Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.

Human herpesvirus 6 (HHV-6) is prevalent in healthy persons, causes disease in immunosuppressed carriers, and may be involved in autoimmune disease. Cytotoxic CD8 T cells are probably important for effective control of infection. However, the HHV-6-specific CD8 T cell repertoire is largely uncharacterized. Therefore, we undertook a virus-wide analysis of CD8 T cell responses to HHV-6. We used a simple anchor motif-based algorithm (SAMBA) to identify 299 epitope candidates potentially presented by the HLA class I molecule B*08:01. Candidates were found in 77 of 98 unique HHV-6B proteins. From peptide-expanded T cell lines, we obtained CD8 T cell clones against 20 candidates. We tested whether T cell clones recognized HHV-6-infected cells. This was the case for 16 epitopes derived from 12 proteins from all phases of the viral replication cycle. Epitopes were enriched in certain amino acids flanking the peptide. Ex vivo analysis of eight healthy donors with HLA-peptide multimers showed that the strongest responses were directed against an epitope from IE-2, with a median frequency of 0.09% of CD8 T cells. Reconstitution of T cells specific for this and other HHV-6 epitopes was also observed after allogeneic hematopoietic stem cell transplantation. We conclude that HHV-6 induces CD8 T cell responses against multiple antigens of diverse functional classes. Most antigens against which CD8 T cells can be raised are presented by infected cells. Ex vivo multimer staining can directly identify HHV-6-specific T cells. These results will advance development of immune monitoring, adoptive T cell therapy, and vaccines.

Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.

​​Since its recent zoonotic spill-over severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is constantly adapting to the human host as illustrated by the emergence of variants of concern with increased transmissibility and immune evasion. Prolonged replication in immunosuppressed individuals and evasion from spike-specific antibodies is known to drive intra-host SARS-CoV-2 evolution. Here we show for the first time the major role of CD8 T cells in SARS-CoV-2 evolution. In a patient with chronic, ultimately fatal infection, we observed three spike mutations that prevented neutralisation by convalescent plasma therapy. Moreover, at least four mutations in non-spike proteins emerged that hampered CD8 T-cell recognition of mutant epitopes, two of these occurred before spike mutations. A comparison with worldwide sequencing data showed that several of these T-cell escape mutations had emerged independently as homoplasies in multiple circulating lineages. We propose that human leukocyte antigen class I contributes to shaping the evolutionary landscape of SARS-CoV-2.