Adaptive Immune Responses to Vaccination Against SARS-CoV-2 in Individuals with Immune Dysregulation

Abstract

The emergence of SARS-CoV-2 and the subsequent onset of the COVID-19 pandemic led to the rapid development of vaccines against the virus. Two of the major vaccines administered in the UK and elsewhere utilised novel mRNA technology to produce an immune response against the viral spike protein. The efficacy of these vaccines was key to control the pandemic and beyond this, vital for the protection of individuals at high risk from disease. The pace of the expeditious approval and subsequent vaccination programme led to gaps in the understanding of the mechanism of protection and the breadth of effectiveness of these vaccines. Individuals with immune dysregulation, such as those with inborn errors of immunity, cancer, obesity, and on immunomodulatory drugs, make up a large proportion of the UK population. These individuals are at increased risk from COVID-19 disease but also are more likely to respond poorly to vaccination. Vaccine efficacy in these groups is vital for the prevention of mortality, disease spread, and viral evolution. In this thesis, the adaptive immune responses of individuals with immune dysregulation, caused by primary immunodeficiency, immune checkpoint blockade therapies, and severe obesity, to mRNA vaccination against SARS-CoV-2 were assessed. Cellular immune responses, driven by cytotoxic CD8+ T cells, appeared to be robust and well maintained across disease states. Impairment of the humoral, antibody and memory B cell, responses to vaccination was seen in those with elevated levels of age associated B cells. Accelerated waning of the neutralising antibody response and consequent loss of protection was associated with immune dysfunction triggered by severe obesity. The development of a nucleotide tagged multimer and monoclonal antibody validation system, enabled the identification of sequenced antigen specific B cells from individuals with severe obesity. In-depth analysis of the V(D)J sequences and differentiation states of these cells was therefore possible. This revealed reduced levels of class switching and B cell differentiation into memory cells, at an early timepoint after vaccination. Further, no deficit was found in the B cell receptors and antibodies themselves of individuals with severe obesity. These results were indicative of a deficiency in the early germinal centre response. Reduced expression of the IL-6R on the immune cells of individuals with severe obesity suggested a mechanism by which germinal centre responses may be impaired. Loss of IL-6 signalling alone was sufficient in mice to cause accelerated waning and impaired class switching following mRNA vaccination. This identifies IL-6 signalling as a key mechanism of immune activation by mRNA vaccines. Targeting IL-6 signalling may improve the germinal centre response and, as such, both age associated B cells and IL-6 signalling emerge from this work as targets for the improvement of mRNA vaccine responses.