Distinct patterns of B-cell activation and priming by natural influenza virus infection versus inactivated influenza vaccination

Xiao-Song He, Tyson H Holmes, Mrinmoy Sanyal, Randy A Albrecht, Adolfo García-Sastre, Cornelia L Dekker, Mark M Davis, Harry B Greenberg, Xiao-Song He, Tyson H Holmes, Mrinmoy Sanyal, Randy A Albrecht, Adolfo García-Sastre, Cornelia L Dekker, Mark M Davis, Harry B Greenberg

Abstract

Background: The human B-cell response to natural influenza virus infection has not been extensively investigated at the polyclonal level.

Methods: The overall B-cell response of patients acutely infected with the 2009 pandemic influenza A(H1N1)pdm09 virus (A[H1N1]pdm09) was analyzed by determining the reactivity of plasmablast-derived polyclonal antibodies (PPAbs) to influenza proteins. Recipients of inactivated influenza vaccine containing the same A(H1N1)pdm09 strain were studied for comparison.

Results: During acute infection, robust plasmablast responses to the infecting virus were detected, characterized by a greater PPAb reactivity to the conserved influenza virus nuclear protein and to heterovariant and heterosubtypic hemagglutinins, in comparison to responses to the inactivated A(H1N1)pdm09 vaccine. In A(H1N1)pdm09 vaccinees, the presence of baseline serum neutralizing antibodies against A(H1N1)pdm09, suggesting previous exposure to natural A(H1N1)pdm09 infection, did not affect the plasmablast response to vaccination, whereas repeated immunization with inactivated A(H1N1)pdm09 vaccine resulted in significantly reduced vaccine-specific and cross-reactive PPAb responses.

Conclusions: Natural A(H1N1)pdm09 infection and inactivated A(H1N1)pdm09 vaccination result in very distinct patterns of B-cell activation and priming. These differences are likely to be associated with differences in protective immunity, especially cross-protection against heterovariant and heterosubtypic influenza virus strains.

Keywords: B-cell response; antibody; influenza vaccine; influenza virus infection; plasmablast.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) binding activity of plasmablast-derived polyclonal antibodies (PPAbs). PPAbs from patients with acute influenza-like illness (ILI) were prepared from blood samples collected 2–8 days after disease onset. A pool of PPAbs from a subset (n = 23) of 2010/2011 inactivated influenza vaccine (IIV) recipients (IIV pool) was also tested. This PPAb pool was assembled by combining equal amounts of immunoglobulin G (IgG) from each PPAb sample prepared with blood samples collected 6–8 days after IIV receipt. A, IgG enzyme-linked immunosorbent assay (ELISA) titration curves of 4 serially diluted PPAb samples: representative ILI patients 4 (A[H1N1]pdm09), 11 (influenza B virus [fluB]), and 6 (coronavirus [CoV]) and the PPAb pool from IIV recipients (IIV pool). B, IgG and immunoglobulin A (IgA) binding activity, shown as area under curve (AUC) of ELISA titration curves of individual ILI PPAb samples and the IIV PPAb pool. Patient number, days between disease onset and blood collection, and infecting agent are shown below the relevant bars in the graph.
Figure 2.
Figure 2.
Immunoglobulin G (IgG) plasmablast-derived polyclonal antibody (PPAb) binding to individual influenza virus proteins. A, Six 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09)–infected patient PPAb samples with detectable binding to A(H1N1)pdm09 virus, PPAb sample from a patient infected with influenza B virus (fluB), and PPAb pool from inactivated influenza vaccine (IIV) recipients (IIV pool) were tested for IgG binding activity to the hemagglutinin (HA) protein of A(H1N1)pdm09 (pH1) and to the nucleoprotein (NP) and matrix 1 protein (M1) of influenza A(H1N1). B, IgG binding activity for NP and M1 were normalized to that for HA by calculating the area under the curve (AUC) ratios (ie, AUCNP/AUCHA and AUCM1/AUCHA) for each PPAb sample. Normalized data from infected patients and the IIV recipients are compared. The A(H1N1)pdm09-infected patient PPAbs with detectable binding to HA (n = 5) and PPAbs from a group of 15 randomly selected 2010/2011 IIV recipients were used for this analysis. The selection of this group was not based on any biological parameters. Horizontal bars indicate the geometric mean of the AUC ratio. The P values were determined by unpaired t tests and adjusted by sequential Bonferroni adjustment for multiple comparisons. The asterisk indicates a statistically significant difference after the adjustment.
Figure 3.
Figure 3.
Cross-reactive plasmablast-derived polyclonal antibody (PPAb) binding activity to influenza virus hemagglutinin (HA). A, The 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09)–infected patient PPAb samples with detectable binding to the homologous HA of A(H1N1)pdm09 (pH1; n = 5) and the inactivated influenza vaccine (IIV) PPAb pool were tested for immunoglobulin G (IgG) binding to the HA of the heterovariant H1N1 strain A/Brisbane/59/2007 (sH1), the heterosubtypic avian H5N1 strain A/Vietnam/1203/2004 (H5), and the HA2 domain of H5 (H5-HA2). B, IgG binding activity for sH1 and H5 were normalized to that for pH1. The A(H1N1)pdm09-infected patient PPAbs with detectable binding to pH1 (n = 5) and PPAbs from the 15 randomly selected individual IIV recipients were included for this analysis. Horizontal bars indicate geometric mean of the area under the curve (AUC) ratio. The P values were determined by unpaired t tests and adjusted by sequential Bonferroni adjustment for multiple comparisons. The asterisks indicate a statistically significant difference after the adjustment.
Figure 4.
Figure 4.
Priming effect of natural 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) infection versus inactivated influenza vaccine (IIV) immunization. Forty-three healthy individuals who did not receive a monovalent A(H1N1)pdm09 vaccine in 2009 and were immunized with an A(H1N1)pdm09-containing IIV for the first time were included for this analysis. A, Plasmablast-derived polyclonal antibodies (PPAbs) were collected after the first immunization with the A(H1N1)pdm09-containing IIV in 2010 or 2011. The PPAb reactivities were analyzed by enzyme-linked immunosorbent assay (ELISA) for binding to the hemagglutinin (HA) protein of homologous A(H1N1)pdm09 (pH1), heterovariant A/Brisbane/59/2007(H1N1) (sH1), and heterosubtypic A/Vietnam/1203/2004(H5N1) (H5). The baseline seronegative (A[H1N1]pdm09 neutralizing titer <10, n = 17) and baseline seropositive (A[H1N1]pdm09 neutralizing titer >10, n = 26) vaccinees were compared. B, A subset (n = 18) of the 2010/2011 IIV vaccinees were immunized with the A[H1N1]pdm09-containing IIV in 2012. The PPAbs collected after each immunization were analyzed by ELISA for binding to the HAs pH1, sH1, and H5. C, Comparison of the priming effect of natural A[H1N1]pdm09 infection versus that of IIV immunization. The priming effect of A(H1N1)pdm09 infection was defined as the ratio of the mean area under the curve (AUC) for baseline seropositive individuals to the mean AUC for baseline seronegative individuals. The priming effect of IIV was defined as the ratio of the mean AUC of the second immunization to the mean AUC of the first immunization. Horizontal bars in panels A and B indicate geometric mean AUCs. Hypotheses were tested with unpaired (A) or paired (B) t tests. Because the 2 data sets (in panels A and B) had some subjects in common, analysis used perturbation resampling [18], which is essentially a smoothed bootstrap. The P values were adjusted by sequential Bonferroni adjustment for multiple comparisons across all 9 tests in the figure. The asterisk indicates a statistically significant difference after the adjustment.

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