Immune imprinting blunts omicron pathogenicity fluctuations and highlights the essential role of cellular immunity in SARS-CoV-2 infection.

Abstract

The emergence of Omicron variants challenged early SARS-CoV-2 vaccination and infection-induced immunity, leading to frequent breakthrough infections. While Omicron is generally considered less pathogenic, our retrospective clinical data and multi-species animal models revealed that subvariants BF.7 and XBB.1 exhibit increased pathogenicity compared to BA.1. Despite escaping neutralization by immunity induced by the prototype strain or BA.1, limited cross-immunity attenuated their virulence in hamsters to BA.1 levels. Additionally, we revealed that heterologous secondary infections maximally expanded the immune imprinting landscape elicited by primary infection with the prototype strain. Furthermore, we confirmed the essential role of serum, CD4T and CD8T cell immune responses in antiviral cross-protection via immunodeficient mice and adoptive-transfer studies. These findings underscore the need for ongoing virulence surveillance, highlight the marginal benefit of vaccination against highly mutable RNA viruses in in early outbreak phase, and emphasize the importance of balanced humoral and cellular responses in vaccine design.