Emergence of mutations in antibody and CD8 T cell epitopes in a B-cell depleted lymphoma patient with chronic SARS-CoV-2 infection

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. We longitudinally analyze SARS-CoV-2 sequences in a B-cell depleted lymphoma patient with chronic, ultimately fatal infection, identifying three mutations in the spike protein that dampen neutralization by convalescent plasma transfused to the patient. Additionally, four mutations emerged in regions encoding three CD8 T cell epitopes, including a 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. Moreover, CD8 T cells from the patient show sequentially reduced interaction with the double-mutant nucleoprotein epitope. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. The potential impact of CD8 T cells on SARS-CoV-2 evolution, at least in those with humoral immunodeficiency, deserves intensified investigation informing on vaccine design.