Background
SARS-CoV-2 variants such as XBB.1.5 and BA.2.86 have emerged with mutations that allow them to evade neutralizing antibodies elicited by ancestral and bivalent mRNA vaccines. Despite the introduction of the XBB.1.5 monovalent booster to improve T cell immunity, it remains unclear whether this vaccine induces stronger XBB.1.5-specific T cell responses compared to the ancestral/BA.5 bivalent vaccines. We hypothesized that the XBB.1.5 booster would significantly increase the percentage of XBB.1.5 mono-reactive T cells.
Methods
We used the IFN-gamma ELISpot assay to determine the targeted epitopes and the functional expansion of specific T cells (FEST) assay to assess the percentage of CD4+ T cells that cross-recognized ancestral, BA.5, and XBB.1.5 spike proteins versus those that were mono-reactive. The FEST assay involves culturing antigen-specific T cells with spike peptides, followed by TCR sequencing to identify expanded clonotypes. 11 participants who received either the ancestral/BA.5 bivalent mRNA vaccine or the XBB.1.5 monovalent mRNA booster vaccine were included in the study.
Results
Our analysis revealed robust T cell responses to ancestral, BA.5, and XBB.1.5 spike proteins. However, the XBB.1.5 booster did not significantly increase the percentage of XBB.1.5 mono-reactive T cells. The percentage of spike-specific CD4+ T cell receptors that were XBB.1.5 mono-reactive did not increase significantly after the booster shot (7.6% pre-booster to 12.3% post-booster, p=0.4375). Instead, cross-reactive CD4+ T cells dominated the spike-specific T cell response. Furthermore, the percentage of T cell-targeted epitopes containing XBB.1.5 mutations did not significantly change after the booster (27.9% pre-booster to 23.75% post-booster, p= 0.6667).
Conclusions
Our findings suggest that the XBB.1.5 monovalent booster does not substantially enhance XBB.1.5-specific T cell responses, with cross-reactive T cells continuing to dominate the immune response. These results have important implications for future vaccine strategies targeting emerging variants.
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