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

The continued evolution of the SARS-CoV-2 Omicron variant has led to the emergence of numerous sublineages with different patterns of evasion from neutralizing antibodies. We investigated neutralizing activity in immune sera from individuals vaccinated with SARS-CoV-2 wild-type spike (S) glycoprotein-based COVID-19 mRNA vaccines after subsequent breakthrough infection with Omicron BA.1, BA.2, or BA.4/BA.5 to study antibody responses against sublineages of high relevance. We report that exposure of vaccinated individuals to infections with Omicron sublineages, and especially with BA.4/BA.5, results in a boost of Omicron BA.4.6, BF.7, BQ.1.1, and BA.2.75 neutralization, but does not efficiently boost neutralization of sublineages BA.2.75.2 and XBB. Accordingly, we found in in silico analyses that with occurrence of the Omicron lineage a large portion of neutralizing B-cell epitopes were lost, and that in Omicron BA.2.75.2 and XBB less than 12% of the wild-type strain epitopes are conserved. In contrast, HLA class I and class II presented T-cell epitopes in the S glycoprotein were highly conserved across the entire evolution of SARS-CoV-2 including Alpha, Beta, and Delta and Omicron sublineages, suggesting that CD8+ and CD4+ T-cell recognition of Omicron BQ.1.1, BA.2.75.2, and XBB may be largely intact. Our study suggests that while some Omicron sublineages effectively evade B-cell immunity by altering neutralizing antibody epitopes, S protein-specific T-cell immunity, due to the very nature of the polymorphic cell-mediated immune, response is likely to remain unimpacted and may continue to contribute to prevention or limitation of severe COVID-19 manifestation. ### Competing Interest Statement U.S. and O.T. are management board members and employees at BioNTech SE. A.M., B.G.L., M.B., A.T., J.G. and O.O. are employees at BioNTech SE. A.P. and H.D. are employees at BioNTech US. Y.F. and K.B. are employees of InstaDeep Ltd. K.G., N.K., S.H. and S.C. are employees at the University Hospital, Goethe University Frankfurt. U.S., O.T. and A.M. are inventors on patents and patent applications related to RNA technology and COVID-19 vaccines. Q.Y, H.C., and K.A.S. are inventors on a patent application related to RNA-based COVID-19 vaccines. U.S., O.T., A.M., B.G.L., M.B., A.T. A.P., H.D., and O.O. have securities from BioNTech SE. S.C. has received an honorarium for serving on a clinical advisory board for BioNTech SE.