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Seasonal influenza contributes to a substantial disease burden, resulting in approximately 10 million hospital visits and 50 thousand deaths in a typical year in the United States. 70 - 85% of the mortality occurs in people over the age of 65. Influenza vaccination is the best protection against the virus, but it is less effective for the elderly, which may be in part due to differences in the quantity or type of B cells induced by vaccination. To investigate this possibility, we sorted pre- and post-vaccination peripheral blood B cells from three young and three older adults with strong antibody responses to the inactivated influenza vaccine and employed single-cell technology to simultaneously profile the gene expression and the B cell receptor (BCR) of the B cells. Prior to vaccination, we observed a higher somatic hypermutation frequency and a higher abundance of activated B cells in older adults than in young adults. Following vaccination, young adults mounted a more clonal response than older adults. The expanded clones included a mix of plasmablasts, activated B cells, and resting memory B cells in both age groups, with a decreased proportion of plasmablasts in older adults. Differential abundance analysis identified additional vaccine-responsive cells that were not part of expanded clones, especially in older adults. We observed broadly consistent gene expression changes in vaccine-responsive plasmablasts and greater heterogeneity among activated B cells between age groups. These quantitative and qualitative differences in the B cells provide insights into age-related changes in influenza vaccination response.

Seasonal influenza causes mild to severe respiratory infections and significant morbidity, especially in older adults. Transcriptomic analysis in populations across multiple flu seasons has provided insights into the molecular determinants of vaccine response. Still, the metabolic changes that underlie the immune response to influenza vaccination remain poorly characterized. We performed untargeted metabolomics to analyze plasma metabolites in a cohort of younger and older subjects before and after influenza vaccination to identify vaccine-induced molecular signatures. Metabolomic and transcriptomic data were combined to define networks of gene and metabolic signatures indicative of high and low antibody response in these individuals. We observed age-related differences in metabolic baselines and signatures of antibody response to influenza vaccination and the abundance of α-linolenic and linoleic acids, sterol esters, fatty-acylcarnitines, and triacylglycerol metabolism. We identified a metabolomic signature associated with age-dependent vaccine response, finding increased tryptophan and decreased polyunsaturated fatty acids (PUFAs) in young high responders (HRs), while fatty acid synthesis and cholesteryl esters accumulated in older HRs. Integrated metabolomic and transcriptomic analysis shows that depletion of PUFAs, which are building blocks for prostaglandins and other lipid immunomodulators, in young HR subjects at Day 28 is related to a robust immune response to influenza vaccination. Increased glycerophospholipid levels were associated with an inflammatory response in older HRs to flu vaccination. This multi-omics approach uncovered age-related molecular markers associated with influenza vaccine response and provides insight into vaccine-induced metabolic responses that may help guide development of more effective influenza vaccines., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The seasonal influenza vaccine is an important public health tool but is only effective in a subset of individuals. The identification of molecular signatures provides a mechanism to understand the drivers of vaccine-induced immunity. Most previously reported molecular signatures of human influenza vaccination were derived from a single age group or season, ignoring the effects of immunosenescence or vaccine composition. Thus, it remains unclear how immune signatures of vaccine response change with age across multiple seasons. In this study we profile the transcriptional landscape of young and older adults over five consecutive vaccination seasons to identify shared signatures of vaccine response as well as marked seasonal differences. Along with substantial variability in vaccine-induced signatures across seasons, we uncovered a common transcriptional signature 28 days postvaccination in both young and older adults. However, gene expression patterns associated with vaccine-induced Ab responses were distinct in young and older adults; for example, increased expression of killer cell lectin-like receptor B1 ( KLRB1 ; CD161 ) 28 days postvaccination positively and negatively predicted vaccine-induced Ab responses in young and older adults, respectively. These findings contribute new insights for developing more effective influenza vaccines, particularly in older adults., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Here, we investigated the relationship of the age-associated expansion of IL-7 receptor alpha low (IL-7Rα low ) effector memory (EM) CD8 + T cells with the global transcriptomic profile of peripheral blood cells in humans. We found 231 aging signature genes of IL-7Rα low EM CD8 + T cells that corresponded to 15% of the age-associated genes (231/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals, having high correlation with chronological age. These aging signature genes were the target genes of several transcription factors including MYC, SATB1, and BATF, which also belonged to the 231 genes, supporting the upstream regulatory role of these transcription factors in altering the gene expression profile of peripheral blood cells with aging. We validated the differential expression of these transcription factors between IL-7Rα low and high EM CD8 + T cells as well as in peripheral blood mononuclear cells (PBMCs) of young and older adults. Finally, we found a significant association with influenza vaccine responses in older adults, suggesting the possible biological significance of the aging signature genes of IL-7Rα low EM CD8 + T cells. The results of our study support the relationship of the expansion of IL-7Rα low EM CD8 + T cells with the age-associated changes in the gene expression profile of peripheral blood cells and its possible biological implications., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

