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Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.

Thakar J, Mohanty S, West AP, Joshi SR, Ueda I, Wilson J, Meng H, Blevins TP, Tsang S, Trentalange M, Siconolfi B, Park K, Gill TM, Belshe RB, Kaech SM, Shadel GS, Kleinstein SH, Shaw AC - Aging (Albany NY) (2015)

Bottom Line: To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty.The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders).These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

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Older subjects have lower baseline titers and a reduced vaccine responseThe influenza antibody response to all three vaccine strains in the seasonal vaccine was measured pre-vaccination and 28 days post-vaccination by HAI. (A) The percentage of young (white bars) and older (grey bars) subjects showing ≥4-fold increase in HAI assay on day 28 to the indicated number of strains. (B) Baseline titers for each of the three strains among young (white bars) and older (grey bars) subjects. Medians are indicated by the bold line, while the box boundaries indicate the 25th (lower line) and 75th (upper line) percentiles, with outliers indicated by (o). (C) and (D) Comparison of baseline (pre-vaccination) HAI titers with fold-change (day 28 vs. pre-vaccination). The size of the circles (small to large) depicts the number of subjects (1 to 7 for young and 4 to 11 for older). The set of vaccine responders and non-responders selected for microarray experiments are indicated by the plus and cross within the circle symbols, respectively. For simplicity, the response against the strain that induced the maximum fold-increase in HAI titer on day 28 in vaccine responders is plotted. For non-responders, the highest baseline titer among the three vaccine strains is depicted.
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Figure 1: Older subjects have lower baseline titers and a reduced vaccine responseThe influenza antibody response to all three vaccine strains in the seasonal vaccine was measured pre-vaccination and 28 days post-vaccination by HAI. (A) The percentage of young (white bars) and older (grey bars) subjects showing ≥4-fold increase in HAI assay on day 28 to the indicated number of strains. (B) Baseline titers for each of the three strains among young (white bars) and older (grey bars) subjects. Medians are indicated by the bold line, while the box boundaries indicate the 25th (lower line) and 75th (upper line) percentiles, with outliers indicated by (o). (C) and (D) Comparison of baseline (pre-vaccination) HAI titers with fold-change (day 28 vs. pre-vaccination). The size of the circles (small to large) depicts the number of subjects (1 to 7 for young and 4 to 11 for older). The set of vaccine responders and non-responders selected for microarray experiments are indicated by the plus and cross within the circle symbols, respectively. For simplicity, the response against the strain that induced the maximum fold-increase in HAI titer on day 28 in vaccine responders is plotted. For non-responders, the highest baseline titer among the three vaccine strains is depicted.

Mentions: We recruited 121 young (21-30 years old, n = 59) and older (≥ 70 years old, n = 62) subjects in two consecutive vaccination seasons (n = 49 in 2010-2011; n = 72 in 2011-12) prior to immunization with the seasonal trivalent inactivated influenza vaccine (TIV). Older subjects were further classified for the geriatric syndrome of frailty using the clinically validated, operational definition of Fried et al. [11]. To assess the response to vaccination, antibody titers to the three viral strains in the vaccine (A/California/7/09 (H1N1)-like virus; A/Perth /16/2009 (H3N2); and B/Brisbane/60/2008), which were the same for both seasons, were measured pre-vaccination and 28 days post-vaccination by hemagglutination inhibition (HAI). In both seasons, pre-vaccination anti-H1 titers in older subjects were significantly lower than in young subjects (2010-11: p=0.015, 2011-12: p=0.002), while titers against the H3 and B strains were similar in both age groups (Figure 1B). After vaccination, 41% of young subjects and 59% of older subjects failed to show a four-fold increase in post-vaccine HAI titer to any of the three strains in the vaccine (Figure 1A). Among these non-responders, 92% of young and 36% of older subjects had pre-existing antibody titers greater than 1:16 against at least one of the three vaccine strains (Figures 1C and 1D). Thus, while a similar frequency of young and older subjects failed to show increases in antibody titers following vaccination, most of the young subjects had elevated pre-vaccine antibody titers against the vaccine strains.


Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.

