Characterising the T cell responses to SARS-CoV-2 including variants of concern induced by natural infection and vaccines

The COVID-19 pandemic, caused by SARS-CoV-2, has profoundly impacted global health, prompting extensive research into vaccine responses and the immune dynamics of SARS-CoV2 variants of concern (VOCs). This thesis investigates the breadth and durability of T cell responses following COVID-19 vaccination, focusing on immune responses against VOCs, including Alpha, Beta, Gamma, Delta, and Omicron, in previously infected and SARS-CoV2-naïve individuals. T cells, as a central component of adaptive immunity, can target a broader array of SARS-CoV-2 proteins compared to antibodies, providing robust and potentially longlasting immunity even in the face of viral mutations. Chapter 1 provides a literature review on SARS-CoV-2 epidemiology, immune responses and variants. Chapter 2 provides an overview of the methods used in this thesis. In Chapter 3, I examine the impact of extended dosing intervals on T cell responses in both previously infected and naïve individuals. Results suggest that extended intervals enhance the polyfunctional T cell response, contributing to higher durability of the immune response, especially in naïve participants. Chapter 4 expands on T cell responses to VOCs, showing that vaccinated individuals maintain significant T cell reactivity across VOCs despite spike protein mutations that diminish antibody neutralization efficacy. Notably, Omicron’s high mutation count challenges antibody responses, yet T cell responses remain comparatively maintained, likely mitigating severe outcomes during Omicron waves. Chapter 5 utilizes peptide mapping to further dissect T cell responses across SARS-CoV-2 epitopes, revealing that vaccinated individuals with prior SARS-CoV-2 exposure show an expanded breadth of T cell responses, targeting diverse viral epitopes, particularly within conserved S1 and S2 domains. This comprehensive approach demonstrates that even as SARSCoV-2 continues to mutate, T cell responses retain broad cross-reactivity, especially against more conserved viral regions. Additionally, I identify associations between certain HLA alleles, such as HLA-DQB1*06, and enhanced T cell responses, suggesting potential genetic underpinnings for varied immune durability. Together, these findings underscore the importance of T cell immunity in sustaining protection against SARS-CoV-2 variants. My results highlight the need for booster strategies tailored to enhance T cell breadth and magnitude, providing insights for next-generation vaccine designs that prioritise broad and long-lasting immunity across diverse populations.