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Abstract Background Seasonal influenza causes significant morbidity and mortality with a disproportionately high disease burden in older adults. Strain-specific hemagglutination-inhibition (HAI) antibody titer is a well-established measure of humoral immunity against influenza and pre-vaccination HAI titer is a valuable indicator of pre-existing humoral immunity at the beginning of each influenza season in highly vaccinated older adults. While vaccine-induced HAI antibody titers are known to wane over time, accurate assessment of their interseason waning has been challenging. This is because pre-vaccination HAI titers are routinely measured using current season vaccine strain antigens instead of the prior season vaccines with which individuals were immunized; as such, they do not accurately represent residual antibody titers from prior season vaccination. This study took advantage of available pre-vaccination HAI titers measured using both current and prior season vaccine strain antigens in a longitudinal influenza immunization study with participants enrolled for multiple consecutive influenza seasons from 2014 through 2017. Influenza A virus (IAV) H3N2 and influenza B virus (IBV) strains in the vaccine formula changed in 2015 and again in 2016 season. IAV H1N1 vaccine strain remained the same from 2014 through 2016 seasons, but changed in 2017. We also investigated factors contributing to pre-existing humoral immunity. Results Interseason waning of HAI titers was evident, but rates of waning varied among vaccine strains and study seasons, from 18% (p = .43) to 61% (p

Abstract Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed “inflammaging”. After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop “Aging and Chronic Inflammation” to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.

Abstract Natural antibodies (nAbs) against aggregation-prone proteins have been found in healthy normal subjects. These proteins likely have a pathogenetic role in neurodegenerative diseases of ageing. They include the amyloid β (Aβ) protein which may play an important role in Alzheimer’s dementia (AD), and α-synuclein, a major determinant of Parkinson’s disease (PD). We measured nAbs to Aβ in a group of Italian patients with AD, vascular dementia, non-demented PD patients and healthy elderly controls. We found that Aβ antibody levels in AD were similar to age- and sex-matched controls, but contrary to our expectations, they were significantly reduced in PD. This may identify patients that could be more prone to amyloid aggregation.

Abstract Background Biological aging represents a loss of integrity and functionality of physiological systems over time. While associated with an enhanced risk of adverse outcomes such as hospitalization, disability and death following infection, its role in perceived age-related declines in vaccine responses has yet to be fully elucidated. Using data and biosamples from a 4-year clinical trial comparing immune responses of standard- and high-dose influenza vaccination, we quantified biological age (BA) prior to vaccination in adults over 65 years old (n = 292) using a panel of ten serological biomarkers (albumin, alanine aminotransferase, creatinine, ferritin, free thyroxine, cholesterol, high-density lipoprotein, triglycerides, tumour necrosis factor, interleukin-6) as implemented in the BioAge R package. Hemagglutination inhibition antibody titres against influenza A/H1N1, A/H3N2 and B were quantified prior to vaccination and 4-, 10- and 20- weeks post-vaccination. Results Counter to our hypothesis, advanced BA was associated with improved post-vaccination antibody titres against the different viral types and subtypes. However, this was dependent on both vaccine dose and CMV serostatus, as associations were only apparent for high-dose recipients (d = 0.16–0.26), and were largely diminished for CMV positive high-dose recipients. Conclusions These findings emphasize two important points: first, the loss of physiological integrity related to biological aging may not be a ubiquitous driver of immune decline in older adults; and second, latent factors such as CMV infection (prevalent in up to 90% of older adults worldwide) may contribute to the heterogeneity in vaccine responses of older adults more than previously thought.