Thakar J, Mohanty S, West AP, Joshi SR, Ueda I, Wilson J, Meng H, Blevins TP, Tsang S, Trentalange M, Siconolfi B, Park K, Gill TM, Belshe RB, Kaech SM, Shadel GS, Kleinstein SH, Shaw AC - Aging (Albany NY) (2015)

Older subjects have lower baseline titers and a reduced vaccine responseThe influenza antibody response to all three vaccine strains in the seasonal vaccine was measured pre-vaccination and 28 days post-vaccination by HAI. (A) The percentage of young (white bars) and older (grey bars) subjects showing ≥4-fold increase in HAI assay on day 28 to the indicated number of strains. (B) Baseline titers for each of the three strains among young (white bars) and older (grey bars) subjects. Medians are indicated by the bold line, while the box boundaries indicate the 25th (lower line) and 75th (upper line) percentiles, with outliers indicated by (o). (C) and (D) Comparison of baseline (pre-vaccination) HAI titers with fold-change (day 28 vs. pre-vaccination). The size of the circles (small to large) depicts the number of subjects (1 to 7 for young and 4 to 11 for older). The set of vaccine responders and non-responders selected for microarray experiments are indicated by the plus and cross within the circle symbols, respectively. For simplicity, the response against the strain that induced the maximum fold-increase in HAI titer on day 28 in vaccine responders is plotted. For non-responders, the highest baseline titer among the three vaccine strains is depicted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356402&req=5

Figure 1: Older subjects have lower baseline titers and a reduced vaccine responseThe influenza antibody response to all three vaccine strains in the seasonal vaccine was measured pre-vaccination and 28 days post-vaccination by HAI. (A) The percentage of young (white bars) and older (grey bars) subjects showing ≥4-fold increase in HAI assay on day 28 to the indicated number of strains. (B) Baseline titers for each of the three strains among young (white bars) and older (grey bars) subjects. Medians are indicated by the bold line, while the box boundaries indicate the 25th (lower line) and 75th (upper line) percentiles, with outliers indicated by (o). (C) and (D) Comparison of baseline (pre-vaccination) HAI titers with fold-change (day 28 vs. pre-vaccination). The size of the circles (small to large) depicts the number of subjects (1 to 7 for young and 4 to 11 for older). The set of vaccine responders and non-responders selected for microarray experiments are indicated by the plus and cross within the circle symbols, respectively. For simplicity, the response against the strain that induced the maximum fold-increase in HAI titer on day 28 in vaccine responders is plotted. For non-responders, the highest baseline titer among the three vaccine strains is depicted.
Mentions: We recruited 121 young (21-30 years old, n = 59) and older (≥ 70 years old, n = 62) subjects in two consecutive vaccination seasons (n = 49 in 2010-2011; n = 72 in 2011-12) prior to immunization with the seasonal trivalent inactivated influenza vaccine (TIV). Older subjects were further classified for the geriatric syndrome of frailty using the clinically validated, operational definition of Fried et al. [11]. To assess the response to vaccination, antibody titers to the three viral strains in the vaccine (A/California/7/09 (H1N1)-like virus; A/Perth /16/2009 (H3N2); and B/Brisbane/60/2008), which were the same for both seasons, were measured pre-vaccination and 28 days post-vaccination by hemagglutination inhibition (HAI). In both seasons, pre-vaccination anti-H1 titers in older subjects were significantly lower than in young subjects (2010-11: p=0.015, 2011-12: p=0.002), while titers against the H3 and B strains were similar in both age groups (Figure 1B). After vaccination, 41% of young subjects and 59% of older subjects failed to show a four-fold increase in post-vaccine HAI titer to any of the three strains in the vaccine (Figure 1A). Among these non-responders, 92% of young and 36% of older subjects had pre-existing antibody titers greater than 1:16 against at least one of the three vaccine strains (Figures 1C and 1D). Thus, while a similar frequency of young and older subjects failed to show increases in antibody titers following vaccination, most of the young subjects had elevated pre-vaccine antibody titers against the vaccine strains.

Bottom Line: To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty.The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders).These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

Show MeSH
Related in: MedlinePlus