Characterisation of immune responses to vaccination against SARS-CoV-2

Abstract

The outbreak of the COVID-19 pandemic highlighted the importance of effective vaccinations that can be rapidly adapted and produced. COVID-19 mRNA vaccines, that had never previously been approved for use against any infectious pathogen, were shown to be extremely effective for protection against severe disease, and billions of doses have since been administered globally. Self-amplifying RNA (saRNA) vaccines display many similarities to mRNA vaccines, but with the potential to be given at lower doses due to the capacity to replicate mRNA within the target cells. A first-in-human clinical trial for a novel COVID-19 saRNA vaccine (COVAC1) demonstrated the safety of this vaccine, but with reduced immunogenicity. Throughout this body of work, I have explored in more detail the humoral and cellular responses following this saRNA vaccination in individuals with or without previous COVID-19, and have made a comparison with mRNA vaccina>on (BNT162b2). I have also endeavoured to look at the differences in early innate responses to both vaccinations. I found that although most individuals seroconverted following saRNA, this was still sub-optimal compared to mRNA. However, BNT162b2 delivery following completion of the saRNA course, resulted in a robust antibody and cellular response, especially evident in those with previous COVID-19. Interestingly, those who received both saRNA and mRNA appeared to have enhanced antigen specific CD8+ T cell responses, characterised by an activated mature memory phenotype. Analysis of soluble mediators at 24-hours following vaccination showed increased concentrations of pro-inflammatory cytokines and chemokines following saRNA compared to mRNA. Coupled with this, transcriptomic analysis demonstrated a more pronounced increase in genes for inflammatory mediators following saRNA. Taken together, the data presented throughout this thesis suggest an immune benefit of saRNA given with mRNA (particularly in COVID-19 convalescence). Additional work needs to be done to optimise this vaccine platform, perhaps with an aim to reduce early inflammation which may result in an improved antigen expression and immune response.