Abstract
Background: Influenza-specific cytolytic T lymphocytes (CTL) have a critical role in clearing the virus from the lungs, but are poorly stimulated by current inactivated influenza vaccines. Our previous work suggests that granzyme B (GrB) activity predicts protection against laboratory-confirmed influenza infection (LCII) in older adults. However, basal GrB (bGrB) activity increases with age and the frequency of GrB+ CTL that do not co-express perforin increases following influenza infection, thereby acting as a potential contributor to immune pathology. Objectives: Using data from a 4-years randomized trial of standard-versus high-dose influenza vaccination, we sought to determine whether measurements of GrB activity alone indicate a protective vs pathologic response to influenza infection. We compared LCII to No-LCII subsets according to: pre-vaccination bGrB activity; and induced GrB activity in ex vivo influenza-challenged peripheral blood mononuclear cells (PBMC) at four and 20weeks post-vaccination. Results: Over four influenza seasons (2014–2018), 27 of 608 adult participants aged 65 years and older developed influenza A/H3N2-LCII (n = 18) or B-LCII (n = 9). Pre-vaccination, there was a significant correlation between bGrB and ex vivo GrB activity in each of the H3N2-LCII, B-LCII, and No-LCII subsets. Although pre-vaccination ex vivo GrB activity was significantly higher in B-LCII vs No-LCII with a trend for H3N2-LCII vs No-LCII, there was no difference in the response to vaccination. In contrast, there was a trend toward increased pre-vaccination bGrB activity and LCII: Odds Ratio (OR) (95% confidence intervals) OR = 1.46 (0.94, 2.33). By 20-weeks post-vaccination, there were significant fold-increases in ex vivo GrB activity specific for the infecting subtype in H3N2-LCII: OR = 1.63 (1.35, 2.00) and B-LCII: OR = 1.73 (1.34, 2.23). Conclusions: Our results suggest that the poor GrB responses to influenza vaccination that led to development of LCII can be attributed to inactivated formulations rather than the aging immune system since LCII cases generated robust ex vivo GrB responses following natural infection. Further, we identified bGrB as a biomarker of those who remain at risk for LCII following vaccination. Future studies will focus on understanding the mechanisms responsible for the shift in GrB-mediated protection vs potential immune pathology caused by GrB release.
Highlights
Despite widespread vaccination programs, the burden of influenza illness continues to be high in older adults, among whom increasing frailty is associated with declines in vaccine effectiveness for the prevention of hospitalization (Andrew et al, 2017)
We discovered that overall granzyme B (GrB) activity in circulating T cells of older adults was substantial and that the level of this “basal” GrB activity: 1) increases with age and in frail compared to non-frail older adults (Verschoor et al, 2021b); 2) is inversely proportional to the frequency of memory CD8+ T cells; and 3) is proportional to the frequency of circulating lateor terminally-differentiated CD8+ T cells some of which may be truly senescent (Haq et al, 2017); our unpublished data has shown a similar correlation between basal GrB (bGrB) activity and the frequency of circulating CD8+ T cells that express GrB in the absence of Perf
30 laboratory-confirmed influenza infection (LCII) cases (HD vaccine n 10 cases, SD vaccine n 20 cases) were detected (as previously reported (Verschoor et al, 2021a)) and corresponded to hospitalization rates for the circulating strains as reported by the Centers for Disease Control Weekly United States Influenza Surveillance Report (FluView) for that influenza season. The majority of these cases occurred in year 4 (2017–2018, n 9 H3N2-LCII vs No-LCII PBMC challenged with A/Victoria (H3N2)-LCII and n 6 B-LCII) when a vaccine strain mismatch to the circulating A/H3N2 occurred in the process of egg adaptation of the virus for vaccine production and led to an earlier influenza season and record-breaking hospitalization rates in the 65+ population
Summary
The burden of influenza illness continues to be high in older adults, among whom increasing frailty is associated with declines in vaccine effectiveness for the prevention of hospitalization (Andrew et al, 2017). We have used an ex vivo influenza challenge model in human peripheral blood mononuclear cells (PBMC) to simulate the cell-mediated immune response to natural infection and have shown that the level of GrB activity in lysates of A/H3N2 challenged PBMC correlates with protection against laboratory-confirmed influenza A/H3N2 infection (LCII) in older adults (McElhaney et al, 2006; McElhaney et al, 2009; Shahid et al, 2010). The decline in vaccine effectiveness with age corresponds to a decreased frequency of GrB+Perf+ CD8+ T cells and related cytolytic activity following influenza vaccination in older compared to young adults (Zhou and McElhaney, 2011; Zhou et al, 2016). Basal GrB (bGrB) activity increases with age and the frequency of GrB+ CTL that do not coexpress perforin increases following influenza infection, thereby acting as a potential contributor to immune pathology
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