Progressive loss of conserved spike protein neutralizing antibody sites in Omicron sublineages is balanced by preserved T cell immunity

Evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to the emergence of sublineages with different patterns of neutralizing antibody evasion. We report that Omicron BA.4/BA.5 breakthrough infection of individuals immunized with SARS-CoV-2 wild-type-strain-based mRNA vaccines results in a boost of Omicron BA.4.6, BF.7, BQ.1.1, and BA.2.75 neutralization but does not efficiently boost BA.2.75.2, XBB, or XBB.1.5 neutralization. In silico analyses showed that the Omicron spike glycoprotein lost most neutralizing B cell epitopes, especially in sublineages BA.2.75.2, XBB, and XBB.1.5. In contrast, T cell epitopes are conserved across variants including XBB.1.5. T cell responses of mRNA-vaccinated, SARS-CoV-2-naive individuals against the wild-type strain, Omicron BA.1, and BA.4/BA.5 were comparable, suggesting that T cell immunity against recent sublineages including XBB.1.5 may remain largely unaffected. While some Omicron sublineages effectively evade B cell immunity, spike-protein-specific T cell immunity, due to the nature of polymorphic cell-mediated immune responses, may continue to contribute to prevention/limitation of severe COVID-19 manifestation.