The Dual Role of Preexisting Immunity in Influenza: Protective Recall Versus Constraint of Novel Responses

Abstract

Preexisting immunity to influenza confers rapid protection against antigenically matched viruses but can also constrain responses to drifted variants. This review asks when and why prior infection or vaccination is protective versus detrimental, and which biological mechanisms—epitope masking by circulating antibody, inhibitory FcγRIIb signaling, and competitive dominance by affinity-matured memory B cells—drive these outcomes. We synthesize human cohort, serological, and vaccine-effectiveness data with mechanistic mouse and fate-mapping studies to explore how vaccine formulation, antigen dose, antigenic distance and T cell help modulate the balance between memory recall and recruitment of naïve B cells. Finally, we outline strategies (higher dose, adjuvants, multivalent display, and considered strain selection) to restore de novo responses against escape epitopes and improve vaccine performance.