Elsevier

Vaccine

Volume 31, Issue 4, 11 January 2013, Pages 685-690
Vaccine

Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination

https://doi.org/10.1016/j.vaccine.2012.11.041Get rights and content

Abstract

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.

Highlights

Influenza vaccination is less effective in CMV-seropositive elderly than young. ► CD8+CD28− T-cells are not associated with poor humoral vaccine responses. ► CD45RA+CCR7−CD27−CD28−CD4+ T-cells accumulate in CMV-seropositive individuals. ► CD45RA+CCR7−CD27−CD28−CD4+ cells are associated with poor humoral vaccine responses.

Introduction

Seasonal influenza is a disease with serious clinical and economic burdens, estimated to be the cause of an average of 226,000 hospitalizations and 36,000 deaths per season between 1979 and 2001 in the United States, with 90% of deaths occurring in individuals over the age of 65 [1], [2]. Annual influenza vaccination is the most effective method for preventing influenza and its complications [3]. However, exactly the group most susceptible to influenza morbidity and mortality, the elderly, does not respond as well as the young to vaccination. While in the young, the clinical vaccine efficacy is estimated at 70–90%, this corresponds to only 17–53% in the elderly, depending on the vaccine matching with the viruses in circulation [4]. This is widely believed to be due to immunosenescence, the diminished state of the immune system observed in the elderly [5], [6].

The specific mechanisms responsible for the decreased ability of the elderly to respond to influenza vaccination are still poorly understood. CD8+ T-cells lacking the costimulatory receptor CD28 have been associated with poor humoral and cellular response to influenza vaccination in the elderly [7], [8], [9]. CD28 down-regulation is the result of several rounds of T-cell division in response to antigenic challenge. Thus, CD8+ T-cells specific for chronic antigens, such as human immunodeficiency virus (HIV), cytomegalovirus (CMV) and to a lesser extent Epstein–Barr virus (EBV) lack the expression of this receptor [10], [11], [12]. CMV is an almost-ubiquitous β-herpes virus present in 30–90% of the population in developed countries with a rising seroprevalence with increasing age [13]. Although asymptomatic in immunocompetent individuals, it has an enormous impact on the immune system of the host – more than 30% of CD4+ and CD8+ T-cells of a healthy middle-aged individual can be specific for this virus [14]. A latent CMV infection is associated with lower levels of naïve T-cells and accumulation of memory T-cells, both hallmark features of immunosenescence [15], [16], [17], [18]. This has led to the increasingly accepted notion that CMV accelerates T-cell immunosenescence [19]. Accordingly, CMV has been associated with poor humoral response to influenza vaccination in the elderly in some [20], [21], but not all studies [22].

Thus, if and how CMV-seropositivity and the accumulation of CD28− late-differentiated T-cells associated with it contribute to poor vaccination outcome in the elderly is still unclear. The few studies demonstrating a negative correlation between CD28−CD8+ T-cells and poor vaccination outcome [7], [8], [9] did not take CMV-serostatus into account, thus failing to demonstrate a direct link between accumulation of these cells and poor responsiveness to influenza vaccine.

Here we have correlated the detailed phenotype of circulating CD4+ and CD8+ T-cell subsets with humoral responses in young and old individuals receiving Intanza, an intradermal influenza vaccine specially designed for the elderly [23]. Our data demonstrate a negative impact of the presence of CD4+ but not CD8+ T-cells with a more late-differentiated phenotype on responsiveness to the vaccine in individuals over the age of 60. This suggests that the negative impact of CMV on vaccination outcome, observed in our study, might be mediated through CD4 T-cells lacking the expression of CCR7, CD27 and CD28 and re-expressing CD45RA.

Section snippets

Study population and design

The current study was embedded in an open-label uncontrolled multicenter phase III trial (UTN U1111-1112-2795) that evaluated the humoral immunogenicity and safety of the Northern Hemisphere 2010–2011 formulation of an intradermal inactivated split-virion influenza vaccine (Intanza®, Sanofi Pasteur) in adults (18–59 yr) and elderly (>60 yr), as required for marketing authorization. Participants at the University of Antwerp were invited after the last visit of the clinical trial (June–July 2010)

CMV serostatus

All subjects were CMV IgM-negative, whereas 26 were CMV IgG-positive. Prevalence of CMV-seropositivity was higher in >60 year-olds than in younger participants (Table 1), but not related to age within the former group (Table 2).

Anti-vaccine humoral responses in vivo

Three weeks after vaccination, anti-influenza humoral responses were detected in 41/54 of study subjects (76%). The response rate was significantly higher in individuals <60 yr of age (96%) compared to >60 yr (60.0%, p = 0.003, Table 1). This was true for responsiveness to

Discussion

Influenza vaccination is less effective in the elderly compared to the young. Identifying immune parameters that differ between responders and non-responders will assist in development of better, more effective vaccines in the elderly or define screening policies for adapted immunization. CD28−CD8+ T-cells have been reported to correlate with poor vaccination outcome in the elderly in three studies [7], [8], [9]. Despite the fact that the frequency of these cells is directly associated with

Role of the funding source

This work was supported by the European Commission [FP7 259679 “IDEAL”]; German Research Foundation [DFG-PA 361/14-1]; German Federal Ministry of Education and Research [BMBF 0315890F, “Gerontoshield”] and the Methusalem funding program of the University of Antwerp (22858). NC and HD are postdoctoral fellows of the Fund for Scientific Research (FWO)-Flanders. The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the

Author's contributions

ED contributed to study design, analysis and interpretation of the data. HD, PVD and NC were involved in the conceptual design of the study, carried out the clinical trial and generated the serological data. KH contributed to generation and analysis of the flow cytometry data. GP contributed to study design and interpretation of the results. All authors were involved in drafting the manuscript and have approved the submitted version.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

We would like to thank Prof. Hans-Peter Pircher (University of Freiburg) for providing the anti-KLRG-1 primary antibody, Lilly Oettinger for antibody titration and flow cytometry quality control and Kevin Lenders for processing the blood samples.

References (42)

  • G. Pawelec et al.

    Alloproliferative human T cell clones primed and cultured in vitro lose proliferative and gain suppressive activity with age

    Hum Immunol

    (1984)
  • M. Miyara et al.

    Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor

    Immunity

    (2009)
  • P. Hoffmann et al.

    Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion

    Blood

    (2006)
  • W.W. Thompson et al.

    Influenza-associated hospitalizations in the United States

    JAMA

    (2004)
  • W.W. Thompson et al.

    Mortality associated with influenza and respiratory syncytial virus in the United States

    JAMA

    (2003)
  • B. Grubeck-Loebenstein et al.

    Immunosenescence and vaccine failure in the elderly

    Aging Clin Exp Res

    (2009)
  • J.J. Goronzy et al.

    Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals

    J Virol

    (2001)
  • M. Saurwein-Teissl et al.

    Lack of antibody production following immunization in old age: association with CD8(+)CD28(−) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines

    J Immunol

    (2002)
  • S.R. Hadrup et al.

    Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly

    J Immunol

    (2006)
  • P. Romero et al.

    Four functionally distinct populations of human effector-memory CD8+ T lymphocytes

    J Immunol

    (2007)
  • V. Appay et al.

    Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections

    Nat Med

    (2002)
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