ABSTRACT
COVID-19 breakthrough cases among vaccinated individuals demonstrate the value of measuring long-term immunity to SARS-CoV-2 and its variants. We demonstrate that anti-spike T-cell responses and IgG antibody levels are maintained but decrease over time and are lower in BNT162b2- versus mRNA-1273-vaccinated individuals. T-cell responses to the variants are relatively unaffected.
Subject(s)
COVID-19 , 2019-nCoV Vaccine mRNA-1273 , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2/genetics , T-LymphocytesSubject(s)
COVID-19 , Neoplasms , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2 , T-Lymphocytes , VaccinationABSTRACT
Chronic lymphocytic leukemia (CLL), the most common leukemia worldwide, is associated with increased COVID-19 mortality. Previous studies suggest only a portion of vaccinated CLL patients develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies. Whether the elicited antibodies are functional and/or accompanied by functional T-cell responses is unknown. This prospective cohort study included patients with CLL who received SARS-CoV-2 and PCV13 vaccines (not concurrently). The primary cohort included adults with CLL off therapy. Coprimary outcomes were serologic response to SARS-CoV-2 (receptor binding domain [RBD] immunoassay) and PCV13 vaccines (23-serotype IgG assay). Characterization of SARS-CoV-2 antibodies and their functional activity and assessment of functional T-cell responses was performed. Sixty percent (18/30) of patients demonstrated serologic responses to SARS-CoV-2 vaccination, appearing more frequent among treatment-naïve patients (72%). Among treatment-naïve patients, an absolute lymphocyte count ≤24 000/µL was associated with serologic response (94% vs 14%; P < .001). On interferon-γ release assays, 80% (16/20) of patients had functional spike-specific T-cell responses, including 78% (7/9) with a negative RBD immunoassay, a group enriched for prior B-cell-depleting therapies. A bead-based multiplex immunoassay identified antibodies against wild-type and variant SARS-CoV-2 (α, ß, γ, and δ) in all tested patients and confirmed Fc-receptor binding and effector functions of these antibodies. Of 11 patients with negative RBD immunoassay after vaccination, 6 (55%) responded to an additional mRNA-based vaccine dose. The PCV13 serologic response rate was 29% (8/28). Our data demonstrate that SARS-CoV-2 vaccination induces functional T-cell and antibody responses in patients with CLL and provides the framework for investigating the molecular mechanisms and clinical benefit of these responses. This trial was registered at www.clinicaltrials.gov as #NCT05007860.
Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Adult , Antibodies, Neutralizing , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunogenicity, Vaccine , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Prospective Studies , SARS-CoV-2ABSTRACT
T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.