Understanding and Manipulating Viral Immunity: Antibody Immunodominance Enters Center Stage

Adaptive immune responses against antigenically variable viruses and cellular pathogens are efficient in many cases, but largely limited to the infecting or immunizing strain. A major factor that limits immunity is immunodominance (ID), the hierarchical focusing of adaptive immune responses on a subset of antigenic determinants. While CD8+ T cell ID has been extensively studied, studies of basic mechanisms of B cell ID are limited, despite the importance of antibodies (Abs) for durable protection against pathogens. Here, we review recent progress in understanding the basic rules and mechanisms of B cell ID, compare B and CD8+ T cell ID, and outline challenges to overcoming ID to develop Ab-based ‘universal’ vaccines for influenza A and other highly variable viruses. ID, a central feature of adaptive immunity, is poorly understood for B cells. The focus of Ab responses on immunodominant antigenic sites drives the selection of viral escape mutants, undermining vaccination for influenza and other highly variable viruses. Similar immunogen- and immune system-dependent factors contribute to B and T cell ID. Understanding the bases of ID is key to manipulating the immune response and targeting vaccines to conserved, cross-reactive antigenic sites.