Overview
Vaccines are a powerful weapon in our arsenal against infectious diseases, with applications now being explored for the development of targeted gene and cancer therapies. Vaccine-preventable infectious diseases still account for an estimated 1.5 million deaths each year, however adenoviral vector-based vaccines have revolutionised our ability to respond rapidly to emerging infectious diseases. This was highlighted during the COVID-19 pandemic which demonstrated the importance of effective vaccines, but also their limitations as many people possess immunological memory to common adenoviruses, which can weaken vaccine responses or cause unwanted, off-target immune activation. Recent vaccination strategies, such as those used for COVID-19, utilised non-human and low seroprevalence viral vectors to circumvent pre-existing immunity that can hamper vaccine performance. However, studies have now identified widespread cross-reactive T-cell responses to these vaccine delivery systems in unexposed individuals.
About this opportunity
In this PhD, we will explore a major unsolved question: why and how these cross-reactive T-cell responses manifest. This knowledge will directly contribute to the overarching aim of designing next-generation adenoviral vectors for use within the development of new vaccines and therapies, achieved through a collaborative link with the Centre for Global Vaccine Research (https://www.liverpool.ac.uk/infection-veterinary-and-ecological-sciences/research/groups/vaccines/) with involvement in vaccine development and clinical trials. The research themes of the studentship will span across 4 major areas: (1) Identification of conserved immunodominant T-cell epitopes shared across adenoviral vectors through MHC-associated peptide proteomics; (2) Immunogenicity screening and functional validation of shared immunodominant T-cell epitopes using in vitro T-cell assays; (3) Clinical assessment of immunogenic adenoviral T-cell epitopes for vaccine efficacy; (4) Development of modified vectors through viral re-engineering of culprit residues for immunogenicity evasion.
Importance and Impact: Pre-existing immunity to adenoviral vectors has long been a concern within vaccine development. Recently, the UK has effectively undertaken a large-scale population experiment in boosting adenovirus immunity, following the widespread deployment of ChAdOx1 and other viral-based platforms. While crucial for pandemic control, long-term consequences for the use of adenoviral vectors remain unclear. There is now strong evidence that future applications of adenoviral vectors will require rational re-engineering to evade ChAdOx1-induced and naturally acquired cellular immune responses. Therefore, this project aims to unlock the full potential of adenoviral vectors by introducing a fundamental shift in vector design.
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, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
Further reading
1. Gardner J, Abrams ST, Toh CH, Parker AL, Lovatt C, Nicolson PLR, Watson SP, Grice S, Hering L, Pirmohamed M, Naisbitt DJ. Identification of cross-reactive T-cell responses in adenovirus-based COVID 19 vaccines. NPJ Vaccines. 2024 Jun 5;9(1):99. doi: 10.1038/s41541-024-00895-z. https://pubmed.ncbi.nlm.nih.gov/38839821/
2. Ogbe A, Kronsteiner B, Skelly DT, Gardner J, Dunachie S. T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses. Nature Communications. 2021 Apr 6;12(1):2055. doi: 10.1038/s41467-021-21856-3. https://pubmed.ncbi.nlm.nih.gov/33824342/
3. Nicolson PLR, Abrams ST, Amirthalingam G, Gardner J, Pirmohamed M.
Understanding mechanisms of thrombosis and thrombocytopenia with adenoviral SARS-CoV-2 vaccines: a comprehensive synopsis National Institute for Health and Care Research. 2025 Jul (PMID: 40632888). https://pubmed.ncbi.nlm.nih.gov/40632888/
4. Sun L, Huai P, Wang Z, Zhao Q, Lin Y, Liu T, Xue X, Ao S, You J, Sun Y, Mi Z, Gardner J, Thomson PJ, Naisbitt DJ, Meng X, Liu J, Liu H, Zhang F.TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity.
Signal Transduct Target Ther. 2025 Jun 21;10(1):196. https://pubmed.ncbi.nlm.nih.gov/40544157/
5. Gardner J, Martinez-Rivera S, Line J, Thomson P, Clarke E, Gibson A, Krantz MS, Ardern-Jones M, Phillips EJ, Naisbitt DJ. Elucidating CD4+ and CD8+ T-cell involvement in patients with vancomycin-induced DRESS Toxicol Sci. 2025 Aug 1;206(2):420-432. doi: 10.1093/toxsci/kfaf074. https://pubmed.ncbi.nlm.nih.gov/40424455/
6. Gardner J, Hammond S, Jensen R, Gibson A, Krantz MS, Ardern-Jones M, Phillips EJ, Pirmohamed M, Chadwick AE, Betts C, Naisbitt DJ. Glycolysis: An early marker for vancomycin-specific T-cell activation. Clin Exp Allergy. 2024 Jan;54(1):21-33. doi: 10.1111/cea.14423. https://pubmed.ncbi.nlm.nih.gov/38177093/