In a recent study posted to the bioRxiv* preprint server, researchers characterized vaccine-induced T cell response specific for spike (S) proteins of several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.
Studies suggest that mutations outside and nearby immunodominant T cell epitopes affect human leukocyte antigen (HLA) binding and the T cell response against SARS-CoV-2 variants.
The proteasome degradation of intracellular SARS-CoV-2 proteins into peptides generates T cell epitopes. Some peptides are translocated into the endoplasmic reticulum (ER) and loaded onto HLA class I molecules via the transporter associated with antigen presentation (TAP). Subsequently, HLA class I complexes are transported to the plasma membrane, where they are presented for recognition by the cluster of differentiation 8 (CD8+) T cells.
It is noteworthy that three epitopes generated from SARS-CoV-2 S protein, viz., RF9, NF9, and QI9, bind strongly to HLA-A*24:02, a predominant HLA-I allele globally.
About the study
In the present study, researchers obtained peripheral blood mononuclear cells (PBMCs) from 29 individuals vaccinated with two doses of BNT162b2 or messenger ribonucleic acid (mRNA)-1273 vaccines. They stained PBMCs with HLA tetramers (peptides) and detected NF9/A24- and QI9/A24-specific T cells in 10/29 (34.5%) and 13/29 (44.8%) HLA-A*24:02+ vaccinated donors, respectively. However, only 2/29, i.e., 6.9% of donors had RF9/A24-specific T cells, thus indicating that CD8+ T cells specific for NF9/A24 and QI9/A24 were the predominant T cells in vaccinated individuals.
Furthermore, the researchers stimulated PBMCs from ten individuals with the NF9 or QI9 peptides to assess whether the NF9/A24- and QI9/A24-specific T cells identified SARS-CoV-2 variants. Additionally, they evaluated the upregulation of two activation markers, CD25 and CD137, in proliferating T cells after 14 days.
The Wilcoxon rank test showed that the percentages of CD25+ and CD137+ T cells after stimulation with the NF9 and QI9 peptides (median 3.5% and 4.5%) were significantly higher than in the absence of peptides. However, there was no significant difference in the cell frequencies, as detected by the Mann-Whitney test (p = 0.6453). These findings suggested that in BNT162b2 or mRNA-1273 vaccinated individuals, the NF9/A24 and QI9/A24 were the immunodominant epitopes presented by the HLA-A*24:02 allele.
Further, a TCR-based quantification assay estimated a three-fold increase in the presentation of the NF9 epitope on the surface of Omicron BA.1 S-expressing cells relative to that of the SARS-CoV-2 prototype. The N-terminal adjacent to the G446S mutation of the NF9 epitope in Omicron BA.1 S was responsible for enhancing NF9/A24-specific T cell recognition.
Amino acid (AA) mutations within and in the epitope-flanking region (here NF9) impact the generation of HLA class I-restricted peptides. Pre-treating Omicron BA.1 S-expressing cells with an inhibitor of tripeptidyl peptidase II (TPPII) reduced its recognition by T cells. The efficient generation of the NF9 epitope required TPPII-mediated removal of two to three amino acids from the N terminus of the epitope.
Recent studies used activation-induced marker (AIM) assays to evaluate the breadth of T cell responses to S proteins in vaccinated and COVID-19 convalescent individuals. However, these assays did not demonstrate the antiviral activity of individual T cells against SARS-CoV-2 variants of concern (VOCs), including the Delta and Omicron, and the effect of mutations on antigen presentation in SARS-CoV-2-infected cells.
In the current study, the researchers found that the G446S mutation in Omicron BA.1 S protein, located adjacent to the N terminus of the NF9 epitope (residues 448-456), was responsible for the efficient recognition of target cells expressing the Omicron BA.1 S. Additionally, the introduction of a serine at the 446 position of Omicron BA.1 S induced enhanced T cell recognition of the NF9 epitope. The enhanced T cell recognition showed a substantial reduction against Omicron BA.2 S and the prototype due to the absence of the G446S mutation.
Furthermore, the level of interferon-gamma (IFN-γ) production by the NF9-specific T cells was higher toward target cells expressing Omicron BA.1 S and lower toward cells expressing Delta S, due to the presence of an L452R mutation in the NF9 epitope in the Delta VOC.
Overall, the study results demonstrated that vaccine-induced T cells had enhanced capacity to recognize and cross-neutralize several SARS-CoV-2 variants, including the Omicron BA.1 sub-variant. Thus, the study findings could help with future vaccine development; likewise, a combination of assays could help evaluate vaccine efficacy against present and yet to emerge SARS-CoV-2 variants.
Future studies should determine how mutations in the S and other SARS-CoV-2 proteins affect antigen presentation for T cell recognition, providing better insights for vaccine design, especially vaccine antigens, to induce efficient cellular immunity.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.