Anschutz Medical Campus, University of Colorado-Denver, Aurora, Colorado, USA
Merck Sharp & Dohme, Kenilworth, New Jersey, USA.
J Virol. 2019 Jul 17;93(15). doi: 10.1128/JVI.00305-19. Print 2019 Aug 1.
Older age is associated with increased infectious morbidity and decreased immune responses to vaccines, but the mechanisms that mediate this effect are incompletely understood. The efficacy and immunogenicity of the live attenuated zoster vaccine (ZVL) have a very-well-described negative association with the age of the vaccinee. In a study of 600 ZVL recipients 50 to >80 years of age, we investigated immunological factors that might explain the effect of age on the immunogenicity of ZVL. Using FluoroSpot assays and flow cytometry, we determined that varicella-zoster virus (VZV)-specific peak T helper 1 (VZV-Th1) responses to ZVL were independently predicted by prevaccination VZV-Th1 responses, regulatory T cells (Treg), and PD1-expressing immune checkpoint T cells (Tcheck) but not by the age of the vaccinee. Persistence of VZV-Th1 1 year after vaccination was independently predicted by the factors mentioned above, by peak VZV-Th1 responses to ZVL, and by the age of the vaccinee. We further demonstrated by blocking experiments the mechanistic role of PD1 and CTLA4 as modulators of decreased VZV-Th1 responses in the study participants. VZV-specific cytotoxic T cell (VZV-CTL) and T follicular helper responses to ZVL did not correlate with age, but similar to other Th1 responses, VZV-CTL peak and baseline responses were independently correlated. These data expand our understanding of the factors affecting the magnitude and kinetics of T cell responses to ZVL in older adults and show the importance of prevaccination Treg and Tcheck in modulating the immunogenicity of ZVL. This presents new potential interventions to increase vaccine responses in older adults. Vaccination is the most effective method to protect older adults against viral infections. However, the immunogenicity of viral vaccines in older adults is notoriously poor. The live attenuated zoster vaccine (ZVL) provides the best example of a gradual decrease of vaccine immunogenicity with every 10-year age increase above 50 years. Here we show that the abundance of regulatory T cells before vaccine administration to older adults has a significant inhibitory effect on immune responses to ZVL and, together with baseline immunity to varicella-zoster virus, explains the effect of age on the immunogenicity of ZVL. Moreover, blockade of regulatory T cell mechanisms of action with biologic modulators restores immune responses to varicella-zoster virus in vaccinees. Collectively, these observations suggest that immune modulators that block regulatory T cell activity may increase responses to viral attenuated vaccines in older adults.
年龄增长与传染性发病率增加和疫苗免疫反应下降有关，但介导这种效应的机制尚不完全清楚。活减毒带状疱疹疫苗（ZVL）的功效和免疫原性与疫苗接种者的年龄呈负相关，这一现象已有明确描述。在一项对 600 名 50 岁至 80 岁以上 ZVL 接种者的研究中，我们研究了可能解释年龄对 ZVL 免疫原性影响的免疫因素。我们使用 FluoroSpot 检测和流式细胞术，确定 ZVL 特异性峰值辅助性 T 细胞 1（VZV-Th1）反应可独立预测接种前 VZV-Th1 反应、调节性 T 细胞（Treg）和 PD1 表达的免疫检查点 T 细胞（Tcheck），而与疫苗接种者的年龄无关。接种后 1 年 VZV-Th1 的持续性也可独立预测上述因素、ZVL 特异性峰值 VZV-Th1 反应和疫苗接种者的年龄。我们通过阻断实验进一步证明，PD1 和 CTLA4 作为研究参与者中 VZV-Th1 反应下降的调节剂的作用机制。ZVL 特异性细胞毒性 T 细胞（VZV-CTL）和滤泡辅助性 T 细胞反应与年龄无关，但与其他 Th1 反应类似，VZV-CTL 峰值和基线反应也独立相关。这些数据扩展了我们对影响老年人 ZVL 特异性 T 细胞反应幅度和动力学的因素的理解，并表明接种前 Treg 和 Tcheck 在调节 ZVL 免疫原性方面的重要性。这为提高老年人疫苗反应提供了新的潜在干预措施。疫苗接种是保护老年人免受病毒感染的最有效方法。然而，老年人对病毒疫苗的免疫原性却很差。活减毒带状疱疹疫苗（ZVL）是一个随着年龄每增加 10 岁，疫苗免疫原性逐渐下降的最佳例子。在这里，我们发现，老年人群在接种疫苗前调节性 T 细胞的丰度对 ZVL 免疫反应有显著的抑制作用，并且与水痘带状疱疹病毒的基线免疫力一起，解释了年龄对 ZVL 免疫原性的影响。此外，用生物调节剂阻断调节性 T 细胞的作用机制可以恢复疫苗接种者对水痘带状疱疹病毒的免疫反应。综上所述，这些观察结果表明，阻断调节性 T 细胞活性的免疫调节剂可能会增加老年人对病毒减毒疫苗的反应。
