Influenza vaccine-mediated protection in older adults: Impact of influenza infection, cytomegalovirus serostatus and vaccine dosage Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Cytomegalovirus infection and responsiveness to influenza vaccination in elderly residents of long-term care facilities. Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. Impact of ageing and a synbiotic on the immune response to seasonal influenza vaccination; a randomised controlled trial
ABSTRACT Age‐related changes in T‐cell function are associated with a loss of influenza vaccine efficacy in older adults . Both antibody and cell‐mediated immunity plays a prominent role in protecting older adults , particularly against the serious complications of influenza . High dose ( HD ) influenza vaccines induce higher antibody titers in older adults compared to st and ard dose ( SD ) vaccines , yet its impact on T‐cell memory is not clear . The aim of this study was to compare the antibody and T‐cell responses in older adults r and omized to receive HD or SD influenza vaccine  as well as determine whether cytomegalovirus ( CMV ) serostatus affects the response to vaccination , and identify differences in the response to vaccination in those older adults who subsequently have an influenza infection . Older adults ( ≥ 65 years ) were enrolled ( n = 106 ) and r and omized to  receive SD or HD influenza vaccine . Blood was collected pre‐vaccination , followed by 4 , 10 and 20 weeks post‐vaccination . Serum antibody titers , as well as levels of inducible granzyme B ( iGrB ) and cytokines were measured in P BMC s challenged ex vivo with live influenza virus . Surveillance conducted during the influenza season identified those with laboratory confirmed influenza illness or infection . HD influenza vaccination induced a high antibody titer and IL‐10 response , and a short‐lived increase in Th1 responses ( IFN‐&ggr ; and iGrB ) compared to SD vaccination in P BMC s challenged ex vivo with live influenza virus . Of the older adults who became infected with influenza , a high IL‐10 and iGrB response in virus‐challenged cells was observed post‐infection ( week 10 to 20 ) , as well as IFN‐&ggr ; and TNF‐&agr ; at week 20 . Additionally , CMV seropositive older adults had an impaired iGrB response to influenza virus‐challenge , regardless of vaccine dose . This study illustrates that HD influenza vaccines have little impact on the development of functional T‐cell memory in older adults . Furthermore , poor outcomes of influenza infection in older adults may be due to a strong IL‐10 response to influenza following vaccination , and persistent CMV infection . HIGHLIGHTSHD vaccination results in development of strong Th2 , but not Th1 memory responses . Influenza infection results in development of strong Th1 and Th2 memory responses . Influenza infection restores the iGrB response to ex vivo influenza challenge . CMV+ older adults have high bGrB levels in unstimulated T‐cells . CMV+ older adults have a poor iGrB response to ex vivo influenza challenge Influenza vaccination is less effective in the elderly compared to the young . Studies that have attempted to identify immune parameters correlating with satisfactory vaccine responses have yielded inconclusive results . Here , we correlate the distribution of different circulating CD4 + and CD8 + T-cell phenotypes with the humoral response to vaccination with Intanza , an intradermal seasonal vaccine , in 54 individuals of different ages . Subjects were stratified according to age ( below or over 60 ) and presence of a latent infection with Cytomegalovirus ( CMV ) . CMV-seropositivity was significantly associated with a lower response rate to the vaccine in people over but not below 60 yr of age . Unlike reported data , late-differentiated ( CD45RA+CCR7-CD27-CD28- ) CD4 + , but not CD8 + T-cells associated with a poorer vaccine response . Thus , latent CMV infection has a deleterious effect on influenza antibody responses in the elderly , which might be mediated through CD4 T-cells lacking CCR7 , CD27 and CD28 and re-expressing CD45RA Ample evidence suggests that infection with cytomegalovirus ( CMV ) leads to accelerated aging of the immune system and may contribute to poor responsiveness to  influenza vaccination in older persons . The objective of this study was to investigate whether CMV infection , acquired earlier in life , affects the response to influenza vaccination  in a r and omized controlled trial among older persons in long-term care facilities . During the 1997 - 1998 influenza season , 731 residents ( median age 83 [ interquartile range 78 - 88 ] , 75.4 % female ) in 14 long-term care facilities in the Netherl and s were r and omly assigned to receive 15 or 30 μg of inactivated influenza vaccine , followed by a 15 μg booster vaccine or a placebo vaccine at day 84 . Blood sample s were collected at day 0 , day 25 , day 84 and day 109 . Seroresponses to influenza vaccination were measured by hemagglutination-inhibition tests to the A/H3N2 strain at all time points . Subsequently , baseline levels of IgG anti-CMV antibodies were measured using an automated chemiluminescent microparticle immunoassay . Participants with CMV antibody level≥6 AU/mL were considered to harbor CMV infection . At baseline , no differences in pre-vaccination geometric mean antibody titers ( GMT ) were observed between participants with ( n=571 , 78.1 % ) or without CMV infection ( n=160 , 21.9 % ) . During follow-up , participants with and without CMV infection had similar responses to influenza vaccination  as measured with changes in GMT ( linear mixed model , adjusted for gender , age , pre-vaccination GMT and vaccination strategy , p=0.46 ) . Analogously , no association was found between CMV infection and a more than 4-fold increase in antibody titer ( Generalized Estimating Equations , adjusted OR 1.14 [ 95%CI 0.80;1.64 ] ) or an antibody titer≥40 ( adjusted OR 1.24 [ 95%CI 0.86;1.80 ] ) . In conclusion , CMV infection did not explain poor responsiveness  to influenza vaccination in residents of long-term care facilities We assessed association between prior cytomegalovirus ( CMV ) infection , proinflammatory  status and effectiveness of the anti-influenza vaccination .  We examined 154 individuals during the epidemic season dividing them according to the age , response to the vaccine and the Senieur Protocol ( SP ) .  The anti-hemagglutinins ( HI ) , tumour necrosis factor alpha ( TNFalpha ) , interleukin ( IL ) 1beta , IL6 , IL10 , ACTH/cortisol axis , anti-CMV antibodies and CD28+CD57- lymphocytes were assessed . Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes ( known to be associated with CMV carrier status ) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol . The  anti-influenza vaccine  induced increase in TNFalpha and IL10 in the all non-responders , while cortisol increased only in the young . Concluding , CMV carrier status eliciting elevated proinflammatory potential could contribute to unresponsiveness to the anti-influenza vaccine Summary Background & aims Ageing increases risk of respiratory infections and impairs the response to influenza vaccination . Pre- and pro-biotics 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 , r and omized controlled trial , 58 young ( 18–35 y ) and 54 older ( 60–85 y ) 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 . Registered under Clinical Trials.gov Identifier no. NCT01066377
Latent infection with cytomegalovirus ( CMV ) is thought to accelerate aging of the immune system .
With age , influenza vaccine responses are impaired .
Although several studies investigated the effect of CMV infection on antibody responses to influenza vaccination , this led to contradicting conclusions .
Therefore , we investigated the relation between CMV infection and the antibody response to influenza vaccination  by performing a systematic review and meta- analysis .