Age-related changes in durability and function of vaccine-elicited influenza-specific CD4+ T-cell responses
Highlights
► Influenza vaccine (TIV) immunogenicity among young (18–49 years old) and elderly (≥70 years old). ► Vaccine elicits predominantly central memory and effector memory CD4+ T-cells. ► Vaccine-elicited T cell responses are short-lived among the elderly. ► PBMC from younger subjects are superior at producing IFN-γ after short-term Ag-specific culture.
Introduction
The influenza pandemic of 1918 saw the introduction of an avian-origin H1N1 that is estimated to have caused over 40 million deaths worldwide [1]. The influenza pandemic of 2009 similarly saw the introduction of an antigenically novel H1N1 into the global population and is estimated to have caused over 18,449 deaths globally [2]. In spite of the dominant emergence of this novel swine-origin H1N1 lineage in 2009, multiple instances of lethal avian influenza infections among humans have also occurred over the past decade. While divergent influenza subtypes including H7N7, H9N2, and H7N3 have circulated sporadically, recurrent outbreaks of the highly pathogenic H5N1 have been documented consistently [3], [4], [5]. Though these outbreaks have primarily occurred in south-east Asia, avian influenza infections among humans and birds have also been reported from Central and Western European nations thus increasing the likelihood of a potential H5N1 pandemic emerging in the future [6].
A number of studies in humans [7], [8], [9], [10] as well as in animal model systems [11], [12] suggest that protective immunity against influenza correlates with the prevalence of influenza-specific antibodies, primarily those directed against the viral hemagglutinin (HA). However, humoral immunity to influenza is predominantly type-specific and affords limited protection against heterosubtypic strains of circulating viruses [13]. Thus, the continual drift- and periodic antigenic shift-events that introduce antigenically novel influenza viruses into the global population have required annual changes in influenza vaccines to achieve reliable vaccine-induced protection [14]. However, instances of mismatches between seasonal influenza Ags found in the vaccine and circulating influenza viruses have generally lead to limited vaccine efficacy in some years [13], [15], [16], [17], [18], [19]. Equally, with subtypes such as H5N1 that show future pandemic potential, several distinct heterotypic strains have been involved in the outbreaks to date, thus increasing uncertainty as to which strain or strains may emerge as a potential avian pandemic strain.
With such antigenic plasticity as a backdrop, cellular immune responses are being increasingly recognized as an alternate correlate of immune protection that could provide protection from influenza viruses of disparate antigenic lineages [20]. A number of studies have recently characterized the existence of subtype-independent, cross-reactive cellular immune responses against diverse influenza strains [21], [22], [23], [24], which may provide protection from influenza infection or reduce severity of influenza disease [24], [25]. Importantly, recent studies clearly suggest that among the elderly, a population that bears the brunt of influenza morbidity and mortality, cell mediated immunity provides a better correlate of protection than do serum antibody responses [20]. As with antibody responses, HA is a major component of protective cellular immunity against influenza [26], [27], including heterosubtypic immunity [28].
Accumulating evidence suggests that cross-reactive T-cell responses can be induced de novo or boosted over pre-existing levels following seasonal vaccination with an unmatched HA antigen [23]. Though our earlier study utilizing a cohort of 18–49-year-olds was unable to assess cross-reactive T-cell responses among the truly elderly [29], we found that ageing reduced the magnitude of T-cells cross-reactive to pandemic H1 even in this relatively young cohort. Also, our use of IFN-γ ELISPOT following expansion in vitro precluded the assessment of HA-specific T-cell frequencies, as well as their memory and activation status directly ex vivo. In the present study, polychromatic flow cytometry was used to compare the ex vivo frequency, maturation and activation phenotypes of HA-specific CD4+ T-cells elicited following seasonal influenza vaccine administration among young (18–49 years of age) and elderly (≥70 years of age) adults. As our trial was conducted in 2007, we also address the ability of seasonal vaccination to induce cross-reactive T-cells against antigens that vaccinees had not yet been exposed to, such as the avian H5 that has only seen sporadic outbreaks in Asia, and the novel pandemic swine-origin H1 of 2009 that emerged two seasons following sample collection.
Section snippets
Human subjects and sample collection
This study was performed at Cincinnati Children's Hospital Medical Center in the fall of 2007 before seasonal influenza circulation in the community and two seasons prior to the emergence of the novel pandemic 2009 H1N1 strain globally. A total of 30 subjects were recruited into the study and provided informed consent following appropriate Institutional Review Board (IRB) and Institutional Biosafety Committee evaluation, and included 15 subjects each in the “young” (18–49 years old) and elderly
Age related changes in global CD4+ T-cell differentiation and activation status
While deficits in both magnitude and functionality of influenza-specific T-cells have previously been documented in relation to ageing of the host [32], [33], [34], the mechanisms underlying these deficits are currently not well understood. It is conceivable that this is a result of global changes in the maturation and activation status of T-cell subsets among the elderly that is not specific to influenza. To address this, total T-cell populations of young and elderly vaccinees were assessed by
Discussion
While the preponderance of influenza specific humoral responses is type-specific, a number of studies have now established the existence of robust cross-reactive T-cell responses against heterosubtypic antigens of influenza [21], [22], [23], [24]. We have previously shown that such heterosubtypic T-cell responses can be boosted by vaccination with unmatched antigens among human vaccinees [23]. Importantly, the major antigenic component of all licensed influenza vaccines, HA, has been identified
Acknowledgements
The authors would like to thank Dr. Alex Klimov and Dr. Xiyan Xu at the Center for Disease Control and Prevention (CDC), as well as BEI Resources for the influenza reagents. We thank Dr. David Bernstein, Tarek Shata and Saleem Basha for discussions; Tara Foltz for clinical study coordination; and Joanne Yu for preparation of Ab-conjugates. We also thank Dr. Martha Nason for help with statistical analysis and power calculations. This work was supported by the Intramural Research Program of the
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