Investigating the impact of pre-existing adenovirus immunity on the safety and efficacy of adenoviral-based vaccines and therapeutics (360G-Wellcome-321990_Z_24_Z)

My research programme aims to improve the safety and efficacy of adenoviral vector-based vaccines and therapies by introducing a fundamental shift in vector design. Human adenoviruses are routinely used as delivery vectors for gene therapies and vaccines. Human adenovirus serotype 5 (HAd5) was the backbone of adenoviral vector development. However, concerns have been raised regarding future suitability due to the high prevalence of pre-existing immunity. Prior exposure to circulating human adenovirus through natural infection can hamper vaccine and therapeutic performance. In addition, immune cross-reactivity is widespread between conserved proteins of HAd5 and non- human adenoviral vector alternatives, such as the Oxford COVID-19 vaccine (ChAdOx1). Key goals: First, we will identify and characterise conserved immunodominant T-cell epitopes shared across adenoviral vector vaccines and circulating human adenoviruses of high seroprevalence using healthy donor models and patients with vaccine-mediated adverse events. Second, we will evaluate the impact of cross-reactive adenoviral T-cell epitopes on vaccine performance and assess the clinical significance of adenovirus cross- reactivity. Lastly, we will engineer modified adenoviral vectors to evade T-cell immunogenicity and off-target immune stimulation. Through innovative modifications that mitigate immunogenicity, this work will broaden therapeutic applications, improve efficacy and underpin the development of next generation adenoviral-based vectors.