SARS-CoV-2 Variants Omicron BA.4/5 and XBB.1.5 Significantly Escape T Cell Recognition in Solid-organ Transplant Recipients Vaccinated Against the Ancestral Strain

Background.Immune-suppressed solid-organ transplant recipients (SOTRs) display impaired humoral responses to COVID-19 vaccination, but T cell responses are incompletely understood. SARS-CoV-2 variants Omicron BA.4/5 (BA.4/5) and XBB.1.5 escape neutralization by antibodies induced by vaccination or infection with earlier strains, but T cell recognition of these lineages in SOTRs is unclear. Methods.We characterized Spike-specific T cell responses to ancestral SARS-CoV-2 and BA.4/5 peptides in 42 kidney, liver, and lung transplant recipients throughout a 3- or 4-dose ancestral Spike mRNA vaccination schedule. As the XBB.1.5 variant emerged during the study, we tested vaccine-induced T cell responses in 10 additional participants using recombinant XBB.1.5 Spike protein. Using an optimized activation-induced marker assay, we quantified circulating Spike-specific CD4(+) and CD8(+)T cells based on antigen-stimulated expression of CD134, CD69, CD25, CD137, and/or CD107a. Results.Vaccination strongly induced SARS-CoV-2-specific T cells, including BA.4/5- and XBB.1.5-reactive T cells, which remained detectable over time and further increased following a fourth dose. However, responses to BA.4/5 (1.34- to 1.67-fold lower) XBB.1.5 (2.0- to 18-fold lower) were significantly reduced in magnitude compared with ancestral strain responses. CD4(+) responses correlated with anti-receptor-binding domain antibodies and predicted subsequent antibody responses in seronegative individuals. Lung transplant recipients receiving prednisone and older adults displayed weaker responses. Conclusions.Ancestral strain vaccination stimulates BA.4/5 and XBB.1.5-cross-reactive T cells in SOTRs, but at lower magnitudes. Antigen-specific T cells can predict future antibody responses. Our data support monitoring both humoral and cellular immunity in SOTRs to track COVID-19 vaccine immunogenicity against emerging variants.