# Immune Imprinting Identified in Phage-Display Antibody Libraries Derived from Early Wild-Type and Late Omicron COVID-19 Convalescents

## TL;DR

The study shows that immune responses to early SARS-CoV-2 infections may limit the effectiveness of antibodies against newer Omicron variants.

## Contribution

The study reveals how immune imprinting leads to dominance of non-neutralizing antibodies in Omicron convalescents.

## Key findings

- WT-AbLib showed reduced diversity and shifted to non-neutralizing antibodies after Omicron antigen selection.
- Omi-AbLib maintained higher diversity but still favored non-neutralizing antibodies targeting conserved RBD sites.
- Immune imprinting is linked to persistent viral evasion and challenges in developing effective therapeutics.

## Abstract

The rapid evolution of SARS-CoV-2, particularly the emergence of Omicron subvariants, has significantly reduced the efficacy of existing vaccines and monoclonal antibodies. This study investigates the phenomenon of immune imprinting by comparing two phage display antibody libraries derived from early 2020 wild-type SARS-CoV-2 convalescents (WT-AbLib) and early 2023 Omicron convalescents (Omi-AbLib). The capacity and diversity of both antibody libraries were systematically evaluated. The libraries were screened using BF.7 and XBB.1.5 antigens. WT-AbLib showed markedly reduced diversity after Omicron antigen selection, with dominant clones shifting from IGHV3-66-class broadly neutralizing antibodies (bnAbs) targeting the receptor-binding motif to IGHV1-46-class broadly non-neutralizing antibodies targeting conserved lateral receptor-binding domain (RBD) sites. Omi-AbLib maintained higher diversity, but dominant antibodies were also non-neutralizing and targeted the same conserved lateral region. These findings suggest that immune imprinting drives the dominance of broadly non-neutralizing antibodies following Omicron breakthrough or reinfection. This phenomenon provides a mechanistic explanation for persistent viral evasion and recurrent infection, and highlights major challenges for the development of next-generation broadly neutralizing therapeutics.