Age-related Changes in the Natural Killer Cell Response to Seasonal Influenza Vaccination are not Influenced by a Synbiotic; a Randomised Controlled Trial

Natural killer (NK) cells are an important component of the immune response to influenza infection, but are subject to alteration during ageing, which may play a role in impaired response to infection and vaccination in older people. Enhancement of NK cell activity could, therefore, present a means to improve the immune response to vaccination in older subjects, and pre- and probiotics offer an opportunity to modulate anti-viral defences via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide (B. longum + Gl-OS), on the NK cell response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial. There were significant effects of ageing on NK cell phenotype, the most notable of which were an increase in CD56dim cells, mainly reflected in the CD16+ subset, a decrease in CD56bright cells, mainly reflected in the CD16- subset, and greater expression of the immunosenescence marker, CD57, on NK cell subsets. However, these changes only partially translated to differences in NK cell activity, observed as trends towards reduced NK cell activity in older subjects when analysed on a per cell basis. Influenza vaccination increased the proportion of CD56bright cells and decreased the proportion of CD56dim cells, in young, but not older subjects. Although NK cell activity in response to vaccination was not significantly different between the young and older subjects, low post-vaccination NK cell activity was associated with poor seroconversion in only the older subjects. There was no influence of the synbiotic on NK cell phenotype or activity, either before or after influenza vaccination. In conclusion, ageing is associated with marked alteration of the phenotype of the NK cell population and there was evidence of an impaired NK cell response to influenza vaccination in older subjects. The effects of ageing on NK cell phenotype and activity could not be offset by B. longum + Gl-OS. Clinical trial identifier: clinicaltrials.gov NCT01066377

Impact of ageing and a synbiotic on the immune response to seasonal influenza vaccination; a randomised controlled trial

Background & Aims Ageing increases risk of respiratory infections and impairs the response to influenza vaccination. Pre- and probiotics offer an opportunity to modulate anti-viral defenses and the response to vaccination via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide, on the B and T cell response to seasonal influenza vaccination in young and older subjects. Methods In a double-blind, randomized controlled trial, 58 young (18-35y) and 54 older (60-85y) subjects were supplemented with the synbiotic for 8 weeks. At 4 weeks they were administered with a seasonal influenza vaccine. B and T cell phenotype and responsiveness to in vitro re-stimulation with the vaccine were assessed at baseline, 4, 6 and 8 weeks. Results B and T cell profiles differed markedly between young and older subjects. Vaccination increased numbers of memory, IgA+ memory, IgG+ memory and total IgG+ B cells in young subjects, but failed to do so in older subjects and did not significantly alter T cell subsets. Seroconversion to the H1N1 subunit in the older subjects was associated with higher post-vaccination numbers of plasma B cells, but seroconversion was less consistently associated with T cell phenotype. B and T cell subsets from both young and older subjects demonstrated a strong antigen-specific recall challenge, and although not influenced by age, responsiveness to the recall challenge was associated with seroconversion. In older subjects, CMV seropositivity was associated with a significantly lower recall response to the vaccine, but the synbiotic did not affect the responsiveness of B or T cells to re-stimulation with influenza vaccine. Conclusions Antigen-specific B and T cell activation following an in vitro recall challenge with the influenza vaccine was influenced by CMV seropositivity, but not by a synbiotic

Impact of ageing and a synbiotic on the immune response to seasonal influenza vaccination; a randomised controlled trial

Background & Aims: Ageing increases risk of respiratory infections and impairs the response to influenza vaccination. Pre- and probiotics offer an opportunity to modulate anti-viral defenses and the response to vaccination via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide, on the B and T cell response to seasonal influenza vaccination in young and older subjects.Methods: In a double-blind, randomized controlled trial, 58 young (18-35y) and 54 older (60-85y) subjects were supplemented with the synbiotic for 8 weeks. At 4 weeks they were administered with a seasonal influenza vaccine. B and T cell phenotype and responsiveness to in vitro re-stimulation with the vaccine were assessed at baseline, 4, 6 and 8 weeks.Results: B and T cell profiles differed markedly between young and older subjects. Vaccination increased numbers of memory, IgA+ memory, IgG+ memory and total IgG+ B cells in young subjects, but failed to do so in older subjects and did not significantly alter T cell subsets. Seroconversion to the H1N1 subunit in the older subjects was associated with higher post38 vaccination numbers of plasma B cells, but seroconversion was less consistently associated with T cell phenotype. B and T cell subsets from both young and older subjects demonstrated a strong antigen-specific recall challenge, and although not influenced by age, responsiveness to the recall challenge was associated with seroconversion. In older subjects, CMV seropositivity was associated with a significantly lower recall response to the vaccine, but the synbiotic did not affect the responsiveness of B or T cells to re-stimulation with influenza vaccine.Conclusions: Antigen-specific B and T cell activation following an in vitro recall challenge with the influenza vaccine was influenced by CMV seropositivity, but not by a synbiotic.Registered under ClinicalTrials.gov Identifier no. NCT01066377

