SARS-CoV-2 Specific T Cells in People with and without Obesity

People with obesity (PWO) have a substantially increased risk of developing severe coronavirus disease 2019 (COVID-19), with an approximately 113% increased risk of hospitalisation, 74% increased ICU admission and 48% higher mortality (1). While our understanding of the acute course of SARS-CoV-2 in PWO continues to advance, relatively little is known regarding immune memory following infection and/or vaccination in this vulnerable population. Our knowledge of immune memory in PWO from other settings provides substantial foundation for concern. Those with obesity have been seen to have impaired responses following influenza, rabies, tetanus, and hepatitis B immunisation (2-5). Antigen specific T cells have a crucial role in the adaptive response to SARS-CoV-2 infection. They are protective against severe disease, durable, and are resilient to antigenic variation observed with variants of concern, such as omicron (6-9). Mucosal associated invariant T (MAIT) cells are innate-like, unconventional T cells that are capable of responding to viral infection in a T cell receptor-independent fashion (10-15). They have been implicated in the acute immune response to SARS-CoV-2 infection and have been seen to augment adenovirus vector vaccine immunogenicity (16). The aims of this thesis were threefold. Firstly, I looked to evaluate if adults with obesity who had SARS-CoV-2 infection 3-9 months previously demonstrate poorer antigen specific T cell immunity compared to controls without obesity. I show that PWO who survive COVID-19 generate robust and durable SARS-CoV-2 specific T cell and humoral immunity that is equivalent to that seen in those without obesity. Secondly, to evaluate if adults with obesity who have a history of SARS-CoV-2 vaccination 5 (±1) months previously demonstrate poorer antigen specific T cell immunity compared to controls without obesity. My findings here build on those of the previous aim, showing that PWO who have completed a primary course of ChAdOx1 COVID-19 vaccination have robust, durable, and functional antigen specific T cell immunity that is comparable to that seen in people without obesity. My final aim is to investigate MAIT cell activation and its relationship to SARS-CoV-2 specific T cell responses of adults – irrespective of body mass index (BMI) – at 4-6 months following ChAdOx1 COVID-19 vaccination. I show MAIT cells to be highly activated in response to spike peptide, with features indicative of immune memory. Furthermore, we observe a strong positive correlation between MAIT cell activation and frequencies of SARS-CoV-2 specific CD8+ T cells. Elucidation of the precise mechanism for MAIT cell responses in this setting represents a potentially important avenue of future research. The findings of this thesis contribute to our evolving understanding of SARS-CoV-2 T cell immunity in people with and without obesity (17, 18). The conclusions of aims 1 and 2 represent good news, showing those with obesity to have robust, durable SARS-CoV-2 specific T cells following both SARS-CoV-2 infection and vaccination. The findings of aim 3 reveal a potentially important role for MAIT cells following ChAdOx1 COVID-19 vaccination upon antigenic re-challenge.