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. 2018 Oct 5;218(10):1571-1581.
doi: 10.1093/infdis/jiy376.

Influence of Immune Priming and Egg Adaptation in the Vaccine on Antibody Responses to Circulating A(H1N1)pdm09 Viruses After Influenza Vaccination in Adults

Feng Liu  1 , Wen-Pin Tzeng  1 , Lauren Horner  1   2 , Ram P Kamal  1   2 , Heather R Tatum  1   2 , Elisabeth G Blanchard  1 , Xiyan Xu  1 , Ian York  1 , Terrence M Tumpey  1 , Jacqueline M Katz  1 , Xiuhua Lu  1 , Min Z Levine  1
Affiliations

Influence of Immune Priming and Egg Adaptation in the Vaccine on Antibody Responses to Circulating A(H1N1)pdm09 Viruses After Influenza Vaccination in Adults

Feng Liu et al. J Infect Dis. .

Abstract

Background: Although ferret antisera used in influenza surveillance did not detect antigenic drift of A(H1N1)pdm09 viruses during the 2015-2016 season, low vaccine effectiveness was reported in adults. We investigated the immune basis of low responses to circulating A(H1N1)pdm09 viruses after vaccination.

Methods: Prevaccination and postvaccination serum samples collected from >300 adults (aged 18-49 years) in 6 seasons (2010-2011 to 2015-2016) were analyzed using hemagglutination inhibition assays to evaluate the antibody responses to 13 A(H1N1) viruses circulated from 1977 to 2016. Microneutralization and serum adsorption assays were used to verify the 163K and 223R specificity of antibodies.

Results: Individual antibody profiles to A(H1N1) viruses revealed 3 priming patterns: USSR/77, TW/86, or NC/99 priming. More than 20% of adults had reduced titers to cell-propagated circulating 6B.1 and 6B.2 A(H1N1)pdm09 viruses compared with the A/California/07/2009 vaccine virus X-179A. Significantly reduced antibody reactivity to circulating viruses bearing K163Q was observed only in the USSR/77-primed cohort, whereas significantly lower reactivity caused by egg-adapted Q223R change was detected across all 3 cohorts.

Conclusion: Both 163K specificity driven by immune priming and 223R specificity from egg-adapted changes in the vaccine contributed to low responses to circulating A(H1N1)pdm09 viruses after vaccination. Our study highlights the need to incorporate human serology in influenza surveillance and vaccine strain selection.

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Conflict of interest statement

Potential conflicts of interest. All authors: No reported conflicts. 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.
Hemagglutination inhibition (HI) antibody response patterns in prevaccination and postvaccination human serum samples. Pre- and postvaccination paired human serum samples from US adults (n = 281; born in 1961–1998; aged 18–49 years) who received inactivated influenza vaccine (IIV) were collected during 6 influenza seasons after the 2009 A(H1N1) pandemic and tested using HI assays. These individuals show 3 age-related HI antibody patterns, the USSR/77 (A), TW/86 (B), and NC/99 (C) priming patterns. Black bars represent prevaccination geometric mean titers (GMTs); colored bars, postvaccination GMTs for viruses from the USSR/77 group (light orange), the TW/86 group (blue), the group with HA 130-deletion (BJ/95, NC/99, SI/06, BR/07, green), and A(H1N1)pdm09 viruses (orange). Dashed lines denote an HI titer of 40. Pre- and postvaccination HI titers were compared for each of the testing viruses, with asterisks denoting significant increases (P < .01). Postvaccination HI titers were also compared between the A(H1N1)pdm09 viruses (†P < .05; ‡P < .01). CI, confidence interval.
Figure 2.
Figure 2.
Distribution of individuals with reduced hemagglutination inhibition (HI) antibody response to R223Q or K163Q viruses after inactivated influenza vaccine vaccination. A, Proportions of the individuals carrying 223R-, 163K-, or 163K+223R-specific HI antibody by priming patterns from each of the 6 seasons. Pie graphs are color coded for NC/99 (green), TW/86 (blue), and USSR/77 (light orange) priming patterns. The 223R-specific HI antibodies (yellow) are defined those with as ≥4-fold reduced titers to 6B.1 and 6B.2 cell-grown A(H1N1)pdm09 viruses versus egg-grown pairs, and 163K-specific HI antibodies (dark red) as ≥4-fold reduced titers to RG-K163Q versus RG-163K virus; 163K+223R-specific HI antibodies (pink) contain both of the 2 antibody populations. B, Distribution of the study individuals by birth year. Each square represents an individual with the priming pattern color coded as in A. Colored dots represent individuals showing HI antibody specific to hemagglutinin (HA) 223R, 163K, or 223R+163K epitope (color coding as in A). C, Proportions of those individuals with HI titers <40 to 6B.1 cell-propagated virus by the specificity to HA 223R, 163K, or 223R+163K epitopes.
Figure 3.
Figure 3.
Reduced postvaccination serum antibody response to R223Q or K163Q viruses were confirmed by both hemagglutination inhibition (HI) and microneutralization (MN) assays. A, B, The 29 USSR/77-primed individuals show significantly reduced HI titers to both RG-K163Q and RG-D127T viruses compared with RG-163K virus by HI (A) and MN (B). C, D, The 25 individuals showing significantly reduced HI titers to 223Q viruses (C) were also confirmed by MN assay (D). Black bars represent prevaccination (Pre) geometric mean titers (GMTs); orange bars, postvaccination (Post) GMTs. Dashed lines denotes titers of 40. *P < .05. CI, confidence interval.
Figure 4.
Figure 4.
Postvaccination serum hemagglutination inhibition (HI) antibody repertoire to A(H1N1)pdm09 viruses demonstrated by serum adsorption assay. A small subset of postvaccination sera of the 29 USSR/77-primed persons showing 163K specificity were adsorbed respectively with purified A(H1N1)pdm09 and pre-2009 sH1N1 viruses. The reduction of preadsorption HI titer to the homologous virus is evaluated in HI by testing the recovered serum after adsorption with heterologous viruses. Cross-reactive antibodies are determined as ≥4-fold reduced titer to the homologous virus after adsorption with heterologous viruses. A, Prevaccination (Pre) and postvaccination (Post) HI titers from 3 representative individuals (I-1 to I-3) to the X-179A, RG-163K, RG-K163Q, 6B.1, and prior-2009 sH1N1 viruses. BY, year of birth. B, HI titers in postadsorption serum samples to the testing virus below each panel of grouped bars for the 3 individuals respectively. Black bars (phosphate-buffered saline [PBS]; mock adsorption) stand for the preadsorption homologous titers to each of the testing viruses. The other color-coded bars represent HI titers to the testing virus after adsorption with different respective heterologous viruses as indicated in the figure. Dashed lines denote the 4-fold reduction in HI titers compared with PBS (mock). C, Proportions of HI antibody populations in postvaccination serum by the specificity to 163K, 223R, or other epitope(s) in the hemagglutinin (HA) of A(H1N1)pdm09 virus. 163K- or 223R-specific antibodies are defined as described in the legend to Figure 2. CR, HI antibodies cross-reactive with X-179A, 6B.1, and some of the prior-2009 sH1N1 viruses.
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