Abstract Background With increasing age, overall health declines while systemic levels of inflammatory mediators tend to increase. Although the underlying mechanisms are poorly understood, there is a wealth of data suggesting that this so-called “inflammaging” contributes to the risk of adverse outcomes in older adults. We sought to determine whether markers of systemic inflammation were associated with antibody responses to the seasonal influenza vaccine. Results Over four seasons, hemagglutination inhibition antibody titres and ex vivo bulk peripheral blood mononuclear cell (PBMC) responses to live influenza viruses assessed via interferon (IFN)-γ/interleukin (IL)-10 production, were measured pre- and 4-weeks post-vaccination in young adults (n = 79) and older adults randomized to standard- or high-dose inactivated vaccine (n = 612). Circulating tumour necrosis factor (TNF), interleukin (IL)-6 and C-reactive protein (CRP) were also measured pre-vaccination. Post-vaccination antibody titres were significantly associated with systemic inflammatory levels; specifically, IL-6 was positively associated with A/H3N2 titres in young adults (Cohen’s d = 0.36), and in older high-dose, but not standard-dose recipients, all systemic inflammatory mediators were positively associated with A/H1N1, A/H3N2 and B titres (d = 0.10–0.45). We further show that the frequency of ILT2(+)CD57(+) CD56-Dim natural killer (NK)-cells was positively associated with both plasma IL-6 and post-vaccination A/H3N2 titres in a follow-up cohort of older high-dose recipients (n = 63). Pathway analysis suggested that ILT2(+)CD57(+) Dim NK-cells mediated 40% of the association between IL-6 and A/H3N2 titres, which may be related to underlying participant frailty. Conclusions In summary, our data suggest a complex relationship amongst influenza vaccine responses, systemic inflammation and NK-cell phenotype in older adults, which depends heavily on age, vaccine dose and possibly overall health status. While our results suggest that “inflammaging” may increase vaccine immunogenicity in older adults, it is yet to be determined whether this enhancement contributes to improved protection against influenza disease.

Abstract The rapidity of SARS-CoV-2 vaccination around the world has substantially reduced the number of new cases of COVID-19 and their severity in highly vaccinated countries. The unanticipated efficacy of SARS-CoV-2 vaccines in older adults has been very encouraging but the longevity of vaccine immunity is currently unknown and protection against emerging variants may be lower. Adoptive immunotherapy with neutralizing mAb may offer an alternative for poor vaccine responders, while the mechanisms underlying failure to respond are still unclear. Further studies of B and T cell responses and their regulation particularly in older populations will provide a more solid foundation to develop suitable approaches to optimize vaccine responses of older adults who fail to mount a durable response.

Abstract The rapidity with which vaccines against COVID-19 have been developed and tested is unprecedented. As classically the case with randomized clinical trials, many studies excluded older adults. However, given the early realisation that senior citizens were most highly susceptible to COVID, older individuals have been included in licensing trials under these unusual conditions. The recently published results from the Comirnaty Vaccine (BNT162b) trial unexpectedly documented that vaccine efficacy was equally exceptionally high in older and younger adults. These extremely encouraging trial results with a neoantigen vaccine may suggest the beginning of a paradigm shift in our view of the impact of immunosenescence on vaccination against novel infectious diseases.

Abstract Background Obesity is associated with chronic low-grade inflammation leading to metabolic and cardiovascular diseases, but a subset of obese individuals is considered insulin sensitive (IS). The underlying pathophysiologic mechanisms remain elusive and clinical studies on the relationship between inflammatory markers and metabolically healthy obesity (MHO) are scarce. Methods In this cross-sectional analysis, we included a sample of 437 older participants (60–84 years) from the Berlin Aging Study II (BASE-II). Peripheral blood mononuclear cells were isolated, immune cell subsets were analyzed with multiparameter flow cytometry and systemic cytokine levels were measured. Immune cell parameters were correlated with metabolic measures and multiple linear regression analysis was conducted and adjusted for various demographic and clinical factors. Results We found that frequencies of naïve and memory CD4+ and CD8+ T cells inversely correlated with measures for insulin sensitivity in the older population. Moreover, the percentages of naïve CD4+ and CD8+ T cells were significantly higher, whereas activated T cells and IL-6 levels were lower in IS compared to insulin resistant (IR) obese individuals. The percentages of naïve CD4+ and CD8+ T cells were predictive for impaired insulin sensitivity (ß = 0.16, p = 0.01 and ß = 0.11, p = 0.04), and the association of naïve CD4+ T cells with insulin sensitivity persisted after multivariate adjustment (ß = 0.14, p = 0.02). Conclusions These findings support the hypothesis that parameters of systemic inflammation can differentiate IS from IR obese individuals that are at higher risk for cardiometabolic diseases and may have clinical implications with regard to obesity treatment stratification. Trial registration DRKS00009277 . Registered 31 August 2015 - Retrospectively registered.

