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. 2023 Feb 1;227(3):381-390.
doi: 10.1093/infdis/jiac068.

The Negative Effect of Preexisting Immunity on Influenza Vaccine Responses Transcends the Impact of Vaccine Formulation Type and Vaccination History

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The Negative Effect of Preexisting Immunity on Influenza Vaccine Responses Transcends the Impact of Vaccine Formulation Type and Vaccination History

Savannah A Moritzky et al. J Infect Dis. .

Abstract

The most effective measure to induce protection from influenza is vaccination. Thus, yearly vaccination is recommended, which, together with infections, establishes diverse repertoires of B cells, antibodies, and T cells. We examined the impact of this accumulated immunity on human responses in adults to split, subunit, and recombinant protein-based influenza vaccines. Enzyme-linked immunosorbent assay (ELISA) assays, to quantify serum antibodies, and peptide-stimulated CD4 T-cell cytokine ELISpots revealed that preexisting levels of hemagglutinin (HA)-specific antibodies were negatively associated with gains in antibody postvaccination, while preexisting levels of CD4 T cells were negatively correlated with vaccine-induced expansion of CD4 T cells. These patterns were seen independently of the vaccine formulation administered and the subjects' influenza vaccine history. Thus, although memory CD4 T cells and serum antibodies consist of components that can enhance vaccine responses, on balance, the accumulated immunity specific for influenza A H1 and H3 proteins is associated with diminished future responses.

Keywords: CD4 T cells; human immunity; immune memory; influenza; vaccines.

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Figures

Figure 1.
Figure 1.
A, ELISAs were used to measure the IgG titers at day 0 and day 14 postvaccination using H1 (left) or H3 (right) proteins. Fold change was calculated as day 14/day 0 and plotted for each protein. B, IFN-γ production was measured using CD4-enriched PBMCs stimulated with overlapping pools of peptides from H1 (left) or H3 (right) HA in cytokine ELISpots at day 0 and day 14 postvaccination. Each point represents an individual subject and the red line is the median. P values were calculated by using a paired Wilcoxon test, where P < .05 was considered significant. H1 and H3 ELISpot assays contained samples from 223 and 182 subjects, respectfully. H1 and H3 ELISAs contained samples from 235 subjects. Abbreviations: D, day; ELISA, enzyme-linked immunosorbent assay; ELISpot, enzyme-linked immunospot; HA, hemagglutinin; IFN-γ, interferon-γ; IgG, immunoglobulin G; PBMC, peripheral blood mononuclear cell.
Figure 2.
Figure 2.
ELISAs were used to measure the IgG titers at day 0 and day 14 postvaccination using H1 (A) or H3 (B) HA proteins. Fold change was calculated as day 14/day 0. A and B, Left, the baseline (day 0) IgG responses were compared to the fold change (D14/D0) IgG response after vaccination. A and B, Right, the top (high) and bottom (low) quartile of day 0 IgG responses were selected, and the fold change response was compared. Mann-Whitney test was used to compare the 2 groups, and P values < .05 were considered significant. C and D, Upper row, the baseline (day 0) IgG responses were compared to the fold change (D14/D0) IgG response after vaccination with symbols colored according to the subjects’ previous season vaccination status: turquoise = unvaccinated and rust = vaccinated. The combined graph is shown on the left, with the 2 right graphs showing the separated vaccinated and unvaccinated subjects. C and D, Lower row, the baseline (day 0) IgG responses were compared to the fold change (D14/D0) IgG response after vaccination with symbols colored according to which vaccine subjects had received: blue = Fluzone, gold = Flucelvax, and red = Flublok. The graph on the left shows the combined plots, with the right graphs showing results separated by vaccine type. Spearman correlation was used, and P values < .05 were considered significant. H1 and H3 ELISAs contained samples from 235 subjects. Abbreviations: D, day; ELISA, enzyme-linked immunosorbent assay; HA, hemagglutinin; IgG, immunoglobulin G.
Figure 3.
Figure 3.
IFN-γ ELISpot assays were used to measure the CD4 T-cell response at day 0 and day 14 postvaccination using H1 (A) or H3 (B) overlapping peptide pools. Fold change was calculated as day 14/day 0. A and B, Left, the baseline (day 0) CD4 responses were compared to the fold change (D14/D0) CD4 response after vaccination. A and B, Right, the top (high) and bottom (low) quartile of day 0 CD4 responses were selected and the fold change response was compared. Mann-Whitney test was used to compare the 2 groups and P values < .05 were considered significant. C and D, Upper row, the baseline (day 0) CD4 responses were compared to the fold change (D14/D0) CD4 response after vaccination with symbols colored according to subjects’ previous season vaccination status: turquoise = unvaccinated and rust = vaccinated. The combined graph is shown on the left, with the 2 right graphs showing the separated vaccinated and unvaccinated subjects. C and D, Lower row, the baseline (day 0) CD4 responses were compared to the fold change (D14/D0) CD4 response after vaccination with symbols colored according to which vaccine subjects had received: blue = Fluzone, gold = Flucelvax, and red = Flublok. The graph on the left shows the combined plots, with the right graphs showing results separated by vaccine type. Spearman correlation was used, and P values < .05 were considered significant. H1 and H3 ELISpot assays contained samples from 223 and 182 subjects, respectfully. Abbreviations: D, day; ELISpot, enzyme-linked immunospot; IFN-γ, interferon-γ.
Figure 4.
Figure 4.
A, H1-specific antibodies were measured using ELISA at day 0 and compared to the H1 CD4 T-cell response measured as fold change (day 14/day 0). B, H3-specific antibodies measured using ELISA at day 0 were compared to the H3 CD4 T-cell response measured as fold change (D14/D0) using IFN-γ ELISpot. A and B, Right, the top (high) and bottom (low) quartile of day 0 CD4 responses were selected and the fold change response was compared. Spearman correlation was used (left graphs) and Mann-Whitney test was used to compare the high and low groups (right graphs). P values < .05 were considered significant. H1 contained samples from 222 subjects and H3 contained samples from 180 subjects. Abbreviations: D, day; ELISA, enzyme-linked immunosorbent assay; ELISpot, enzyme-linked immunospot; IFN-γ, interferon-γ.
Figure 5.
Figure 5.
Multivariable logistic regression analysis was performed to identify factors affecting (A) the antibody responses or (B) CD4 T-cell response after vaccination. A response to vaccination was defined as subjects who had a ≥ 3-fold change (day 14/day 0) response. Previous season vaccination status, year of birth, sex, and type of vaccination received were all included as variables, as well as the preexisting antibody and CD4 T cells. The adjusted odds ratios (OR) are shown with 95% confidence intervals shown by bars. A P value of < .05 was considered statistically significant.

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