Estimation of the association between antibody titers and protection against confirmed influenza virus infection in children

Abstract

Antibody titers measured by hemagglutination inhibition (HAI) correlate with protection against influenza virus infection and are used to specify criteria for vaccine licensure. In a randomized, controlled trial of seasonal influenza vaccination in 773 children aged 6-17 years, we estimated that HAI titers of 1:40 against A(H1N1)pdm09 and B(Victoria lineage) were associated with 48% (95% confidence interval [CI], 30%-62%) and 55% (95% CI, 32%-70%) protection against PCR-confirmed infection with each strain. Our analysis accounted for waning in antibody titers over time, and could be particularly useful in settings where influenza activity is delayed or prolonged relative to measurement of antibody titers.

Keywords: antibody; children; immunity; influenza; vaccine.

Figure 1.

A, Timeline of the study. Dashed line showing cumulative percentage of 773 participants who received TIV/placebo, provided postvaccination serum specimens, and provided poststudy sera at the end of follow-up; shaded area indicates the follow-up period. In addition, midstudy sera were collected from 25% of participants in April–May 2010. The overlaid histogram displays the monthly numbers of polymerase chain reaction (PCR)-confirmed influenza virus infections in the study participants. B, Influenza activity in the community was based on a proxy measure calculated as the product of the weekly proportion of influenza-like illness consultations among outpatient visits reported by the local Centre for Health Protection multiplied by the weekly proportion of detections of each influenza strain among specimens tested by the local Public Health Laboratory Service. C and D, Postvaccination, midstudy, and poststudy hemagglutination-inhibiting (HAI) antibody titers against influenza A(H1N1)pdm09 and B(Victoria lineage) virus in children who received trivalent inactivated influenza vaccine (TIV, represented by red circles) or placebo (represented by gray circles). Of the 773 participants, 770, 281, and 729 provided prevaccination, midstudy, and end-of-study serum, respectively. Regression lines for each group (TIV, red; placebo, gray), accounting for repeated measures are also shown to indicate the rates of antibody waning. E and F, Correlation between HAI titers and protection against PCR-confirmed influenza A(H1N1)pdm09 and B(Victoria lineage) virus infection. Antibody titers were measured by HAI using A/California/04/2009 and B/Brisbane/60/2008–like (Victoria lineage) viruses, respectively. Protection was calculated as the relative risk reduction compared with the risk at an HAI titer <1:10, corrected for waning in HAI titers throughout the follow-up period in the absence of infection.

Figure 2.

The estimated protection against infection among study participants, based on hemagglutination-inhibiting (HAI) antibody titers at 1 to 9 months following receipt of trivalent inactivated influenza vaccine. The estimated protection for participants at the 25th, 50th, 75th, and 100th percentile of HAI titer are shown for (A) participants aged 6–8 years and (B) participants aged 9–17 years.