Characterising the magnitude and breadth of T cell responses to SARS-CoV-2 vaccination

Chauke, Valencia Masego

Characterising the magnitude and breadth of T cell responses to SARS-CoV-2 vaccination

Thesis / Dissertation

2024

Publisher

University of Cape Town

Department

Department of Pathology

Faculty

Faculty of Health Sciences

Abstract

Spike protein which serves as the immunogen in the current vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is targeted by the CD4 and CD8 T cells. While most studies frequently measure the magnitude of spike-specific CD4 and CD8 responses, only a few studies have characterised their breadth of targeting across the spike. This characterization is crucial for predicting cross-reactivity in T cell responses against emerging variants of concern (VOC) that may have mutations in the targeted regions. This study aimed to examine the magnitude and breadth of SARS-CoV-2 spike-specific memory CD4 and CD8 T cells induced by a heterologous prime-boost vaccination strategy consisting of Ad26.COV2.S and mRNA-1273 vaccines. Twenty healthcare workers (HCW) who participated in the SHERPA study where participants who had previously received either one (n=8) or two (n=12) doses of the Ad26.COV2.S vaccine received the mRNA-1273 vaccine booster at baseline (BL) were selected. The median time since last Ad26.COV2.S vaccine dose was 340 days [IQR: 335-355] and 187 days [IQR: 340-458] for the one and two prior dose groups, respectively. Ninety-five percent (19/20) of the participants had a history of SARS-CoV-2 infection. CD4 and CD8 T cell responses to the SARS-CoV-2 spike protein were characterized using intracellular cytokine staining interferon-γ (IFN-γ) or interleukin-2 (IL-2) and flow cytometry. The magnitude of T cell responses to full spike was examined, as well as crude T cell breadth, using 7 peptide pools spanning the entire length of the spike protein at BL and 4 weeks (W4) post-vaccination. Boosting with mRNA-1273 resulted in a significant increase in the magnitude of spike-specific CD4 responses (median % memory CD4 T cells: 0.085 vs. 0.157; p=0.04) and CD8 responses (median % memory CD8 T cells: 0 vs. 0.015; p=0.025). A strong positive correlation was observed between the magnitude of the full spike and the combined seven pools for both CD4 (p < 0.0001; r = 0.78) and CD8 (p < 0.0001; r = 0.74) responses. On average, participants had CD4 responses targeted against five pools (range 2-7) at BL. Following mRNA-1273 vaccination, the number of pools targeted slightly increased to a median of 5.5 (range 4-7). Only 8/20 (40%) participants had CD8 responses against the spike pools at BL (median: 0; range 0-6). At W4, the median number of targeted pools increased to one (range 0-6) among the participants. There was no statistical difference in CD4 or CD8 responses against the pools between those who had received one or two initial doses. All seven spike pools were targeted by the CD4 and CD8 cells at both timepoints. The highest median magnitude of CD4 responses was detected for pool 2 (0.025%) which covers the N terminal domain (131-315 aa), pool 5 (0.023%) which covers the fusion peptide domain (686- 890 aa), pool 6 (0.019%) which includes the heptapeptide repeat sequence and pool 3 (0.015%) covers a portion of the receptor binding domain (305-515 aa). Since most CD8 responders targeted only a single pool, no pool dominated in terms of the median magnitude. The data suggest that CD4 cells exhibit a broader breadth of responses compared to CD8 responses which were narrowly targeted against one region of the spike. This is consistent with what other published studies found. The broad targeting of the CD4 responses suggests that cross-reactivity against emerging VOCs may be better preserved than the CD8 responses, especially when mutations occur in the targeted epitopes. As new variants continue to emerge, it is important to introduce vaccines that induce broader CD8 responses to bolster cross reactivity.

Keywords

Medicine

Reference:

Collections

Masters

Full item page