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The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects.

Haralambieva IH, Painter SD, Kennedy RB, Ovsyannikova IG, Lambert ND, Goergen KM, Oberg AL, Poland GA - PLoS ONE (2015)

Bottom Line: TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025).In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination.Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.

View Article: PubMed Central - PubMed

Affiliation: Mayo Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America; Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT

Background: Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly.

Methods: We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles - TREC content, peripheral white blood cell telomerase - TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination.

Results: TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively).

Conclusion: Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.

No MeSH data available.


Related in: MedlinePlus

Correlations between markers of immunosenescence (and/or immune outcomes) and influenza A/H1N1 vaccine-induced immune responses.A. The panel illustrates the positive correlation between early change in TERT expression at Day 3 relative to baseline on x-axis and influenza-specific B cell ELISPOT response change on y-axis (Day 28 compared to baseline). B and C. The panels illustrate the positive correlation between TREC levels on x-axis and influenza-specific B cell ELISPOT response on y-axis (Day 0 or Day 3). D, E and F. The panels illustrate the positive correlation between CD28 expression (MFI) on CD4+ T cells on x-axis (or change in expression at Day 3 relative to baseline, panel F) and influenza-specific B cell ELISPOT response on y-axis (Day 75 or increase at Day 28 compared to baseline for panel F). G and H. The panels illustrate the positive correlation between CD28 expression (MFI) on CD8+ T cells on x-axis (Day 0 or Day 3) and influenza-specific B cell ELISPOT response at Day 75 on y-axis. I. The panel illustrates the positive correlation between early change in influenza-specific B cell ELISPOT response (Day 3 relative to baseline, on x-axis) and influenza-specific HAI titer increase (Day 28 compared to baseline, on y-axis). The values on the x-axis for panels A, B, C, and F, y-axis for panels D, E, G, and H, and both x- and y-axes for panel I are displayed on the cube root scale for ease of visualization, but labeled on the raw scale. Influenza A/H1N1-specific memory-like IgG B cell ELISPOT response is presented as median SFUs per 2 x 105 cells; TERT expression is presented as TERT relative abundance value (relative expression in mRNA) divided by the GAPDH abundance value (ratio); TREC levels are presented as TREC versus CCR5 copies (ratio) in genomic DNA; HAI represents the influenza A/H1N1-specific hemagglutination inhibition titer as the reciprocal of the highest serum dilution that completely inhibits hemagglutination. The expression of CD28 on CD4+ and/or CD8+ T cells is measured by the mean fluorescence intensity/MFI using flow cytometry. “rs” indicates Spearman’s correlation coefficient.
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pone.0122282.g002: Correlations between markers of immunosenescence (and/or immune outcomes) and influenza A/H1N1 vaccine-induced immune responses.A. The panel illustrates the positive correlation between early change in TERT expression at Day 3 relative to baseline on x-axis and influenza-specific B cell ELISPOT response change on y-axis (Day 28 compared to baseline). B and C. The panels illustrate the positive correlation between TREC levels on x-axis and influenza-specific B cell ELISPOT response on y-axis (Day 0 or Day 3). D, E and F. The panels illustrate the positive correlation between CD28 expression (MFI) on CD4+ T cells on x-axis (or change in expression at Day 3 relative to baseline, panel F) and influenza-specific B cell ELISPOT response on y-axis (Day 75 or increase at Day 28 compared to baseline for panel F). G and H. The panels illustrate the positive correlation between CD28 expression (MFI) on CD8+ T cells on x-axis (Day 0 or Day 3) and influenza-specific B cell ELISPOT response at Day 75 on y-axis. I. The panel illustrates the positive correlation between early change in influenza-specific B cell ELISPOT response (Day 3 relative to baseline, on x-axis) and influenza-specific HAI titer increase (Day 28 compared to baseline, on y-axis). The values on the x-axis for panels A, B, C, and F, y-axis for panels D, E, G, and H, and both x- and y-axes for panel I are displayed on the cube root scale for ease of visualization, but labeled on the raw scale. Influenza A/H1N1-specific memory-like IgG B cell ELISPOT response is presented as median SFUs per 2 x 105 cells; TERT expression is presented as TERT relative abundance value (relative expression in mRNA) divided by the GAPDH abundance value (ratio); TREC levels are presented as TREC versus CCR5 copies (ratio) in genomic DNA; HAI represents the influenza A/H1N1-specific hemagglutination inhibition titer as the reciprocal of the highest serum dilution that completely inhibits hemagglutination. The expression of CD28 on CD4+ and/or CD8+ T cells is measured by the mean fluorescence intensity/MFI using flow cytometry. “rs” indicates Spearman’s correlation coefficient.