We evaluated in vivo innate immune responses in monocyte populations from 67 young (aged 21-30 years) and older (aged ≥65 years) adults before and after influenza vaccination. CD14(+)CD16(+) inflammatory monocytes were induced after vaccination in both young and older adults. In classical CD14(+)CD16(-) and inflammatory monocytes, production of tumor necrosis factor α and interleukin 6, as measured by intracellular staining, was strongly induced after vaccination. Cytokine production was strongly associated with influenza vaccine antibody response; the highest levels were found as late as day 28 after vaccination in young subjects and were substantially diminished in older subjects. Notably, levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were markedly elevated in monocytes from older subjects before and after vaccination. In purified monocytes, we found age-associated elevation in phosphorylated signal transducer and activator of transcription-3, and decreased serine 359 phosphorylation of the negative IL-10 regulator dual-specificity phosphatase 1. These findings for the first time implicate dysregulated IL-10 production in impaired vaccine responses in older adults., (© 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.)

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.

Alterations in T cell immunity occur with aging. Influenza causes significant morbidity and mortality in the elderly. We investigated the relationship of serum IgG responses with hemagglutinin inhibition (HI) antibody titers and the frequency of distinct T cell subsets in young and elderly people who received the inactivated influenza vaccine. Influenza vaccine-specific IgG responses correlated with the increase of HI antibody titers and the frequency of CD4(+) T cells producing IFN-γ and IL-17 in young, but not elderly, people. Also, only in young people, such IgG responses correlated with the frequency of memory T cells, especially central memory cells, CD45RA(-) effector memory CD8(+) T cells and IL-7 receptor alpha high effector memory CD8(+) T cells with potent survival and proliferative capacity. These findings suggest that aging alters the association of influenza-vaccine specific IgG responses with HI antibody titers, cytokine-producing capacity and proportions of memory T cells in humans., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21-30 y) and older (> or =65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-alpha, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-alpha and IFN-alpha production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.

Seasonal and pandemic strains of influenza have widespread implications for the global economy and global health. This has been highlighted recently as the epidemiologic characteristics for hospitalization and mortality for pandemic influenza H1N1 2009 are now emerging. While treatment with neuraminidase inhibitors are effective for seasonal and pandemic influenza, prevention of morbidity and mortality through effective vaccines requires a rigorous process of research and development. Vulnerable populations such as older adults (i.e., > age 65 years) suffer the greatest impact from seasonal influenza yet do not have a consistent seroprotective response to seasonal influenza vaccines due to a combination of factors. This short narrative review will highlight the emerging epidemiologic characteristics of pandemic H1N1 2009 and focus on immunosenescence, innate immune system responses to influenza virus infection and vaccination, and influenza vaccine responsiveness as it relates to seasonal and H1N1 pandemic influenza vaccines.

Background: Innate immunity, including Toll-like receptor (TLR)-mediated expression of the B7 costimulatory molecules CD80 and CD86, is critical for vaccine immunity. We examined whether CD80 and CD86 expression vary with aging and predict response to the trivalent inactivated influenza vaccine., Methods: One hundred sixty-two subjects between 21 and 30 years of age (the young group) or > or =65 years of age (the older group) enrolled before vaccination. We determined TLR-induced monocyte CD80/CD86 expression by flow cytometry and vaccine antibody responses by hemagglutination inhibition., Results: The mean increase in TLR-induced CD80(+) monocytes was reduced in older, compared with young, adults by 68% (P=.0002), and each decile increase of CD80(+) cells was associated with an 8.5% increase in mean number of vaccine strains with a > or =4-fold titer increase (P=.01) and a 3.8% increase in mean number of strains with a postvaccine titer > or =1 : 64 (P=.037). Each decile decrease of CD86(+) cells was associated with an 11% increase in the mean number of strains with a 4-fold increase (P=.002) and a 3.9% increase in the mean number of strains with a postvaccine titer > or =1 : 64 (P=.07)., Conclusions: CD80 and CD86 expression on activated monocytes is highly associated with influenza vaccine response. This approach prospectively identifies adults unlikely to respond to immunization who may benefit from alternative vaccines or antiviral prophylaxis during influenza outbreaks.