Phenotypic and molecular analyses of yellow fever 17DD vaccine viruses associated with serious adverse events in Brazil
Phenotypic and molecular analyses of yellow fever 17DD vaccine viruses associated with serious adverse events in Brazil
复制标题
DOI：
10.1006/viro.2001.1168
复制
发表时间：
2001-11-25
期刊：
影响因子：
3.7
通讯作者：
Monath, TP
中科院分区：
文献类型：
--
作者：
Galler, R;Pugachev, KV;Monath, TP
黄热病（YF）17D病毒是迄今为止开发的最成功的疫苗之一，估计其使用量超过4亿剂，且安全性良好。过去3年，巴西加强了黄热病疫苗接种，以应对该疾病城市暴发的较高风险。报告了两起与 YF 疫苗接种暂时相关的致命不良事件。两例病例均具有与黄热病相似的特征，包括肝炎和多器官衰竭。受影响的患者以及数十万其他个体接种了两批不同批次的 YF 17DD 病毒疫苗，没有报告任何其他严重不良事件。这些批次是由二次种子制备的，自 1984 年以来一直在持续使用。核苷酸测序显示，二次种子批次病毒和从患者身上分离的病毒在某些核苷酸位置上存在微小差异；这些差异在分离株之间不一致，代表异源位置中每个核苷酸相对量的差异，并且不会导致氨基酸取代。通过脑内（ic）或肝内（ih）途径给恒河猴接种从两名患者身上分离出的病毒，导致病毒血症最小，并且没有感染的临床症状或实验室标记物的改变。接种ic的恒河猴中枢神经系统组织学评分在预期范围内，接种ih的动物未出现组织病理学病变。总而言之，这些结果证明了导致两名患者致命疾病的病毒的遗传稳定性和减毒表型。因此，疫苗接种者经历的致命不良事件与调节细胞对黄热病病毒的易感性的个体遗传决定的宿主因素有关。这种易感性增加导致临床上明显的疾病表现似乎极为罕见。 (C) 2001 年学术出版社。
The yellow fever (YF) 17D virus is one of the most successful vaccines developed to date, Its use has been estimated to be over 400 million doses with an excellent record of safety, In the past 3 years, yellow fever vaccination was intensified in Brazil in response to higher risk of urban outbreaks of the disease. Two fatal adverse events temporally associated with YF vaccination were reported. Both cases had features similar to yellow fever disease, including hepatitis and multiorgan failure. Two different lots of YF 17DD virus vaccine were administered to the affected patients and also to hundreds of thousands of other individuals without any other reported serious adverse events. The lots were prepared from the secondary seed, which has been in continuous use since 1984. Nucleotide sequencing revealed minor variations at some nucleotide positions between the secondary seed lot virus and the virus isolates from patients; these differences were not consistent across the isolates, represented differences in the relative amount of each nucleotide in a heterogeneous position, and did not result in amino acid substitutions. Inoculation of rhesus monkeys with the viruses isolated from the two patients by the intracerebral (ic) or intrahepatic (ih) route caused minimal viremia and no clinical signs of infection or alterations in laboratory markers. Central nervous system histological scores of rhesus monkeys inoculated ic were within the expected range, and there were no histopathological lesions in animals inoculated ih. Altogether, these results demonstrated the genetic stability and attenuated phenotype of the viruses that caused fatal illness in the two patients. Therefore, the fatal adverse events experienced by the vaccinees are related to individual, genetically determined host factors that regulate cellular susceptibility to yellow fever virus. Such increased susceptibility, resulting in clinically overt disease expression, appears to be extremely rare. (C) 2001 Academic Press.