T cell responses to SARS-CoV-2 vaccines and innovative assays for their measurement

Thesis

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the subsequent coronavirus disease 2019 (COVID-19) pandemic had enormous health, social, and economic impacts globally. Serological correlates of protection (CoP) against infection with SARS-CoV-2 after vaccination were rapidly identified. However, the role of T cell responses in protection against infection and their utility as CoP remains incompletely defined. Establishing evidence for T cell CoP is difficult in part due to the challenges of studying T cell responses at scale, meaning there is a more limited evidence base of large studies investigating T cell responses to SARS-CoV-2 vaccines compared to antibody responses.

This thesis investigates whether T cell responses to SARS-CoV-2 vaccination are associated with subsequent protection against infection in two nested case-control studies. In Chapter 3, antibody and T cell responses after vaccination were compared in a subset of participants in the ‘Protective Immunity from T cells to COVID-19 in Health workers’ (PITCH) cohort study to investigate protection against subsequent infection with the Delta variant. This study found SARS-CoV-2 spike (S)-specific T cell interferon gamma (IFNγ) responses, as well as anti-S immunoglobulin G responses, were lower in cases who went on to experience infection compared to controls who did not. In Chapter 4, this work was built on through study of a subset of participants in the COV001 and COV002 AZD1222 vaccine trials, in which cases had subsequently experienced infection with pre-Alpha/Alpha, Delta or Omicron variants. A detailed phenotyping of T cell responses after the first vaccine dose was carried out using a combined activation-induced marker and intracellular cytokine staining assay, and this data revealed a lower frequency of S-specific circulating T follicular helper cells among cases compared to controls.

Whole blood assays have advantages that can help overcome some of the challenges associated with studying T cell responses at scale or in low-resource settings. In Chapter 5, a whole blood assay for SARS-CoV-2 was optimised and its results compared to an inhouse IFNγ Enzyme Linked Immunosorbent spot (ELISpot) assay. Results from the measurement of the chemokine monokine induced by gamma (MIG) after whole blood stimulation were shown to correlate well with, and have high sensitivity and specificity relative to, the in-house IFNγ ELISpot.

This thesis contributes evidence to support the measurement of T cell responses alongside antibody responses for assessment of protection against infection with SARS-CoV-2. Furthermore, it supports whole blood assays as a useful tool in the assessment of T cell responses, which may help promote broader measurement of T cells in low-resource settings and for future emerging pathogens.

Authors: Neale, I

• DOI: 10.5287/ora-mprnqbno8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: vaccines; correlates of protection; T cells; T cell assays; SARS-CoV-2
• Subjects: Cellular immunity; Vaccines