Initial antigen encounter determines robust T-cell immunity against SARS-CoV-2 BA.2.86 variant three years later

Background The emergence of the hypermutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2.86 variant raises significant concerns due to its potential to evade pre-existing immunity. Methods We measured cross-reactivity of neutralizing antibodies and T-cell responses to BA.2.86 in 52 previously exposed participants and investigated clinic-demographic and viral genetic determinants affecting T-cell responses. Findings We found that 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-g, IL-2 and IFN-g + 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 lineage-defining mutations to have reduced peptide presentation. This effect is expected to be mitigated due to total TCEs across the genome. Remarkably, T-cell responses and cross-recognition were 3.5 (IFN-g), 2 (IL-2) and 2.4 (IFN-g + IL-2) times higher when first induced by natural infection rather than vaccination three years before, by increasing number of infections, and by ancestral/Delta than Omicron infections. Interpretation Our findings underscore the critical role and the factors influencing T-cell immunity against evolving SARS-CoV-2 variants, such as first antigen encounter (vaccination or infection), which is essential for developing effective control strategies against SARS-CoV-2 variants. Funding European Union (Horizon Europe), Fundacio Privada Daniel Bravo Andreu, Catalan Government (PERIS, CERCA), Spanish Ministry of Science, Rosetrees Trust, Pears Foundation.