背景:提高老年人流感疫苗有效性的努力取得了一些成功,例如引入高剂量分裂病毒流感疫苗(HD-SVV),然而,对这些疫苗的细胞介导的免疫反应的研究仍然有限。我们已经证明了细胞溶解介质的活性,颗粒酶B(GrB),在用甲型流感/H3N2病毒攻击的外周血单核细胞(PBMC)中,与老年人标准剂量疫苗接种(SD-SVV)后对流感的保护相关。Further,干扰素-γ(IFNγ)与白细胞介素-10(IL-10)的比例可以是保护的相关性,这取决于相对于暴露于流感的疫苗接种时间。
方法:在一项双盲试验(ClinicalTrials.govNCT02297542)中,老年人(≥65岁,n=582)从2014/15至2017/18随机接受SD-SVV或HD-SVV(Fluzone®)。年轻人(20-40岁,n=79)接受SD-SVV。接种后0、4、10和20周,血清抗体滴度,IFNγ,在离体流感病毒攻击的PBMC中测量IL-10和诱导型GrB(iGrB)。iGrB定义为循环T细胞中GrB活性从基线水平(bGrB)的倍数变化。将老年人的反应与年轻对照组进行比较,虽然我们专门针对老年人分析了年龄的影响,性别,巨细胞病毒(CMV)血清状态,脆弱,和疫苗剂量。
结果:在接种疫苗之前,年轻的成年人产生显著更高的IFNγ,IL-10和iGrB水平,但IFNγ:IL-10比例没有差异。相对于SD-SVV接受者,年龄较大的HD-SVV受者在接种后4周表现出显著较低的IFNγ:IL-10比率.相比之下,IFNγ和iGrB水平在年轻的SD和年龄较大的SD或HD接受者;与SD组相比,只有HD组显示出对疫苗接种的显着IFNγ反应,而所有三组均显示出对疫苗接种的显着iGrB反应。在回归分析中,女性和HD-SVV与更高的IL-10水平相关,而SD-SVV与较低的iGrB水平相关。前一季流感疫苗接种显示iGrB水平下降,但IFNγ和IL-10水平上升,与甲型流感/H3N2血凝抑制抗体滴度相关。
结论:总体而言,HD-SVV扩增IL-10应答与增强的抗体应答一致,在年轻人或老年人中,相对于SD-SVV的iGrB反应几乎没有影响。这些结果表明HD-SVV的增强保护很大程度上是抗体介导的。
BACKGROUND: Efforts to improve influenza vaccine effectiveness in older adults have resulted in some successes, such as the introduction of high-dose split-virus influenza vaccine (HD-SVV), yet studies of cell-mediated immune responses to these vaccines remain limited. We have shown that the activity of the cytolytic mediator, granzyme B (GrB), in peripheral blood mononuclear cells (PBMC) challenged with influenza A/H3N2 virus, correlates with protection against influenza following standard dose vaccination (SD-SVV) in older adults. Further, the interferon-γ (IFNγ) to interleukin-10 (IL-10) ratio can be a correlate of protection depending on the timing of vaccination relative to exposure to influenza.
METHODS: In a double-blind
trial (ClinicalTrials.gov NCT02297542) older adults (≥65 years, n=582) were randomized to receive SD-SVV or HD-SVV (Fluzone®) from 2014/15 to 2017/18. Young adults (20-40 years, n=79) received SD-SVV. At 0, 4, 10 and 20 weeks post-vaccination, serum antibody titers, IFNγ, IL-10, and inducible GrB (iGrB) were measured in ex vivo influenza virus-challenged PBMC. iGrB is defined as the fold change in GrB activity from baseline levels (bGrB) in circulating T cells. Responses of older adults were compared to younger controls, while specifically for older adults we analyzed effects of age, sex, cytomegalovirus (CMV) serostatus, frailty, and vaccine dose.
RESULTS: Prior to vaccination, younger adults produced significantly higher IFNγ, IL-10 and iGrB levels, but with no difference in the IFNγ:IL-10 ratio. Relative to SD-SVV recipients, older HD-SVV recipients exhibited significantly lower IFNγ:IL-10 ratios at 4 weeks post-vaccination. In contrast, IFNγ and iGrB levels were higher in younger SD vs. older SD or HD recipients; only the HD group showed a significant IFNγ response to vaccination compared to the SD groups while all three groups showed a significant iGrB response to vaccination. In a regression analysis, female sex and HD-SVV were associated with higher IL-10 levels, while SD-SVV was associated with lower iGrB levels. Prior season influenza vaccination showed a decline in iGrB levels but an increase in IFNγ and IL-10 levels, which correlated with influenza A/H3N2 hemagglutination inhibition antibody titers.
CONCLUSIONS: Overall, HD-SVV amplified the IL-10 response consistent with enhanced antibody responses, with little effect on the iGrB response relative to SD-SVV in either younger or older adults. These results suggest that enhanced protection with HD-SVV is largely antibody-mediated.