Background: The hemagglutination inhibition antibody (HAI) titer mediates only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by post-vaccination HAI titers.

Methods: Causal mediation analyses were conducted using data collected for a randomized, active-comparator controlled, phase 3 trial of a candidate inactivated, split-virion seasonal quadrivalent influenza vaccine (QIV) in children aged 3 to 8 years conducted from October 2010 to December 2011 in eight countries. Vaccine efficacy was estimated with a weighted Cox proportional hazards regression model. Estimates were decomposed into the direct and indirect effects mediated by post-vaccination HAI titers.

Results: The proportions of vaccine efficacy mediated by post-vaccination HAI titers were estimated to be 22% (95% CI: 18%, 47%) for influenza A(H1N1), 20% (95% CI: 16%, 39%) for influenza A(H3N2), and 37% (95% CI: 26%, 85%) for influenza B/Victoria.

Conclusions: HAI titers partially mediate influenza vaccine efficacy against influenza A(H1N1), A(H3N2), and B/Victoria. Our estimates were lower than previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons. Data from more influenza seasons are needed to understand better the mediating effects of HAI titers on vaccine efficacy.