Durability of SARS-CoV-2-Specific T-Cell Responses at 12 Months Postinfection

Abstract

Background: Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions.

Methods: We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2-specific antibodies.

Results: SARS-CoV-2-specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity.

Conclusions: SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease.

Keywords: 12 months; COVID-19; SARS-CoV-2; T cell; antibody; cytotoxicity; durability; memory; polyfunctionality.

Figure 1.

Adaptive immune responses to SARS-CoV-2 viral components at 12 months PSO. A, SARS-CoV-2–specific CD4 and CD8 T-cell responses were detected at 12 months PSO by expression of IFN-γ upon peptide stimulation and intracellular cytokine staining. B, Antibodies to SARS-CoV-2 nucleocapsid protein at 12 months postinfection. Threshold shows the global MFI of antibodies to endemic hCoVs using the same sera in the same assay. C, Frequency of CD4 T-cell responses to the tested viral components N, M, and S in all patient groups. D, Frequency of CD8 T-cell responses to the tested viral components N, M, and S in all patient groups. Bars represent the median value in each group. P values in the plots indicate the significance by Mann-Whitney test. Abbreviations: CMV, cytomegalovirus; hCoV, human coronavirus; IFN-γ, interferon-γ; IP, inpatient; M, membrane; MFI, mean fluorescence intensity; N, nucleocapsid; O₂, oxygen supplementation; OP, outpatient; PSO, post symptoms onset; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Memory phenotype characterization of SARS-CoV-2–specific T-cell responses. A, A representative flow plot of the essential markers used for memory phenotyping. B, Memory phenotypes of IFN-γ⁺ CD4 T cells to SARS-CoV-2N protein as an example in each patient separated by patient group. C, Memory phenotypes of IFN-γ⁺ CD8 T cells to SARS-CoV-2N protein in each patient separated by patient group. Abbreviations: IFN-γ, interferon-γ; IP, inpatient; N, nucleocapsid; O₂, oxygen supplementation; OP, outpatient; P, patient; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCM, central memory T cells; TEM, effector memory T cells; TEMRA, effector memory T cells reexpressing CD45RA.

Figure 3.

Polyfunctionality, cytotoxicity, and activation of SARS-CoV-2–specific CD4 or CD8 T cells. A, Polyfunctionality of CD4 T-cell responses to SARS-CoV-2N protein measured by IL-2 and IFN-γ. B, Cytotoxicity of IFN-γ⁺ CD8 T cells to SARS-CoV-2N protein measured by expression of intracellular granzyme B and membrane CD107a. C, Frequencies of CD69 and PD-1 in SARS-CoV-2 N-specific IFN-γ⁺ CD4 T cells in each patient group. Gray symbols in the inpatient group represent inpatients without oxygen supplementation. D, A representative flow plot of cytotoxic CD8 T cells by the expression of granzyme B and CD107a. Abbreviations: GrB, granzyme B; IFN-γ, interferon-γ; IL, interleukin; IP, inpatient; O₂, oxygen supplementation; OP, outpatient; P, patient; PD-1, programmed cell death protein 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.