Antigenic Variation and Immune Recognition Inference From the COVID-19 Pandemic: An In Silico Comparative Analysis of...

With increased transmission but reduced disease severity, the Omicron SARS-CoV-2 variants have contributed to the multifaceted transition of COVID-19 from a global pandemic to an endemic disease. Nonetheless, the persistence of hypermutable viral variants and their ability to infect both vaccinated and previously infected individuals raise concerns about continued viral evolution and immune evasion.

This study employs comprehensive in silico analyses to compare the five former variants of concern (VOCs) to elucidate their T cell antigenic variations in relation to human leukocyte antigen (HLA) recognition and binding.

Our major histocompatibility complex (MHC) class I and II epitope predictions suggest that the Omicron BA.1 variant harbors more putative epitopes than other VOCs (2.0-11.0 times more). Moreover, the distribution of predicted MHC-II epitopes across HLA alleles differs substantially, with Omicron displaying significant differences from at least three VOCs in all analyses. Investigation of HLA-epitope binding affinities indicates that Omicron epitopes often exhibit enhanced HLA binding compared with the Wuhan Reference (57.8%, 81.8%, and 60.0% of MHC-I, MHC-II regular, and MHC-II promiscuous pairs, respectively), which could influence immune responses.

These findings reveal marked differences in the putative epitope profiles of Omicron BA.1 and the Wuhan Reference, as well as other pre-Omicron VOCs, highlighting its altered HLA recognition status. Given the continued transmission and emergence of new SARS-CoV-2 lineages, this study highlights the importance of ongoing research to understand the evolutionary dynamics of high-risk SARS-CoV-2 variants, their host immune system interactions, and the downstream implications in vaccine and therapeutic development.