Abstract Despite widespread influenza vaccination programs, influenza remains a major cause of morbidity and mortality in older adults. Age-related changes in multiple aspects of the adaptive immune response to influenza have been well-documented including a decline in antibody responses to influenza vaccination and changes in the cell-mediated response associated with immune senescence. This review will focus on T cell responses to influenza and influenza vaccination in older adults, and how increasing frailty or coexistence of multiple (≥2) chronic conditions contributes to the loss of vaccine effectiveness for the prevention of hospitalization. Further, dysregulation of the production of pro- and anti-inflammatory mediators contributes to a decline in the generation of an effective CD8 T cell response needed to clear influenza virus from the lungs. Current influenza vaccines provide only a weak stimulus to this arm of the adaptive immune response and rely on re-stimulation of CD8 T cell memory related to prior exposure to influenza virus. Efforts to improve vaccine effectiveness in older adults will be fruitless until CD8 responses take center stage.

Abstract The emergence of SARS-CoV-2 and its inordinately rapid spread is posing severe challenges to the wellbeing of millions of people worldwide, health care systems and the global economy. While many younger people experience no or mild symptoms on infection, older adults are highly susceptible to life-threatening respiratory and systemic conditions which demand a full understanding and leveraging of knowledge of the differences between immunity in young and old people. Consequently, we welcome papers addressing any issues relevant to immunity and ageing in the context of SARS-CoV-2, and will endeavour to fast-track peer-review. We aim to provide a platform exclusively for discussions of individual and age differences in susceptibility and immune responses to COVID caused by SARS-CoV-2 infection and how to prevent or reduce severity of disease in older adults.

Abstract Background Cytokines are signaling molecules operating within complex cascade patterns and having exceptional modulatory functions. They impact various physiological processes such as neuroendocrine and metabolic interactions, neurotrophins’ metabolism, neuroplasticity, and may affect behavior and cognition. In our previous study, we found that sex and Cytomegalovirus (CMV)-serostatus may modulate levels of circulating pro- and anti-inflammatory cytokines, metabolic factors, immune cells, and cognitive performance, as well as associations between them. Results In the present study, we used a graph-theoretical approach to investigate the network topology dynamics of 22 circulating biomarkers and 11 measures of cognitive performance in 161 older participants recruited to undergo a six-months training intervention. For network construction, we applied coefficient of determination (R 2 ) that was calculated for all possible pairs of variables (N = 33) in four groups (CMV− men and women; CMV+ men and women). Network topology has been evaluated by clustering coefficient (CC) and characteristic path length (CPL) as well as local (E local ) and global (E global ) efficiency, showing the degree of network segregation (CC and E local ) and integration (CPL and E global ). We found that networks under consideration showed small-world networks properties with more random characteristics. Mean CC, as well as local and global efficiency were highest and CPL shortest in CMV− males (having lowest inflammatory status and highest cognitive performance). CMV− and CMV+ females did not show any significant differences. Modularity analyses showed that the networks exhibit in all cases highly differentiated modular organization (with Q-value ranged between 0.397 and 0.453). Conclusions In this work, we found that segregation and integration properties of the network were notably stronger in the group with balanced inflammatory status. We were also able to confirm our previous findings that CMV-infection and sex modulate multiple circulating biomarkers and cognitive performance and that balanced inflammatory and metabolic status in elderly contributes to better cognitive functioning. Thus, network analyses provide a useful strategy for visualization and quantitative description of multiple interactions between various circulating pro- and anti-inflammatory biomarkers, hormones, neurotrophic and metabolic factors, immune cells, and measures of cognitive performance and can be in general applied for analyzing interactions between different physiological systems.

Abstract Ageing has a profound detrimental impact on almost all living organisms. Immune systems play a particularly important role in protection against external challenges (pathogens) and internal insults (cancer) but their protective capacity commonly wanes with advancing age. With the rapid increase in the numbers of older people around the world, research in the field of immunity and ageing is becoming increasingly important. This realization, together with recent and ongoing technical advances in analytical capabilities, is facilitating rapid progress towards a better understanding of immunity and ageing and the resulting anticipated improved application of this knowledge to medical treatments in the years ahead.