Mentions: We assessed the correlations between influenza vaccine-specific humoral immunity measures and other overall humoral immune response variables measured over time, and age/immunosenescent markers (TREC, TERT, CD28 expression on CD4+ and CD8+ T cells) (Table 1, Fig. 2). The HAI and neutralization titers at Day 28 following influenza vaccination were inversely correlated with age (r = -0.2, p-value = 0.04 and r = -0.19, p-value = 0.05, for HAI and VNA, respectively, Table 1). The activity of the peripheral white blood cell (WBC) telomerase TERT (as assessed by the expression of TERT mRNA at different timepoints relative to vaccination), a measure linked to telomere length maintenance and inversely linked to replicative senescence, was positively associated with HAI and neutralization antibody levels measured at Day 3 post-vaccination. The early change in the TERT expression (Day 3 compared to baseline) was positively correlated with the observed increase in the influenza-specific B cell ELISPOT response at Day 28 post-vaccination compared to baseline (r = 0.225, p-value = 0.025, Table 1). In addition, TERT levels were positively correlated with the overall frequencies of several B cell and plasma cell populations at different timepoints post-vaccination (e.g., CD20-/CD27high plasma cells/% of B cells at Day 0 and Day 3; CD20+/CD27+ B cells/% of B cells at Day 28, Table 1). The TREC levels (by-products of the DNA rearrangements during the process of TCR recombination, and an estimate of thymic function and immunosenescence) were positively correlated with the baseline (Day 0) and early (Day 3) influenza A/H1N1-specific B cell ELISPOT response (p-value = 0.04 and p-value = 0.035, respectively, Table 1). In addition, we observed a negative correlation between TREC levels and the overall IgD-CD27- B cell frequencies (% of B cells), as well as the overall IgD-CD27-memory B cell frequencies (% of B cells) at Day 28 following vaccination (p-value = 0.025 and p = 0.008, respectively, Table 1). The expression of CD28 on CD4+ and CD8+ T cells (as measured by the mean fluorescence intensity/MFI using flow cytometry) at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific B cell ELISPOT response at baseline and Day 75 (p≤0.05, Table 1). In addition, the early change/increase of CD4+ T cell CD28 expression at Day 3 (relative to baseline) was significantly correlated with the observed increase in the influenza-specific B cell ELISPOT response at Day 28 post-vaccination compared to baseline (r = 0.216, p-value = 0.031, Table 1). Consistent with these findings, our univariable analysis demonstrated an inverse correlation (r = -0.186) between the frequencies of CD8+ T cells with low and/or negative CD28 expression (as % of CD8+ T cells) and influenza A/H1N1-specific B cell ELISPOT response at Day 75 that did not quite reach statistical significance (p = 0.06, data not shown).


The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects.

Haralambieva IH, Painter SD, Kennedy RB, Ovsyannikova IG, Lambert ND, Goergen KM, Oberg AL, Poland GA - PLoS ONE (2015)

