Repeated Omicron Infections Overcome T Cell Immune Imprinting to Original SARS‐CoV‐2

Multiple studies demonstrate the existence of attenuated neutralizing activity to the Omicron variants in the original SARS-CoV-2 strain vaccinated population undergoing breakthrough infection, which reflects a phenomenon of immune imprinting in humoral immunity. Herein, through designing spike protein peptide pools from four Omicron subvariants and the wild type (WT) counterpart, we intended to determine antiviral T cell immunoreactivity in Omicron-infected COVID-19 patients with or without previous vaccination. We have demonstrated that IFN-γ producing cells against the Omicron subvariants-derived peptide pools were significantly less than those against WT counterpart peptide pools in the Omicron BA.5/BA.7 infected patients receiving original inactivated SARS-CoV-2 vaccination whereas comparable in the unvaccinated group. Notably, reinfection with the Omicron subvariants restored viral-specific T cell immunity to the infected Omicron strains in vaccinated individuals. Therefore, similar to humoral immunity vaccination with the original SARS-CoV-2 strain-derived vaccines induces T cell immune imprinting when undergoing Omicron subvariants breakthrough infection. Since reinfection of Omicron subvariants can restore T cell immunoreactivity to the infected strains, it is necessary to design multivalent immunogens for vaccine development to overcome both B cell and T cell immune imprinting against SARS-CoV-2 and other highly mutant pathogens.