Objectives: We aimed to evaluate the adaptive immune responses' cross-recognition of the hypermutated SARS-CoV-2 BA.2.86 variant and identify the determinants influencing this recognition.
Methods: We measured BA.2.86 neutralizing antibodies and T-cell responses cross-reactivity in previously exposed participants. We investigated clinic-demographic factors and used a novel in silico analysis to assess viral genetic determinants affecting T-cell responses.
Results: Despite notable escape from neutralizing antibodies, T-cell responses remained generally preserved, albeit with a significant but small loss in T-cell cross-recognition (7.5%, 14.2%, and 10.8% average loss for IFN-γ, IL-2, and IFN-γ + IL-2, respectively, p<0.05). This is consistent with the prediction of 6 out of 10 immunodominant T-cell epitopes (TCEs) altered by BA.2.86 mutations to have reduced peptide presentation. This effect is expected to be mitigated by total TCEs across the genome. Remarkably, T-cell responses and cross-recognition were 3.5 (IFN-γ), 2 (IL-2) and 2.4 (IFN-γ + IL-2) times higher when first induced by infection rather than vaccination three years before, by increasing number of infections, and by ancestral/Delta than Omicron infections.
Conclusions: Our findings underscore the critical role and factors influencing T-cell immunity against evolving SARS-CoV-2 variants, such as first antigen encounter (vaccination or infection), as it is essential for developing effective control strategies.
Keywords: BA.2.86 cross-recognition; COVID-19; Pirola; T cells; neutralizing antibodies.
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