Segal Lawrence, Morelle Danielle, Kaaber Kari, Destexhe Eric, Garçon Nathalie
GSK Vaccines, Rue de l'Institut, 89, 1330, Rixensart, Belgium.
CiToxLAB Scantox A/S, Hestehavevej, 36A, 4623, Lille Skensved, Denmark.
J Appl Toxicol. 2015 Dec;35(12):1577-85. doi: 10.1002/jat.3131. Epub 2015 Mar 6.
The human papillomavirus (HPV)-16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus-like particles assembled from the L1 major capsid proteins of the cervical cancer-causing viral types HPV-16 and HPV-18, and Adjuvant System 04 (AS04), which contains the immunostimulant MPL and aluminium salt. To evaluate potential local and systemic toxic effects of the HPV-16/18 vaccine or AS04 alone, three repeated-dose studies were performed in rabbits and rats. One rabbit study also included a single-dose evaluation. In rabbits (2.5 kg), the full human dose (HD) of the vaccine was evaluated (0.5 ml per injection site), and in rats (250 g), 1/5 HD of vaccine was evaluated, corresponding to ≥ 12 times the dosage in humans relative to body weight. In both animal models, the treatment-related changes included a slight transient increase in the number of circulating neutrophils as well as a local inflammatory reaction at the injection site. These treatment-related changes were less pronounced after four doses of AS04 alone than after four doses of the HPV-16/18 vaccine. Additional treatment-related changes in the rat included lower albumin/globulin ratios and microscopic signs of inflammation in the popliteal lymph nodes. In both animal models, 13 weeks after the fourth dose, recovery was nearly complete, although at the injection site in some animals there were signs of discoloration, muscle-fibre regeneration and focal points of macrophage infiltration. Therefore, in these non-clinical models, the single and repeated dose administrations of the HPV-16/18 vaccine or AS04 alone were safe and well tolerated.
人乳头瘤病毒（HPV）-16/18疫苗（希瑞适®）是一种预防宫颈癌的预防性疫苗。该疫苗包含由宫颈癌致病病毒类型HPV-16和HPV-18的L1主要衣壳蛋白组装而成的重组病毒样颗粒，以及佐剂系统04（AS04），后者含有免疫刺激剂MPL和铝盐。为了评估HPV-16/18疫苗或单独的AS04的潜在局部和全身毒性作用，在兔和大鼠中进行了三项重复剂量研究。一项兔研究还包括单剂量评估。在兔（约2.5千克）中，评估了疫苗的全人剂量（HD）（每个注射部位0.5毫升），在大鼠（约250克）中，评估了1/5 HD的疫苗，相对于体重，相当于人类剂量的≥12倍。在两种动物模型中，与治疗相关的变化包括循环中性粒细胞数量的轻微短暂增加以及注射部位的局部炎症反应。单独使用四剂AS04后的这些与治疗相关的变化不如使用四剂HPV-16/18疫苗后明显。大鼠中与治疗相关的其他变化包括白蛋白/球蛋白比率降低以及腘窝淋巴结的微观炎症迹象。在两种动物模型中，第四剂后13周，恢复几乎完全，尽管在一些动物的注射部位有变色、肌纤维再生和巨噬细胞浸润焦点的迹象。因此，在这些非临床模型中，单独使用HPV-16/18疫苗或AS04的单剂量和重复剂量给药是安全的且耐受性良好。
