Immune responsiveness following diverse SARS-CoV-2 vaccination platforms

Thesis

Even among immunocompetent individuals, immune responses following SARS-CoV-2 vaccination are heterogenous, and the mechanisms underlying this variability are not fully understood. The overall aim of this thesis was to characterise vaccine-induced immune responses in real-world populations and to identify immunological and demographic factors associated with variability in vaccine-induced immune responses.

First, immune responses were characterised in vaccinated UK healthcare workers who self-reported no documented breakthrough infection. These individuals had robust spike-specific antibodies and T-cell responses consistent with vaccination. Approximately half also had non-spike-specific immune responses, suggesting previously unrecognised viral exposure.

Second, blood proteomic profiling of healthy UK vaccine recipients was performed to identify protein markers associated with T-cell responses following mRNA vaccination. Multivariable analysis identified eukaryotic translation initiation factor 5A (EIF5A), interleukin 1 receptor-like 2 (IL1RL2), collagen type IX alpha 1 chain (COL9A1), matrix metallopeptidase 1 (MMP1) and Src kinase-associated phosphoprotein 2 (SKAP2), along with age, sex and serostatus to CMV, as predictors of T-cell responses. Immunophenotypic analysis using high-dimensional flow cytometry further demonstrated that T-cell non-response group exhibited markers associated with T-cell senescence and functional exhaustion, whereas T-cell response group showed higher frequencies of naïve CD8+ T-cells and regulatory T cells than non-response group.

Third, humoral and cellular immune responses were compared across vaccine platforms before vaccination and one month after the second vaccine dose. mRNA vaccines elicited higher spike-specific responses following vaccination compared with other vaccine platforms in previously infected individuals. Inactivated vaccines induced nucleocapsid-specific IgA responses in blood.

Collectively, this thesis demonstrates that humoral and cellular immune responses to SARS-CoV-2 vaccination are shaped by baseline immune competence, exposure history, and vaccine platform. This work highlights the importance of considering both host immune landscape and vaccine platform to understand vaccine immunogenicity to inform the optimisation of vaccination strategies.

Authors: Tayipto, Y

• DOI: 10.5287/ora-9enmvdonm
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: SARS-CoV-2 vaccination; antibody; T cell responses
• Subjects: Immunology