CD8+ T-cell Responses in Flavivirus-Naive Individuals Following Immunization with a Live-Attenuated Tetravalent Dengue Vaccine Candidate
CD8+ T-cell Responses in Flavivirus-Naive Individuals Following Immunization with a Live-Attenuated Tetravalent Dengue Vaccine Candidate
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DOI：
10.1093/infdis/jiv258
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发表时间：
2015-11-15
影响因子：
6.4
通讯作者：
Partidos, Charalambos D.
中科院分区：
文献类型：
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作者：
Chu, Haiyan;George, Sarah L.;Partidos, Charalambos D.
我们正在研发一种减毒活四价登革热疫苗（TDV）候选株，它基于一种减毒的登革热2型病毒（TDV - 2）以及3种嵌合病毒，这些嵌合病毒包含登革热病毒（DENVs）-1、-3和-4的前膜蛋白和包膜蛋白基因，这些基因在减毒的TDV - 2基因组背景下表达（分别为TDV - 1、TDV - 3和TDV - 4）。在这项研究中，我们分析并描述了未感染过黄病毒的人类志愿者在皮下或皮内途径接种两剂TDV（间隔90天）后的CD8(+) T细胞反应。通过肽阵列和细胞内细胞因子染色，我们证明了TDV可诱导针对TDV - 2的非结构蛋白NS1、NS3和NS5的CD8(+) T细胞。这些细胞的特征是产生干扰素 - γ、肿瘤坏死因子 - α，在较小程度上产生白细胞介素 - 2。在第一剂接种后第90天反应最强，在第二剂接种后180天仍可检测到。此外，CD8(+) T细胞具有多功能性，可同时产生≥2种细胞因子，并且对其他3种登革热病毒血清型的NS蛋白具有交叉反应性。总体而言，这些发现描述了我们的登革热疫苗候选株激发细胞免疫反应的能力，并支持在未来TDV临床试验的样本中进一步评估T细胞反应。
We are developing a live-attenuated tetravalent dengue vaccine (TDV) candidate based on an attenuated dengue 2 virus (TDV-2) and 3 chimeric viruses containing the premembrane and envelope genes of dengue viruses (DENVs) -1, -3, and -4 expressed in the context of the attenuated TDV-2 genome (TDV-1, TDV-3, and TDV-4, respectively). In this study, we analyzed and characterized the CD8(+) T-cell response in flavivirus-naive human volunteers vaccinated with 2 doses of TDV 90 days apart via the subcutaneous or intradermal routes. Using peptide arrays and intracellular cytokine staining, we demonstrated that TDV elicits CD8(+) T cells targeting the nonstructural NS1, NS3, and NS5 proteins of TDV-2. The cells were characterized by the production of interferon-gamma, tumor necrosis factor-alpha, and to a lesser extent interleukin-2. Responses were highest on day 90 after the first dose and were still detectable on 180 days after the second dose. In addition, CD8(+) T cells were multifunctional, producing >= 2 cytokines simultaneously, and cross-reactive to NS proteins of the other 3 DENV serotypes. Overall, these findings describe the capacity of our candidate dengue vaccine to elicit cellular immune responses and support the further evaluation of T-cell responses in samples from future TDV clinical trials.