presentation_1.PDF

<p>Natural killer (NK) cells are an important component of the immune response to influenza infection, but are subject to alteration during aging, which may play a role in impaired response to infection and vaccination in older people. Enhancement of NK cell activity could, therefore, present a means to improve the immune response to vaccination in older subjects, and pre- and probiotics offer an opportunity to modulate antiviral defenses via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide (B. longum + Gl-OS), on the NK cell response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial. There were significant effects of aging on NK cell phenotype, the most notable of which were an increase in CD56^dim cells, mainly reflected in the CD16⁺ subset, a decrease in CD56^bright cells, mainly reflected in the CD16⁻ subset, and greater expression of the immunosenescence marker, CD57, on NK cell subsets. However, these changes only partially translated to differences in NK cell activity, observed as trends toward reduced NK cell activity in older subjects when analyzed on a per cell basis. Influenza vaccination increased the proportion of CD56^bright cells and decreased the proportion of CD56^dim cells, in young, but not older subjects. Although NK cell activity in response to vaccination was not significantly different between the young and older subjects, low post-vaccination NK cell activity was associated with poor seroconversion in only the older subjects. There was no influence of the synbiotic on NK cell phenotype or activity, either before or after influenza vaccination. In conclusion, aging is associated with marked alteration of the phenotype of the NK cell population and there was evidence of an impaired NK cell response to influenza vaccination in older subjects. The effects of aging on NK cell phenotype and activity could not be offset by B. longum + Gl-OS.</p>Clinical Trial Registration<p>www.ClinicalTrials.gov, identifier NCT01066377.</p

presentation_2.PDF

<p>Natural killer (NK) cells are an important component of the immune response to influenza infection, but are subject to alteration during aging, which may play a role in impaired response to infection and vaccination in older people. Enhancement of NK cell activity could, therefore, present a means to improve the immune response to vaccination in older subjects, and pre- and probiotics offer an opportunity to modulate antiviral defenses via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide (B. longum + Gl-OS), on the NK cell response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial. There were significant effects of aging on NK cell phenotype, the most notable of which were an increase in CD56^dim cells, mainly reflected in the CD16⁺ subset, a decrease in CD56^bright cells, mainly reflected in the CD16⁻ subset, and greater expression of the immunosenescence marker, CD57, on NK cell subsets. However, these changes only partially translated to differences in NK cell activity, observed as trends toward reduced NK cell activity in older subjects when analyzed on a per cell basis. Influenza vaccination increased the proportion of CD56^bright cells and decreased the proportion of CD56^dim cells, in young, but not older subjects. Although NK cell activity in response to vaccination was not significantly different between the young and older subjects, low post-vaccination NK cell activity was associated with poor seroconversion in only the older subjects. There was no influence of the synbiotic on NK cell phenotype or activity, either before or after influenza vaccination. In conclusion, aging is associated with marked alteration of the phenotype of the NK cell population and there was evidence of an impaired NK cell response to influenza vaccination in older subjects. The effects of aging on NK cell phenotype and activity could not be offset by B. longum + Gl-OS.</p>Clinical Trial Registration<p>www.ClinicalTrials.gov, identifier NCT01066377.</p

Additional file 1: Figure S1. of Effect of a synbiotic on the response to seasonal influenza vaccination is strongly influenced by degree of immunosenescence

Effect of B. longum + Gl-OS on levels of vaccine-specific IgA, IgG1, IgD and IgM. Data are optical density units (OD450nm) ± 2 SEM, change from baseline (week 4) for n = 54–58 subjects per group, 2 (week 6) and 4 (week 8) weeks after vaccination. ☐ Maltodextrin, (gray square) B. longum + Gl-OS. Data were analysed using a Linear Mixed Model (LMM) with fixed factors of time, age and treatment. For IgA (plot A), there was a significant effect of age (p < 0.001) and time (p < 0.001) and a significant age*time interaction (p < 0.001). Data split by cohort showed a significant effect of time in both the young (p < 0.01) and older (p < 0.001) cohorts. For IgG1 (plot B), there were significant effects of time (p < 0.001) and age (p < 0.001). Data split by cohort showed a significant effect of time (p < 0.001) and a trend for a treatment effect (p = 0.03) in the older cohort, and a significant effect of time (p < 0.001) in the young cohort. For IgD (plot C), there were significant effects of age (p < 0.001) and time (p < 0.001) for the combined cohorts and a significant effect of time in both the young (p < 0.001) and older cohorts (p < 0.001) when considered separately. For IgM (plot D), there was a significant effect of time (p < 0.001), but no effect of age or treatment. (DOCX 52 kb

Additional file 2: Figure S2. of Effect of a synbiotic on the response to seasonal influenza vaccination is strongly influenced by degree of immunosenescence

Copy numbers of B. longum + Gl-OS in faecal samples. Data are mean ± 2SEM for n = 58 young and n = 54 older subjects. ☐ Maltodextrin, (gray square) B. longum + Gl-OS. Data were analysed using a Linear Mixed Model (LMM) with fixed factors of time, age and treatment. There were no statistically significant effects, either for combined or separate cohorts. (DOCX 25 kb

High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation.

By developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation (http://www.immunophenotype.org). Specifically, high-throughput phenotyping of 530 unique mouse gene knockouts identified 140 monogenic 'hits', of which most had no previous immunologic association. Furthermore, hits were collectively enriched in genes for which humans show poor tolerance to loss of function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with each other and with specific physiologic traits. Such linkages limit freedom of movement for individual immune parameters, thereby imposing genetically regulated 'immunologic structures', the integrity of which was associated with immunocompetence. Hence, we provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease