Wieten Rosanne W, Jonker Emile F F, van Leeuwen Ester M M, Remmerswaal Ester B M, Ten Berge Ineke J M, de Visser Adriëtte W, van Genderen Perry J J, Goorhuis Abraham, Visser Leo G, Grobusch Martin P, de Bree Godelieve J
Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands.
PLoS One. 2016 Mar 15;11(3):e0149871. doi: 10.1371/journal.pone.0149871. eCollection 2016.
Prompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T-cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity.
PBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF-tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07-3.1%). On day 180, these cells were still present (median 0.06%, range 0.02-0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells.
The presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35-40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity.
近期黄热病（YF）疫苗接种指南从加强免疫改为单剂接种策略，且缺乏临床数据支持这一调整，在此背景下，我们将初次接种后YF特异性CD8 + T细胞亚群谱和中和抗体作为潜在持久免疫力的替代指标。
在第0、3、5、12、28和180天收集了6名个体的外周血单核细胞（PBMC）和血清，在YF疫苗接种10年后收集了99名个体的样本。使用I类四聚体确定YF四聚体 + CD8 + T细胞的表型特征。使用标准化蚀斑减少中和试验（PRNT）测量抗体反应。此外，比较了接受初次接种和加强接种个体之间YF四聚体阳性CD8 + T细胞的特征。在第12天可检测到YF四聚体 + CD8 + T细胞（四聚体 + 细胞占CD8 + T细胞的百分比中位数为0.2%，范围为0.07 - 3.1%）。在第180天，这些细胞仍然存在（中位数为0.06%，范围为0.02 - 0.78%）。YF四聚体阳性CD8 + T细胞的表型从第12天的急性期效应细胞转变为第28天的晚期分化或效应记忆表型（CD45RA - / + CD27 - ）。YF四聚体阳性T细胞的两个亚群（CD45RA + CD27 - 和CD45RA + CD27 + ）持续到第180天。在所有表型亚群中，接种后第28天T-bet：Eomes比值往往较高，在第180天转向主要表达Eomes（中位数6.0（第28天）对2.2（第180天），p = 0.0625），提示与长寿记忆特性相容的印记。接种疫苗后长达18年可检测到YF四聚体阳性CD8 + T细胞，单剂接种后长达40年可检测到YF特异性抗体。加强接种并未增加YF特异性抗体滴度（平均值12. versus 13.1，p = 0.583），也未诱导YF四聚体 + CD8 + T细胞的频率或改变其表型。
初次接种18年后存在功能健全的YF特异性记忆T细胞库，且35 - 40年后有足够滴度的中和抗体，这表明单剂接种可能足以提供长期免疫力。
