Effect of a synbiotic on the response to seasonal influenza vaccination is strongly influenced by degree of immunosenescence

Abstract

Background: 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 52,486, combined with a prebiotic, gluco-oligosaccharide (B. longum + Gl-OS), on the response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial, taking into account the influence of immunosenescence markers at baseline.

Results: Vaccination resulted in a significant increase in total antibody titres, vaccine-specific IgA, IgM and IgG and seroprotection to all three subunits of the vaccine in both young and older subjects, and in general, the increases in young subjects were greater. There was little effect of the synbiotic, although it tended to reduce seroconversion to the Brisbane subunit of the vaccine and the vaccine-specific IgG response in older subjects. Immunological characterization revealed that older subjects randomized to the synbiotic had a significantly higher number of senescent (CD28(-)CD57(+)) helper T cells at baseline compared with those randomized to the placebo, and they also had significantly higher plasma levels of anti-CMV IgG and a greater tendency for CMV seropositivity. Moreover, higher numbers of CD28(-)CD57(+) helper T cells were associated with failure to seroconvert to Brisbane, strongly suggesting that the subjects randomized to the synbiotic were already at a significant disadvantage in terms of likely ability to respond to the vaccine compared with those randomized to the placebo.

Conclusions: Ageing was associated with marked impairment of the antibody response to influenza vaccination in older subjects and the synbiotic failed to reverse this impairment. However, the older subjects randomized to the synbiotic were at a significant disadvantage due to a greater degree of immunosenscence at baseline compared with those randomized to the placebo. Thus, baseline differences in immunosenescence between the randomized groups are likely to have influenced the outcome of the intervention, highlighting the need for detailed immunological characterization of subjects prior to interventions.

Trial registration: Clinicaltrials.gov NCT01066377.

Keywords: Ageing; Influenza; Prebiotic; Probiotic; Vaccination.

Figures

Fig. 1

Recruitment flow diagram

Fig. 2

Effect of B. longum + GI-OS on antibody responses to the influenza vaccine in young and older subjects. Data are log2 transformed geometric mean antibody titres (GMT) (±2SEM) at baseline and weeks 6 and 8 for n = 54–58 subjects per group. □ Maltodextrin, B. longum + Gl-OS. The reference line at the Y axis indicates seroprotection (GMT = 32). Data were analysed using a Linear Mixed Model (LMM) with fixed factors of time, age and treatment. a H1N1; For the LMM, there were significant effects of age (p < 0.001) and time (p < 0.001) and a trend for a treatment effect (p < 0.02). For data split by cohorts, there was a significant effect of time in both cohorts (p < 0.001), but no significant effect of treatment. b H3N2; for the LMM overall, there was a significant effect of time (p < 0.001) and an age*time interaction (p < 0.01). For data split by cohort there was a significant effect of time (p < 0.001) and a time*treatment interaction (p < 0.01) in the older cohort, and a significant effect of time (p < 0.001) in the young cohort. c Brisbane; for the LMM overall, there were significant effects of age (p < 0.005), time (p < 0.001) and an age*time interaction (p < 0.001). For data split by cohort, there was a significant effect of time (p < 0.001) and a time*treatment interaction (p < 0.01) in the older cohort, and a significant effect of time (p < 0.001) in the young cohort. There was a borderline effect of treatment (p < 0.05)

Fig. 3

Numbers of CD28−CD57+ helper T cells at baseline differ in older subjects randomized to B. longum + Gl-OS and placebo. Data are absolute numbers of T-cell subsets × 1000/ml ± 2SEM for n = 58 young and n = 54 older subjects randomized to B. longum + Gl-OS ■ or placebo □. Data were analysed using Student’s independent t-tests for differences between young and older subjects. ** Denotes significant difference between treatment groups within age cohort (p < 0.01)

Fig. 4

Baseline levels of anti-CMV IgG differ in older subjects randomized to B. longum + Gl-OS and placebo. Data are anti-CMV IgG (AU/ml) ± 2SEM for n = 45 young and n = 45 older subjects randomized to B. longum + Gl-OS or placebo. Data were analysed using Student’s independent t-tests for differences between young and older subjects. * Denotes significant difference between treatment groups within age cohort (p < 0.05)

Fig. 5

Lower numbers of circulating CD28-CD57+ T helper cells in seroconverters to the Brisbane subunit compared with non-converters amongst subjects randomized to B. longum + Gl-OS. Data are absolute numbers of T cell subset x1000/ml ± 2SE for n = 58 young and n = 54 older subjects. * Denotes significantly different from non-seroconverters (P < 0.05, independent values T-test)

Fig. 6

Study design