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This review asks when and why prior infection or vaccination is protective versus detrimental, and which biological mechanisms\u2014epitope masking by circulating antibody, inhibitory Fc\u03b3RIIb signaling, and competitive dominance by affinity\u2010matured memory B cells\u2014drive these outcomes. We synthesize human cohort, serological, and vaccine\u2010effectiveness data with mechanistic mouse and fate\u2010mapping studies to explore how vaccine formulation, antigen dose, antigenic distance and T cell help modulate the balance between memory recall and recruitment of na\u00efve 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.<\/jats:p>","DOI":"10.1111\/imr.70146","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:30:16Z","timestamp":1784957416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Dual Role of Preexisting Immunity in Influenza: Protective Recall Versus Constraint of Novel Responses"],"prefix":"10.1111","volume":"341","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0565-7146","authenticated-orcid":false,"given":"Annette","family":"Fox","sequence":"first","affiliation":[{"name":"WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity Royal Melbourne Hospital  Melbourne Victoria Australia"},{"name":"Department of Infectious 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