give rise to transferrable skills, both in the lab and informatically, that could be applied to any pathogen. 

Where regions of similarity between viruses that are targeted by T cells are identified, the effect of any differences between viruses can be investigated in detail. This could involve measures of T cell receptor avidity for different functions, antigen specific cell labelling with HLA tetramers, or single cell sequencing. These techniques would be used to investigate differences in the responses to different but related sequences from different viruses. 

Some of the principles uncovered in this work can then be directly tested using samples from human experimental medicine studies testing heterologous flavivirus exposure. 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.

For more info, visit:

Lance Turtle

Kate Baker

Lance is on Twitter: @LanceTurtle

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply