Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax™-DEN2) vaccine:: Phase I clinical trial for safety and immunogenicity
Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax™-DEN2) vaccine:: Phase I clinical trial for safety and immunogenicity
复制标题
DOI：
10.4161/hv.2.2.2555
复制
发表时间：
2006-03-01
期刊：
影响因子：
--
通讯作者：
Monath, Thomas P.
中科院分区：
文献类型：
--
作者：
Guirakhoo, Farshad;Kitchener, Scott;Monath, Thomas P.
进行了一项随机双盲 I 期试验，以评估黄热病 (YF)-登革热 2 (DEN2) 嵌合体 (ChimeriVax(TM)DEN2) 与 YF 疫苗 (YF-VAX(R)) 的安全性、耐受性和免疫原性。 42 名健康 YF 初治成人通过皮下途径 (SC) 随机接受单剂量 ChimeriVax(TM)-DEN2（高剂量，5 log 斑块形成单位 [PFU] 或低剂量，3 log PFU）或 YF-VAX(R)。为了确定 YF 预免疫对 ChimeriVax(TM)-DEN2 疫苗的影响，之前接种过 YF 疫苗的 14 名受试者接受了高剂量的 ChimeriVax(TM)-DEN2 作为开放标签疫苗。大多数不良事件与 YF-VAX(R) 相似，且为轻度至中度，没有严重的副作用。分别接种 5.0 和 3.0 log(10) PFU ChimeriVax(TM)-DEN2 的 YF 初次受试者中，100% 和 92.3% 血清转化为 wt DEN2（菌株 1668 1）；接种 YF-VAX(R) 的受试者中有 92% 血清转化为 YF 17D 病毒，但接种 ChimeriVax-DEN2 的 YF 初次接种受试者均未血清转化为 YF 17D 病毒。在接种 ChimeriVax(TM)-DEN2 或 YF-VAX(R) 的 YF 初治受试者中观察到异源 DEN 血清型 1、3 和 4 的血清转化率较低。相比之下，接种 ChimeriVax(TM)-DEN2 血清型的 YF 免疫受试者 100% 转化为所有 4 种 DEN 血清型。令人惊讶的是，YF 免疫受试者中的 DEN 1、2 和 3 病毒中和抗体水平在 1 年后持续存在。这些数据表明：(1) ChimeriVax(TM)-DEN2 疫苗的安全性和免疫原性特征与 YF-VAX(R) 一致，(2) YF 病毒预免疫不会干扰 ChimeriVax(TM)-DEN2 免疫，但会诱导针对所有 4 种 DEN 血清型的持久交叉中和抗体反应。后一个观察结果可能对登革热疫苗的开发具有实际意义。
A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax(TM)DEN2) in comparison to that of YF vaccine (YF-VAX(R)). Forty-two healthy YF naive adults randomly received a single dose of either ChimeriVax(TM)-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX(R) by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax(TM)-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax(TM)-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX(R) and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naive subjects inoculated with 5.0 and 3.0 log(10) PFU of ChimeriVax(TM)-DEN2, respectively, seroconverted to wt DEN2 (strain 1668 1); 92% of subjects inoculated with YF-VAX(R) seroconverted to YF 17D virus but none of YF naive subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naive subjects inoculated with either ChimeriVax(TM)-DEN2 or YF-VAX(R). In contrast, 100% of YF immune subjects inoculated with ChimeriVax(TM)-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax(TM)-DEN2 vaccine is consistent with that of YF-VAX(R), and (2) preimmunity to YF virus does not interfere with ChimeriVax(TM)-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.