Cytokine Profile of Children Hospitalized with Virologically-Confirmed Dengue during Two Phase III Vaccine Efficacy Trials.
Cytokine Profile of Children Hospitalized with Virologically-Confirmed Dengue during Two Phase III Vaccine Efficacy Trials.
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DOI：
10.1371/journal.pntd.0004830
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发表时间：
2016-07
影响因子：
3.8
通讯作者：
Guy B
中科院分区：
文献类型：
--
作者：
Harenberg A;de Montfort A;Jantet-Blaudez F;Bonaparte M;Boudet F;Saville M;Jackson N;Guy B
在亚洲（NCT01373281）和拉丁美洲（NCT01374516）进行的两项针对重组黄热病- 17d -登革热病毒减毒四价登革热候选疫苗（CYD-TDV）的大规模疗效研究显示，在为期两年的主动监测（活动期）期间，对登革热具有显著的保护作用。目前正在对导致住院治疗的突破性疾病的参与者进行长期随访（医院阶段）。在两项研究的长期随访开始的第二年，我们评估了住院（包括活动期）的选定参与者急性血清中的细胞因子谱。使用Milliplex Human Cytokine MAGNETIC BEAD预混38 Plex商用试剂盒（Millipore, Billerica， MA， USA）一式两份检测38种细胞因子的血清浓度。无论采用何种分层，偏最小二乘判别分析均未显示因突破性登革热住院的CYD-TDV和安慰剂接受者的总体细胞因子特征有任何差异。此外，突破性登革热的细胞因子谱在年龄<9岁和年龄≥9岁的人群中没有差异。这些探索性发现表明，与安慰剂相比，CYD-TDV不会诱导特定的免疫特征，证实了所观察到的临床特征。在两项大规模、安慰剂对照的III期疗效研究中，一种减毒四价登革热活疫苗（CYD-TDV）已被证明可提供预防登革热的保护。随后对研究参与者进行了持续监测，以更好地确定疫苗的长期效力和安全性。在随访的第3年，发现9岁以下儿童因登革热住院的发生率较高，但原因不明。虽然CYD-TDV和安慰剂接受者住院病例的临床结果相似，但进一步研究突破感染诱导的免疫特征在两个研究组之间是否存在差异是很重要的。我们比较了两组突破性疾病参与者急性期血清中38种细胞因子、趋化因子和生长因子的特征。在CYD-TDV和安慰剂接受者之间没有观察到总体概况的差异。同样，在年龄<9岁和≥9岁的人群中，突破性登革热的细胞因子谱也没有差异。基于这些分析的因素，我们的研究表明，与安慰剂相比，CYD-TDV不会引起突破性疾病的整体免疫学改变，这与两组观察到的相似的临床表现和病毒血症一致。
Two large-scale efficacy studies with the recombinant yellow fever-17D–dengue virus, live-attenuated, tetravalent dengue vaccine (CYD-TDV) candidate undertaken in Asia (NCT01373281) and Latin America (NCT01374516) demonstrated significant protection against dengue disease during two years’ active surveillance (active phase). Long-term follow up of participants for breakthrough disease leading to hospitalization is currently ongoing (hospital phase). We assessed the cytokine profile in acute sera from selected participants hospitalized (including during the active phase) up to the beginning of the second year of long-term follow up for both studies. The serum concentrations of 38 cytokines were measured in duplicate using the Milliplex Human Cytokine MAGNETIC BEAD Premixed 38 Plex commercial kit (Millipore, Billerica, MA, USA). Partial least squares discriminant analyses did not reveal any difference in the overall cytokine profile of CYD-TDV and placebo recipients hospitalized for breakthrough dengue regardless of stratification used. In addition, there was no difference in the cytokine profile for breakthrough dengue among those aged <9 years versus those aged ≥ 9 years. These exploratory findings show that CYD-TDV does not induce a particular immune profile versus placebo, corroborating the clinical profile observed. A live-attenuated, tetravalent dengue vaccine (CYD-TDV) has been shown to provide protection against dengue disease in two large-scale, placebo-controlled, phase III efficacy studies. Continued surveillance of study participants was subsequently undertaken to better define longer term vaccine efficacy and safety. A yet unexplained higher incidence of hospitalization for dengue disease was observed among children aged <9 years in year 3 of follow up. While the clinical outcome of the hospitalized cases was similar between CYD-TDV and placebo recipients, it was important to further investigate whether the immune profile induced by breakthrough infection differed between the two study groups. We compared the profile of 38 cytokines, chemokines and growth factors in acute phase sera collected from participants with breakthrough disease in the two groups. No difference in overall profile was observed between CYD-TDV and placebo recipients. Similarly, no difference in the cytokine profile for breakthrough dengue was observed between those aged <9 years and those aged ≥ 9 years. Based on these analyzed factors, our study shows that CYD-TDV does not induce an overall altered immunological profile with breakthrough disease compared with placebo, in agreement with the similar clinical pictures and viremia observed in the two groups.