Influenza Hemagglutination-inhibition Antibody Titer as a Mediator of Vaccine-induced Protection for Influenza B

Abstract

Background: The hemagglutination inhibition (HAI) assay is an established correlate of protection for the inactivated influenza vaccine. However, the proportion of vaccine-induced protection that is mediated by the post-vaccination HAI titer has not been assessed.

Methods: We used data from a randomized, placebo-controlled trial of a split-virion inactivated influenza vaccine in children aged 6-17 years. Sera were collected before and 30 days after receipt of vaccination or placebo and tested by the HAI assay against B/Brisbane/60/2008-like (B/Victoria lineage). We fitted Cox proportional hazards models to the time to laboratory-confirmed influenza B. We used causal mediation analysis to estimate the proportion of the total effect of vaccination that was mediated by higher HAI titers.

Results: We estimated that vaccine efficacy against confirmed B/Victoria infection was 68% (95% confidence interval, 33%, 88%), and post-vaccination HAI titers explained 57% of the effect of vaccination on protection.

Conclusions: The majority of the effect of inactivated influenza vaccination in children is mediated by the increased HAI titer after vaccination; however, other components of the immune response to vaccination may also play a role in protection and should be further explored. Causal mediation analysis provides a framework to quantify the role of various mediators of protection.

Keywords: correlate of protection; hemagglutination inhibition; influenza; vaccination.

Figure 1.

Mediation model showing the hypothesized relationship between influenza vaccination and risk of disease from influenza virus infection. The hemagglutination inhibition (HAI) titer measured 30 days after receipt of vaccination or placebo acts as a mediator of the protective effect of vaccination on risk of disease from infection. Influenza vaccination has an indirect effect on risk of disease from infection, which operates via a change in HAI titers (arrow a) and the higher HAI titers reducing the risk of disease from infection (arrow b). Influenza vaccination may also have a direct effect on risk of disease from infection that is not mediated by the HAI titer but operates through other immune mechanisms (arrow c). Age is shown as a confounder of the relationship between post-vaccination HAI titers and the risk of disease from infection, since age affects HAI titers (arrow d) and the risk of disease from infection (arrow e). Abbreviation: HAI, hemagglutination inhibition.

Figure 2.

(A) Post-vaccination antibody titers by the hemagglutination inhibition (HAI) assay against the B/Brisbane/60/2008 (Victoria lineage) virus that was included in the trivalent inactivated influenza vaccine. Titers are compared between placebo and vaccine recipients; the horizontal line indicates the median titer and the vertical line indicates the interquartile range. Titers are measured in intervals (eg, a titer of “10” indicates a titer of ≥10 but <20), and plotted in those intervals accordingly. (B) Timing of polymerase chain reaction (PCR)-confirmed infections during the study period in the children who received placebo (black, solid line) or vaccine (red, dashed line). (C) Distribution of HAI titers in all children (left-hand side) and in the children who had PCR-confirmed infection during follow-up (right-hand side). Black bars represent the children who received placebo, and red bars represent the children who received influenza vaccination. The range of titer dilutions shown is <1:10 to 1:2560, with corresponding titers <10 to ≥2560, and bars are plotted in the respective intervals. The lowest bar corresponds to children with HAI titers <10. (D) Correlation of HAI titer with protection against infection in a proportional hazards model. Note in this panel that an HAI titer of 40 was estimated to correspond to approximately 50% protection compared to a low HAI titer. Abbreviation: HAI, hemagglutination inhibition.