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迈向替代无细胞百日咳疫苗安全性测试:体外细胞毒性活性和体内活性在小鼠中的比较。

Towards replacement of the acellular pertussis vaccine safety test: Comparison of in vitro cytotoxic activity and in vivo activity in mice.

机构信息

Division of Bacterial, Parasitic and Allergenic Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.

出版信息

Vaccine. 2017 Dec 18;35(51):7160-7165. doi: 10.1016/j.vaccine.2017.10.082. Epub 2017 Nov 6.

Abstract

Because of the exquisite sensitivity of the murine histamine sensitization test (HIST) in detecting minute amounts of active pertussis toxin (PTx), this animal-based test has been used to assure the safety of acellular pertussis vaccines in the United States and other countries around the world. Prompted by humane considerations, efforts are underway to find a suitable in vitro replacement assay that has critical attributes comparable to that of the HIST. In this study, we compared the sensitivity of the in vivo HIST with an in vitro Chinese Hamster Ovary (CHO) cell-based assay. Using vaccine samples that had been spiked with PTx, we found that both assays were capable of detecting as little as 4-10 ng of active pertussis toxin per dose of vaccine; thus, the sensitivities of the two assays are comparable. Because the strength of adsorption of PTx to the vaccine adjuvant could change over time, we also used both assays to examine the bioavailability of PTx in spiked vaccine samples that had been stored at 25 °C for 9 weeks, mimicking long term vaccine storage conditions. We found that both assays detected similar amounts of active PTx in these samples, indicating that bioavailability of the toxin in stored samples was similar. Taken together, our results indicate that critical attributes of the HIST are met by the CHO cell assay used in this study and provide proof of concept that the CHO cell assay may be further considered as a replacement for the in vivo HIST.

摘要

由于鼠类组胺致敏试验(HIST)在检测微量活性百日咳毒素(PTx)方面具有极高的灵敏度,因此该动物试验已被用于确保无细胞百日咳疫苗在美国和世界其他国家的安全性。出于人道考虑,人们正在努力寻找一种合适的体外替代检测方法,该方法具有与 HIST 相当的关键属性。在这项研究中,我们比较了体内 HIST 的灵敏度和体外中国仓鼠卵巢(CHO)细胞测定法的灵敏度。使用添加了 PTx 的疫苗样本,我们发现两种检测方法均能够检测到每剂疫苗中低至 4-10ng 的活性百日咳毒素;因此,两种检测方法的灵敏度相当。由于 PTx 对疫苗佐剂的吸附强度可能随时间而变化,我们还使用两种检测方法来检测在 25°C 下储存 9 周的添加疫苗样本中 PTx 的生物利用度,模拟长期疫苗储存条件。我们发现两种检测方法在这些样本中均检测到了相似量的活性 PTx,表明储存样本中毒素的生物利用度相似。综上所述,我们的研究结果表明,本研究中使用的 CHO 细胞检测法符合 HIST 的关键属性,并为 CHO 细胞检测法可进一步考虑替代体内 HIST 提供了概念验证。

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