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. 2021 Aug 2;224(3):469-480.
doi: 10.1093/infdis/jiaa665.

Impact of Immune Priming, Vaccination, and Infection on Influenza A(H3N2) Antibody Landscapes in Children

Michael Hinojosa  1   2 , Samuel S Shepard  1 , Jessie R Chung  1 , Jennifer P King  3 , Huong Q McLean  3 , Brendan Flannery  1 , Edward A Belongia  3 , Min Z Levine  1
Affiliations

Impact of Immune Priming, Vaccination, and Infection on Influenza A(H3N2) Antibody Landscapes in Children

Michael Hinojosa et al. J Infect Dis. .

Abstract

Background: Preexisting antibodies to influenza, shaped by early infection and subsequent exposures, may impact responses to influenza vaccination.

Methods: We enrolled 72 children (aged 7-17 years) in 2015-2016; all received inactivated influenza vaccines. Forty-one were also vaccinated in 2014-2015, with 12 becoming infected with A(H3N2) in 2014-2015. Thirty-one children did not have documented influenza exposures in the prior 5 seasons. Sera were collected pre- and postvaccination in both seasons. We constructed antibody landscapes using hemagglutination inhibition antibody titers against 16 A(H3N2) viruses representative of major antigenic clusters that circulated between 1968 and 2015.

Results: The breadth of the antibody landscapes increased with age. Vaccine-induced antibody responses correlated with boosting of titers to previously encountered antigens. Postvaccination titers were the highest against vaccine antigens rather than the historic A(H3N2) viruses previously encountered. Prevaccination titers to the vaccine were the strongest predictors of postvaccination titers. Responses to vaccine antigens did not differ by likely priming virus. Influenza A(H3N2)-infected children in 2014-2015 had narrower antibody landscapes than those uninfected, but prior season infection status had little effect on antibody landscapes following 2015-2016 vaccination.

Conclusions: A(H3N2) antibody landscapes in children were largely determined by age-related immune priming, rather than recent vaccination or infection.

Keywords: antibody landscape; birth cohorts; immune priming; infection; influenza vaccination.

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Conflict of interest statement

Potential conflicts of interest. H. Q. M. has received research funding from Seqirus, unrelated to the present work. All other authors report no potential conflicts of interest.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study design. Study recruitment and sera used for antibody landscape analysis. Abbreviations: IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; UU, unvaccinated and uninfected; VI, vaccinated and infected; VU, vaccinated and uninfected.
Figure 2.
Figure 2.
Antibody landscapes pre- and postvaccination for children vaccinated in both 2014–2015 and 2015–2016 seasons and those only vaccinated in 2015–2016. A, Antibody landscapes in 2014–2015 among children vaccinated in both seasons (n = 41). B, Antibody landscapes in 2015–2016 among children vaccinated in both seasons (n = 41). C, Antibody landscapes in 2015–2016 among children previously unvaccinated and uninfected (UU group, n = 31). Y-axis: log2 geometric mean titer with 95% confidence interval; dashed line denotes the titer of 40. X-axis: A(H3N2) viruses in chronological order.
Figure 3.
Figure 3.
Antibody landscape changes following vaccination in children grouped by birth cohort. A, Antibody landscapes of children vaccinated in both seasons (n = 41) grouped by birth cohort. B, Antibody landscapes of children in the unvaccinated and uninfected (UU) group (n = 31) grouped by birth cohort. Y-axis: log2 geometric mean titer with 95% confidence interval; dashed line denotes the titer of 40. X-axis: A(H3N2) viruses plotted in chronological order by year of isolation: (1) A/Aichi/2/1968, (2) A/Victoria/03/1975, (3) A/Bangkok/1/1979, (4) A/Shanghai/11/1987, (5) A/Beijing/353/1989, (6) A/Beijing/32/1992, (7) A/Wuhan/359/1995, (8) A/Sydney/05/1997, (9) A/Panama/2007/1999, (10) A/Fujian/411/2002, (11) A/California/07/2004, (12) A/Wisconsin/67/2005, (13) A/Brisbane/10/2007, (14) A/Perth/16/2009, (15) A/Texas/50/2012, (16) A/Switzerland/9715293/2013.
Figure 4.
Figure 4.
Antigenic cartographic map of A(H3N2) viruses and antibody landscape changes following vaccination in children grouped by A(H3N2) virus priming cohorts. A, Antigenic cartographic map of the 16 A(H3N2) viruses constructed using ferret antisera hemagglutination inhibition titers. Gridlines in the x- and y-axes indicate 1 antigenic unit. B, Antibody landscapes for children enrolled in both seasons (n = 41) grouped by 5 immune priming cohorts. Y-axis: average log2-transformed (titer/5). X-axis: A(H3N2) viruses graphed along the summary path on the x-axis based on antigenic distance of each virus from Texas/2012 calculated from antigenic map in (A); see details in the Supplementary Methods.
Figure 5.
Figure 5.
Impact of prior season vaccination on antibody landscapes changes. A, Change of prevaccination antibody landscape in 2014–2015 and 2015–2016 among children enrolled in both seasons (n = 41). B, Antibody landscape changes pre- and postvaccination in 2015–2016 stratified by prior season vaccination status. Children who received inactivated influenza vaccine (IIV) in both the 2014–2015 and 2015–2016 seasons (IIV/IIV, n = 32) compared with those in the unvaccinated and uninfected (UU) group who received IIV in 2015–2016 (UU/ IIV, n = 31). Antibody titers to each virus were compared between the 2 groups at pre- and postvaccination. *P < .05; **P < .01. In both (A) and (B), the dashed line denotes a titer of 40. Y-axis: log2 geometric mean titer with 95% confidence interval. X-axis: A(H3N2) viruses in chronological order. C, Fold-rise to all A(H3N2) viruses following vaccination with Switzerland/2013 in 2015–2016. *P < .05; **P < .01, ***P < .001; dashed line denotes 4-fold rise. Y-axis: mean fold-rise with standard error. X-axis: A(H3N2) viruses in chronological order. Abbreviations: IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; UU, unvaccinated and uninfected; VI, vaccinated and infected; VU, vaccinated and uninfected.
Figure 6.
Figure 6.
Impact of prior season infection on antibody landscape changes. A, Antibody landscape changes from the 2014–2015 to 2015–2016 seasons in the vaccinated and infected group (VI, n = 12). B, Antibody landscape changes from 2014–2015 to 2015–2016 season in the vaccinated but uninfected group (VU, n = 29). C, Comparison of pre- and postvaccination antibody landscapes in 2014–2015 among the VI (prior to infection) and VU groups. Statistically significant differences in titers between the VI and VU groups postvaccination for each virus are indicated by *P < .05, **P < .01, and ***P < .001. D, Comparison of antibody landscapes in 2015–2016 season stratified by prior season (2014–2015) exposure status: VI, VU, and UU (unvaccinated and uninfected, n = 31). Statistically significant difference in titers between the 3 groups postvaccination for each virus were indicated by *P < .05. Y-axis: log2 geometric mean titer with 95% confidence interval. X-axis: A(H3N2) viruses in chronological order. Dashed line denotes a titer of 40.
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