Influenza vaccine-mediated protection in older adults: Impact of influenza infection, cytomegalovirus serostatus and vaccine dosage
Introduction
Older adults are at increased risk of death and complications due to influenza infection (Simonsen et al., 2000, Schanzer et al., 2007), accounting for 90% of influenza-related deaths (Thompson et al., 2010). While vaccinations rates have increased over the years (Gionet, 2015), hospitalizations rates remain unchanged (Thompson et al., 2004).
One of the causes of increased influenza associated morbidity and mortality in older adults is decreasing vaccine effectiveness with age (Goodwin et al., 2006, Simonsen et al., 2007). The current influenza vaccine strategy hinges on inducing an antibody response, but has poor efficacy in older adults. Age-related changes in both B and T-cells are associated with a decline in the antibody response to vaccination (Goronzy et al., 2001, Saurwein-Teissl et al., 2002, Frasca et al., 2010, Frasca et al., 2016). Furthermore, influenza antibody titers have been shown to be a poor correlate of protection in older adults (McElhaney et al., 2006, McElhaney et al., 2009). Cytotoxic T-lymphocyte (CTL) responses have been identified to be protective against influenza disease (La Gruta and Turner, 2014), thus underlining the importance of including measures of the cellular immune response in the assessment of influenza vaccine efficacy (Effros, 2007). Specifically, granzyme B (GrB) activity and IFN-γ:IL-10 ratios in influenza virus-challenged PBMCs have been found to correlate with protection against influenza in older adults (McElhaney et al., 2006, McElhaney et al., 2009, Shahid et al., 2010) and could be useful measures when evaluating vaccine efficacy.
The majority of older adults are seropositive for cytomegalovirus (CMV) (Staras et al., 2006) which may be a confounding factor in evaluating the immune response to influenza vaccination (Frasca et al., 2015, Furman et al., 2015, McElhaney et al., 2015, Haq et al., 2016). Persistent CMV infection has been shown to be a major driver of terminal differentiation of CD8+ T-cells (Derhovanessian et al., 2009, McElhaney et al., 2009). These terminally differentiated CD8+ T-cells express and release the cytolytic mediator, GrB, in the absence of perforin in both the resting and activated state (Zhou and McElhaney, 2011), and can contribute to toxicity in the extracellular space (McElhaney et al., 2012). The presence of high levels of baseline GrB (bGrB) in the resting state of unstimulated T-cells hinders the inducible GrB (iGrB) response to ex vivo influenza challenge (McElhaney et al., 2012, Haq et al., 2016) and may result in a compromised response to infection.
Previous studies comparing high dose (HD) and standard dose (SD) influenza vaccine formulations in older adults found significantly higher antibody titers in those receiving HD vaccinations (Couch et al., 2007, Falsey et al., 2009, DiazGranados et al., 2013, DiazGranados et al., 2014) but the impact of vaccine dose on cellular immune response requires further investigation.
Here we present the results of a randomized study comparing SD and HD influenza vaccines in older adults using longitudinal sampling and an ex vivo infection model. Changes in cell-mediated immune responses pre- and post-vaccination were measured to determine the impact of vaccine dose, influenza infection, and CMV seropositivity.
Section snippets
Population
Ethics approval was obtained from local ethics committees: University of Connecticut Health Centre and Health Sciences North (ClinicalTrials.gov Identifier: NCT02297542). Older adults (≥ 65 years of age, n = 106) and young adults (20–40 years of age, n = 19) were recruited through the UConn Center on Aging Recruitment Core (UCARC) and the Health Sciences North Research Institute. Written informed consent was obtained from all study participants. The inclusion criteria for this study required older
Cohort statistics
One hundred and six older adults were enrolled and vaccinated in the study at the beginning of the 2014/2015 flu season. Demographic data was comparable between the vaccine groups: SD (n = 53) and HD (n = 53) (Table 1). Each group had a similar mean age (± standard deviation) of 75 years ± 7.5 (SD) and 75 years ± 7.8 (HD), along with other cohort characteristics including CMV status (~ 55% CMV+), sex (~ 30% male), medical conditions and medication usage. For the measures of frailty, the Frailty Index was
Discussion
The study presented here investigates the impact of influenza vaccine dose, influenza infection and CMV serostatus on the antibody and cellular immune response in older adults using an ex vivo live influenza virus-challenge model.
The decline with aging, in the antibody response to influenza vaccination and the associated loss of vaccine efficacy has been attributed to age-related changes in the T-cells (Goronzy et al., 2001, Saurwein-Teissl et al., 2002). The HD vaccine was designed to overcome
Conclusion
This study provides new insights into the role of vaccine dose, CMV status and influenza on antibody and cellular immune responses to influenza in older adults. Here we demonstrated that HD influenza vaccines induce strong and long lived Th2 responses (antibody and IL-10), but have a limited impact on Th1 responses (iGrB, IFN-γ). In contrast, recent influenza infection is associated with the development of strong Th1 and Th2 memory responses and restores the iGrB response to ex vivo influenza
Acknowledgements
We would like to thank all participants in this study.
Funding
This work was supported by: the National Institutes of Health, National Institute on Aging (R01 AG048023) and the Northern Ontario Heritage Fund Corporation (A-17-07).
Author contributions
Study design by JEM and GAK. Data analysis was performed by SM and AK. The manuscript was written by SM. Final review and editing of manuscript by SM, AK, GAK and JEM.
Conflict of interest
JEM has participated on advisory boards for GlaxoSmithKline, Sanofi Pasteur, and Pfizer and on data monitoring boards for Sanofi Pasteur; she has participated in clinical trials sponsored by GlaxoSmithKline and has received honoraria and travel and accommodation reimbursements for presentations sponsored by GlaxoSmithKline, Sanofi Pasteur and Pfizer.
SM, AK and GAK have no conflict of interest to declare.
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