A large-scale human sera cohort analysis mapped population-level neutralizing antibody immunity across three high-pandemic-risk influenza subtypes — H5, H7, and H9 — uncovering stark mechanistic and demographic divergences. H5 viruses were neutralized primarily via conserved stem-domain epitopes driven by IgG1 antibodies, while H7 immunity relied mainly on head-domain epitopes dominated by non-glycan-targeted IgG2 antibodies. Cross-reactive antibodies against Group 2 pandemic HA proteins showed significantly lower avidity compared to closely related seasonal strains, characterizing existing immunity as broadly distributed but low-potency — capable of being boosted but insufficient as standalone pandemic protection. Age-dependent neutralizing response patterns aligned predictably with historical H1N1 and H3N2 seasonal circulation.
This preprint, not yet peer-reviewed, arrives at a critical moment: H5N1 spillovers into mammals and farm workers are accelerating globally, yet population immunological baselines have been poorly characterized. The mechanistic distinction between H5 and H7 epitope targeting is particularly significant — it implies that cross-protective vaccines would need subtype-tailored antigen designs rather than universal stem-only approaches. The low-avidity finding for Group 2 cross-reactive antibodies tempers optimism about herd-level preexisting protection. A key limitation is that avidity and neutralization titers may not fully predict in vivo protection. Age stratification adds actionable nuance for priority vaccination planning. If findings survive peer review, this represents a genuinely informative advance in pandemic preparedness immunology.