Guirakhoo Farshad, Kitchener Scott, Morrison Dennis, Forrat Remi, McCarthy Karen, Nichols Richard, Yoksan Sutee, Duan Xiaochu, Ermak Thomas H, Kanesa-Thasan Niranjan, Bedford Philip, Lang Jean, Quentin-Millet Marie-Jose, Monath Thomas P
Acambis, Inc., Cambridge, Massachusetts 02139, USA.
Hum Vaccin. 2006 Mar-Apr;2(2):60-7. doi: 10.4161/hv.2.2.2555. Epub 2006 Mar 15.
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-DEN2) in comparison to that of YF vaccine (YF-VAX). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log10 PFU of ChimeriVax-DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX seroconverted to YF 17D virus but none of YF naïve 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 naïve subjects inoculated with either ChimeriVax-DEN2 or YF-VAX. In contrast, 100% of YF immune subjects inoculated with ChimeriVax-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-DEN2 vaccine is consistent with that of YF-VAX, and (2) preimmunity to YF virus does not interfere with ChimeriVax-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.
开展了一项随机双盲I期试验，以评估黄热病（YF）-登革2型（DEN2）嵌合体（ChimeriVax-DEN2）与YF疫苗（YF-VAX）相比的安全性、耐受性和免疫原性。42名未感染过YF的健康成年人通过皮下途径（SC）随机接受单剂量的ChimeriVax-DEN2（高剂量，5 log蚀斑形成单位[PFU]或低剂量，3 log PFU）或YF-VAX。为了确定YF预免疫对ChimeriVax-DEN2疫苗效果的影响，14名先前接种过YF疫苗的受试者接受高剂量的ChimeriVax-DEN2作为开放标签疫苗。大多数不良事件与YF-VAX相似，强度为轻度至中度，无严重副作用。分别接种5.0和3.0 log10 PFU ChimeriVax-DEN2的未感染过YF的受试者中，100%和92.3%血清转化为野生型DEN2（16681株）；接种YF-VAX的受试者中92%血清转化为YF 17D病毒，但接种ChimeriVax-DEN2的未感染过YF的受试者中无人血清转化为YF 17D病毒。接种ChimeriVax-DEN2或YF-VAX的未感染过YF的受试者中，对异源DEN血清型1、3和4的血清转化率较低。相比之下，接种ChimeriVax-DEN2的YF免疫受试者中100%血清转化为所有4种DEN血清型。令人惊讶的是，YF免疫受试者中针对DEN 1、2和3病毒的中和抗体水平在1年后仍持续存在。这些数据表明：（1）ChimeriVax-DEN2疫苗的安全性和免疫原性特征与YF-VAX一致；（2）YF病毒的预免疫不干扰ChimeriVax-DEN2免疫，但可诱导对所有4种DEN血清型产生持久的交叉中和抗体反应。后一观察结果对登革疫苗的开发可能具有实际意义。
