Age-Related Priming Determined Breadth of Influenza A(H3N2) Antibody Landscape in Children

Pediatric vaccination, influenza
Pediatric vaccination, influenza
Researchers assessed whether pre-existing antibodies to influenza, which are shaped by early infection and subsequent exposures, impact children’s responses to influenza vaccination.

Immune priming and age, rather than recent vaccination or infection, were major factors that determined the breadth of influenza A(H3N2) antibody landscapes among children, according to study results published in the Journal of Infectious Diseases.

Sera collected over 2 influenza seasons in 2014 to 2015 and 2015 to 2016, where there was an antigenic drift between vaccine antigens from 2014-2015 (A/Texas/50/2012 [clade 3C.1]) to 2015-2016 (A/Switzerland/9725193/2013 [clade 3C.3a]), were used to examine the effects of vaccine response, infection, and vaccine strain changes on antibody landscapes in children.

The study included 72 children between ages 7 and 17 years (median age, 13 years) from the Marshfield Clinic Research Institute in Wisconsin. All children received the 2015 to 2016 trivalent inactivated influenza vaccine (Fluzone, Sanofi Pasteur). Of the 72 children, 31 were newly enrolled in 2015 to 2016 and were unvaccinated and uninfected with no documented influenza exposures in the prior 5 seasons; the remaining 41 children were previously enrolled in 2014 to 2015 and were vaccinated with either the 2014 to 2015 trivalent inactivated influenza vaccine (Sanofi Pasteur) or the quadrivalent live attenuated influenza vaccine (FluMist, MedImmune).

Sera were collected pre- and post-vaccination in both seasons. Vaccine responses were measure by hemagglutination inhibition (HI) assays. For each child, antibody landscapes were constructed using HI antibody titers against 16 A(H3N2) viruses representative of antigenic clusters that circulated between 1968 and 2016.

At pre-vaccination, the number of viruses with HI titers of at least 40 increased with the age of the birth cohorts. Regardless prior vaccination status, children in the same birth cohort had similar shapes of antibody landscape before vaccination. Compared with children who received a vaccine in the prior season, children who were unvaccinated and uninfected had lower titers but similar shapes of landscapes to older viruses, “indicating these children were also exposed to A(H3N2) viruses early in life,” the researchers noted. After the 2015 to 2016 vaccination, children in older birth cohorts induced broader antibody responses to earlier viruses, and the number of post-vaccination titers of at least 80 increased with birth cohort years.

Similar to birth cohorts, children in 5 priming cohorts, which were based on a child’s post-vaccination antibody landscape, had broader breadth of antibody landscape at baseline. For each priming cohort, fold-rise in antibody titers to A(H3N2) priming virus was associated with fold-rise to vaccine virus in 2015-2016 season. However, the multivariate model indicated that pre-vaccination titers to the likely priming virus were not significant predictors of responses to vaccine viruses.

When children were stratified based on their 2014-2015 A(H3N2) infection and vaccination status, the magnitude of the titers increased but the patterns of the landscapes were retained between pre- and post-vaccination in each group. In each of the 3 groups (vaccinated and infected, vaccinated and unaffected, unvaccinated and uninfected), the highest fold-rise was the vaccine virus Switzerland/2013, rather than any of the historic A(H3N2) viruses.

In the 12 children infected with A(H3N2) after receiving Texas/2012 in 2014-2015, antibody landscape were narrower in breadth and lower in magnitude than those vaccinated but uninfected. Following the 2015-2016 vaccination, however, prior season infection status had little effect on antibody landscapes.

Limitations of this study included a small sample size, results based only on HI antibody responses, and the sole focus on A(H3N2) antibody landscape.

“Further studies through antibody landscape analysis and other approaches are needed to elucidate immunological determinants of influenza vaccine response and protection, in order to improve influenza vaccine effectiveness,” the researchers concluded.


Hinojosa M, Shepard SS, Chung JR, et al. Impact of immune priming, vaccination and infection on influenza A(H3N2) antibody landscapes in children. J Infect Dis. Published online October 22, 2020. doi: 10.1093/infdis/jiaa665