Immune function and responses to COVID-19 vaccines in immunocompromised people

Thesis

mRNA and ChAdOx1-vectored COVID-19 vaccines were highly effective at protecting against severe SARS-CoV-2 infection, but factors relating to the vaccine regimen and the recipient of the vaccine have been identified that impact vaccine immunogenicity. In particular, immunocompromising conditions increased the risk of severe COVID-19 even after vaccination. The aim of this thesis is to investigate the impact of the vaccine regimen and various immunocompromising conditions (diseases and/or immunosuppressive therapies) on SARS-CoV-2-specific antibody and T cell responses induced by COVID-19 vaccines.

First, I present data from two large observational cohort studies of COVID-19 vaccine immunogenicity and SARS-CoV-2 infection outcomes in individuals from 14 different immunocompromising conditions and healthy donors. These studies identify clinical subgroups at particular risk of immune non-responsiveness to vaccine, demonstrate the impact of SARS-CoV-2 mutations on vaccine-induced immune responses in immunocompromised individuals, and reveal the association between vaccine immunogenicity and subsequent COVID-19 severity in the immunocompromised cohort.

Next, I demonstrate the dominant impact of the vaccine dosing interval on the quality of antigen-specific T cells induced by mRNA and ChAdOx-1-vectored COVID-19 vaccines in healthy individuals. Through the combination of an activation induced marker assay and single-cell RNA- and T cell receptor sequencing, I provide insight into the broad functional and clonal heterogeneity of vaccine-induced T cells.

To understand how immunocompromising conditions shape the immune landscape prior to vaccination, I perform a comparative analysis of the transcriptome, inflammatory proteome and immune cell phenotype using pre-vaccination blood samples from immunocompromised individuals known to have poor immune responses to vaccines. By integrating this data with vaccine immunogenicity measures, I identify pre-vaccine immune signatures that are predictive of vaccine immune responsiveness in immunocompromised individuals.

Finally, I apply combined single-cell sequencing approaches to characterise COVID-19 vaccine-induced antigen-specific B and T cells and broader peripheral blood immune cells in immunocompromised individuals. This analysis characterises disease-specific vaccine-induced B and T cell populations and identifies new pathways of immune dysfunction in immune-vulnerable patient groups.

Overall, this thesis provides a comprehensive characterisation of the impact of immunocompromising diseases and therapeutics on COVID-19 vaccine responses and identifies new avenues to optimise vaccination strategies in at-risk populations.

Authors: Murray, S

• DOI: 10.5287/ora-n1rqnadk7
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English