HLA-E-restricted SARS-CoV-2 epitopes drive CD8+ T cell memory in convalescent and vaccinated individuals: implications for the design of next-generation vaccines and immunotherapeutics

Human leukocyte antigen-E (HLA-E) is a non-polymorphic, non-classical HLA class Ib molecule that presents signal peptides from classical HLA class Ia molecules to natural killer (NK) cell receptors. Emerging evidence suggests that HLA-E also presents viral peptides to CD8+ T cells, potentially influencing the control of viral infections. However, CD8+ T cell responses to viral epitopes presented by HLA-E remain largely unexplored. This study investigates the potential of SARS-CoV-2-derived peptides presented by HLA-E to elicit CD8+ T cell responses and to identify T cell-mediated immunity in SARS-CoV-2 infection. We describe seven peptides from SARS-CoV-2 that display substantial conservation among the predominant strains from December 2021 to February 2025. These peptides fit within the HLA-E pocket and elicit HLA-E-restricted CD8+ T cell responses by producing cytokines. HLA-E/SARS-CoV-2-restricted CD8+ T cells were identified in the blood of convalescent patients, predominantly expressing TNF-α, with lower levels of IFN-γ and IL-2, in response to predicted immunogenic epitopes. These cytokines were detected at higher frequencies in convalescent patients but were nearly absent in hospitalized patients with severe COVID-19. HLA-E/SARS-CoV-2-restricted CD8+ T cells were induced after BNT162b2 mRNA vaccination, with their frequencies increasing with more vaccine doses. Furthermore, they were significantly elicited in vaccinated individuals after SARS-CoV-2 infection. These findings underscore the translational potential of targeting HLA-E-restricted CD8+ T cell responses in next-generation vaccine design. The high conservation of HLA-E-presented epitopes across SARS-CoV-2 variants suggests that these peptides may offer a potentially valuable basis for expanding studies on vaccineinduced cellular immunity, independent of viral sequence drift. This strategy could be extended beyond SARS-CoV-2 to other rapidly evolving pathogens, providing a framework for broad-spectrum, T cell-focused vaccine platforms in precision vaccinology.