Summary Objectives Hemagglutination inhibiting (HI) antibodies correlate with influenza vaccine protection but their association with protection induced by natural infection has received less attention and was studied here. Methods 940 people from 270 unvaccinated households participated in active ILI surveillance spanning 3 influenza seasons. At least 494 provided paired blood samples spanning each season. Influenza infection was confirmed by RT-PCR on nose/throat swabs or serum HI assay conversion. Results Pre-season homologous HI titer was associated with a significantly reduced risk of infection for H3N2 (OR 0.61, 95%CI 0.44–0.84) and B (0.65, 95%CI 0.54–0.80) strains, but not H1N1 strains, whether re-circulated (OR 0.90, 95%CI 0.71–1.15), new seasonal (OR 0.86, 95%CI 0.54–1.36) or pandemic H1N1-2009 (OR 0.77, 95%CI 0.40–1.49). The risk of seasonal and pandemic H1N1 decreased with increasing age (both p Highlights • The determinants of influenza immunity were examined in an unvaccinated cohort. • The risk of H3N2 and B infection decreased with increasing pre-season HI titer. • Pre-season HI titer had less effect on H1N1 infection. • H1N1 immunity increased with age and seasonal H1N1 induced pandemic H1N1 immunity. • The contribution of non-HI antibodies to immunity may be relatively high for H1N1.