Correlations between markers of immunosenescence (and/or immune outcomes) and influenza A/H1N1 vaccine-induced immune responses.A. The panel illustrates the positive correlation between early change in TERT expression at Day 3 relative to baseline on x-axis and influenza-specific B cell ELISPOT response change on y-axis (Day 28 compared to baseline). B and C. The panels illustrate the positive correlation between TREC levels on x-axis and influenza-specific B cell ELISPOT response on y-axis (Day 0 or Day 3). D, E and F. The panels illustrate the positive correlation between CD28 expression (MFI) on CD4+ T cells on x-axis (or change in expression at Day 3 relative to baseline, panel F) and influenza-specific B cell ELISPOT response on y-axis (Day 75 or increase at Day 28 compared to baseline for panel F). G and H. The panels illustrate the positive correlation between CD28 expression (MFI) on CD8+ T cells on x-axis (Day 0 or Day 3) and influenza-specific B cell ELISPOT response at Day 75 on y-axis. I. The panel illustrates the positive correlation between early change in influenza-specific B cell ELISPOT response (Day 3 relative to baseline, on x-axis) and influenza-specific HAI titer increase (Day 28 compared to baseline, on y-axis). The values on the x-axis for panels A, B, C, and F, y-axis for panels D, E, G, and H, and both x- and y-axes for panel I are displayed on the cube root scale for ease of visualization, but labeled on the raw scale. Influenza A/H1N1-specific memory-like IgG B cell ELISPOT response is presented as median SFUs per 2 x 105 cells; TERT expression is presented as TERT relative abundance value (relative expression in mRNA) divided by the GAPDH abundance value (ratio); TREC levels are presented as TREC versus CCR5 copies (ratio) in genomic DNA; HAI represents the influenza A/H1N1-specific hemagglutination inhibition titer as the reciprocal of the highest serum dilution that completely inhibits hemagglutination. The expression of CD28 on CD4+ and/or CD8+ T cells is measured by the mean fluorescence intensity/MFI using flow cytometry. “rs” indicates Spearman’s correlation coefficient.
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pone.0122282.g002: Correlations between markers of immunosenescence (and/or immune outcomes) and influenza A/H1N1 vaccine-induced immune responses.A. The panel illustrates the positive correlation between early change in TERT expression at Day 3 relative to baseline on x-axis and influenza-specific B cell ELISPOT response change on y-axis (Day 28 compared to baseline). B and C. The panels illustrate the positive correlation between TREC levels on x-axis and influenza-specific B cell ELISPOT response on y-axis (Day 0 or Day 3). D, E and F. The panels illustrate the positive correlation between CD28 expression (MFI) on CD4+ T cells on x-axis (or change in expression at Day 3 relative to baseline, panel F) and influenza-specific B cell ELISPOT response on y-axis (Day 75 or increase at Day 28 compared to baseline for panel F). G and H. The panels illustrate the positive correlation between CD28 expression (MFI) on CD8+ T cells on x-axis (Day 0 or Day 3) and influenza-specific B cell ELISPOT response at Day 75 on y-axis. I. The panel illustrates the positive correlation between early change in influenza-specific B cell ELISPOT response (Day 3 relative to baseline, on x-axis) and influenza-specific HAI titer increase (Day 28 compared to baseline, on y-axis). The values on the x-axis for panels A, B, C, and F, y-axis for panels D, E, G, and H, and both x- and y-axes for panel I are displayed on the cube root scale for ease of visualization, but labeled on the raw scale. Influenza A/H1N1-specific memory-like IgG B cell ELISPOT response is presented as median SFUs per 2 x 105 cells; TERT expression is presented as TERT relative abundance value (relative expression in mRNA) divided by the GAPDH abundance value (ratio); TREC levels are presented as TREC versus CCR5 copies (ratio) in genomic DNA; HAI represents the influenza A/H1N1-specific hemagglutination inhibition titer as the reciprocal of the highest serum dilution that completely inhibits hemagglutination. The expression of CD28 on CD4+ and/or CD8+ T cells is measured by the mean fluorescence intensity/MFI using flow cytometry. “rs” indicates Spearman’s correlation coefficient.
Mentions: We assessed the correlations between influenza vaccine-specific humoral immunity measures and other overall humoral immune response variables measured over time, and age/immunosenescent markers (TREC, TERT, CD28 expression on CD4+ and CD8+ T cells) (Table 1, Fig. 2). The HAI and neutralization titers at Day 28 following influenza vaccination were inversely correlated with age (r = -0.2, p-value = 0.04 and r = -0.19, p-value = 0.05, for HAI and VNA, respectively, Table 1). The activity of the peripheral white blood cell (WBC) telomerase TERT (as assessed by the expression of TERT mRNA at different timepoints relative to vaccination), a measure linked to telomere length maintenance and inversely linked to replicative senescence, was positively associated with HAI and neutralization antibody levels measured at Day 3 post-vaccination. The early change in the TERT expression (Day 3 compared to baseline) was positively correlated with the observed increase in the influenza-specific B cell ELISPOT response at Day 28 post-vaccination compared to baseline (r = 0.225, p-value = 0.025, Table 1). In addition, TERT levels were positively correlated with the overall frequencies of several B cell and plasma cell populations at different timepoints post-vaccination (e.g., CD20-/CD27high plasma cells/% of B cells at Day 0 and Day 3; CD20+/CD27+ B cells/% of B cells at Day 28, Table 1). The TREC levels (by-products of the DNA rearrangements during the process of TCR recombination, and an estimate of thymic function and immunosenescence) were positively correlated with the baseline (Day 0) and early (Day 3) influenza A/H1N1-specific B cell ELISPOT response (p-value = 0.04 and p-value = 0.035, respectively, Table 1). In addition, we observed a negative correlation between TREC levels and the overall IgD-CD27- B cell frequencies (% of B cells), as well as the overall IgD-CD27-memory B cell frequencies (% of B cells) at Day 28 following vaccination (p-value = 0.025 and p = 0.008, respectively, Table 1). The expression of CD28 on CD4+ and CD8+ T cells (as measured by the mean fluorescence intensity/MFI using flow cytometry) at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific B cell ELISPOT response at baseline and Day 75 (p≤0.05, Table 1). In addition, the early change/increase of CD4+ T cell CD28 expression at Day 3 (relative to baseline) was significantly correlated with the observed increase in the influenza-specific B cell ELISPOT response at Day 28 post-vaccination compared to baseline (r = 0.216, p-value = 0.031, Table 1). Consistent with these findings, our univariable analysis demonstrated an inverse correlation (r = -0.186) between the frequencies of CD8+ T cells with low and/or negative CD28 expression (as % of CD8+ T cells) and influenza A/H1N1-specific B cell ELISPOT response at Day 75 that did not quite reach statistical significance (p = 0.06, data not shown).

Bottom Line: TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025).In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination.Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.

View Article: PubMed Central - PubMed

Affiliation: Mayo Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America; Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT

Background: Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly.

Methods: We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles - TREC content, peripheral white blood cell telomerase - TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination.

Results: TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively).

Conclusion: Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.

No MeSH data available.


Related in: MedlinePlus