Anti‐idiotypic antibodies as molecular mimics of conserved influenza hemagglutinin epitopes

Abstract Broadly neutralizing antibodies (bNAbs) provide insights for developing universal influenza vaccines through their ability to neutralize diverse viral strains. However, designing antigens that reliably elicit bNAb responses remains challenging due to the difficulty in targeting conserved epitopes with a single antigen. We developed a method using anti‐idiotypic antibodies (IDs) to generate antigens that induce cross‐reactive antibodies against diverse influenza A and B hemagglutinins. Our approach leverages IDs that mimic the conformational epitopes targeted by bNAbs. Structural analysis reveals conformational similarity between bNAb–ID and bNAb–HA‐binding interfaces, providing mechanistic insight into molecular mimicry. These epitope‐mimicking IDs function as effective immunogens, inducing highly cross‐reactive antibodies. This study demonstrates the feasibility and structural basis of molecular mimicry‐based antigen design for targeting conserved conformational epitopes. Although these findings establish proof of concept, vaccine applicability requires further investigation.