Data from: A single 17D Yellow Fever vaccination provides lifelong immunity; characterization of Yellow-Fever-specific neutralizing antibody and T-cell responses after vaccination

Introduction: 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. Methods and Findings: 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. Conclusion: 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.

引言：鉴于近期黄热病（Yellow Fever，YF）疫苗接种指南从加强接种策略调整为单剂接种方案，且目前缺乏支持该调整的临床数据，本研究以初次接种黄热疫苗后黄热病毒特异性CD8阳性T细胞（CD8+ T-cell）亚群特征与中和抗体水平作为评估潜在长期免疫的替代标志物展开分析。

方法与结果：本研究于接种后第0、3、5、12、28及180天采集6名受试者的外周血单个核细胞（Peripheral Blood Mononuclear Cells，PBMC）及血清，并在黄热疫苗接种时长超过10年的99名受试者中采集样本。采用I类四聚体检测黄热病毒四聚体阳性CD8阳性T细胞的表型特征；通过标准空斑减少中和试验（plaque reduction neutralization test，PRNT）检测抗体应答水平。此外，对比了初次接种与加强接种受试者的黄热病毒四聚体阳性CD8阳性T细胞特征。
结果显示，接种后第12天即可检测到黄热病毒四聚体阳性CD8阳性T细胞，其占CD8阳性T细胞的中位数为0.2%，范围为0.07%~3.1%；至第180天，此类细胞仍可被检出，占比中位数为0.06%，范围为0.02%~0.78%。黄热病毒四聚体阳性CD8阳性T细胞的表型从接种后第12天的急性期效应细胞，转变为第28天的晚期分化型或效应记忆型表型（CD45RA-/+CD27-）。两种黄热病毒四聚体阳性T细胞亚群（CD45RA+CD27-与CD45RA+CD27+）可存活至接种后第180天。在所有表型亚群中，接种后第28天的T-bet与Eomes比值偏高，至第180天则转向以Eomes表达为主，中位数分别为6.0（第28天）与2.2（第180天），P=0.0625，提示其具备与长寿记忆特性相符的细胞印记特征。黄热病毒四聚体阳性CD8阳性T细胞在接种后最长可维持18年，而黄热病毒特异性抗体在单剂接种后最长可维持40年。加强接种既未提升黄热病毒特异性抗体滴度，两组均值分别为12.5与13.1，P=0.583，也未改变黄热病毒四聚体阳性CD8阳性T细胞的细胞频率或表型特征。

结论：初次接种黄热疫苗18年后仍可检测到功能健全的黄热病毒特异性记忆T细胞库，且35~40年后仍可维持足够滴度的中和抗体，这提示单剂接种足以提供长期免疫保护。