4种疫苗引起小鼠异常毒性检查中腹膜刺激症状的原因探讨

目的:探讨4种疫苗引起小鼠异常毒性检查中腹膜刺激症状的原因。方法:按照2010年版《中国药典》(三部)"异常毒性检查法"项下规定,除阳性对照组(0.6%冰醋酸溶液)的给药剂量为每只0.2 ml外,其余组剂量均为每只0.5 ml,每组5只小鼠,给药方式为腹腔注射。分别进行甲型肝炎灭活疫苗(简称甲肝疫苗)、重组乙型肝炎疫苗(CHO细胞,简称乙肝疫苗)、流感病毒裂解疫苗(简称流感疫苗)、麻疹风疹联合减毒活疫苗(简称麻疹疫苗)、阴性对照(0.9%氯化钠注射液)、阳性对照的ICR小鼠异常毒性检查;甲肝疫苗、流感疫苗的ICR和昆明种小鼠异常毒性检查;甲肝疫苗、吸附前甲肝疫苗、吸附后甲肝疫苗、氢氧化铝佐剂、0.1%甲醛溶液、阳性对照、阴性对照的ICR小鼠异常毒性检查。观察出现腹膜刺激的动物数、出现时间、消失时间、其他异常表现以及7 d后体质量变化情况。结果:甲肝疫苗、乙肝疫苗和阳性对照均致3⁵只小鼠出现腹膜刺激,出现时间在15只小鼠出现腹膜刺激,出现时间在1¹5 min,消失时间除阳性对照外均在30 min内,麻疹疫苗和阴性对照均未引起腹膜刺激;甲肝疫苗和流感疫苗均致所有ICR和昆明种小鼠出现腹膜刺激,出现时间在115 min,消失时间除阳性对照外均在30 min内,麻疹疫苗和阴性对照均未引起腹膜刺激;甲肝疫苗和流感疫苗均致所有ICR和昆明种小鼠出现腹膜刺激,出现时间在1⁵ min,消失时间在85 min,消失时间在8¹0 min;甲肝疫苗、吸附后甲肝疫苗、氢氧化铝佐剂和阳性对照均致所有小鼠出现腹膜刺激,出现时间在110 min;甲肝疫苗、吸附后甲肝疫苗、氢氧化铝佐剂和阳性对照均致所有小鼠出现腹膜刺激,出现时间在1⁵ min,消失时间除阳性对照外均在12 min内,全部小鼠均无其他异常表现且体质量正常。结论:疫苗中的氢氧化铝佐剂可能是导致小鼠腹膜刺激症状出现的原因。

Investigation of the Reasons for Mice Peritoneal Stimulation Symptom in Abnormal Toxicity Test of 4 Kinds of Vaccines

OBJECTIVE： To investigate the reasons for mice peritoneal stimulation symptom in abnormal toxicity test of 4 kinds of vaccines. METHODS： According to the requirements in volume IU of Chinese Pharmacopoeia （2010 edition）, mice were given intraperitoneal injection of 0.6% glacial acetic acid solution （positive control） 0.2 ml, and intraperitoneal injection of other drugs 0.5 ml with 5 mice in each group. Abnormal toxicity tests of ICR mice were conducted for inactivated hepatitis A vaccine （ab- breviated as hepatitis A vaccine）, recombinant hepatitis B vaccine （CHO cell, abbreviated as hepatitis B vaccine）, influenza virus split vaccine （abbreviated as influenza vaccine）, measles and rubella vaccine （abbreviated as measles vaccine）, negative control （0.9% sodium chloride） and positive control. Abnormal toxicity tests of ICR mice and Kunming mice were conducted for hepatitis A vaccine and influenza vaccine. Abnormal toxicity tests of ICR mice were conducted for hepatitis A vaccine, pre-adsorbed hepati- tis A vaccine, post-adsorbed hepatitis A vaccine, aluminum hydroxide adjuvants, 0.1% formaldehyde, positive control, negative control. The amount of mice suffering from peritoneal stimulation, onset time, disappearance time, other abnormal symptoms and change of body weight were observed. RESULTS： 3-5 mice suffered from peritoneal stimulation in hepatitis A vaccine group, hepa- titis B vaccine group and positive control group, and the symptoms occurred in 1-15 min and lasted for 30 min except for positive control group; no peritoneal stimulation was found in measles vaccine group and negative control group. ICR mice and Kunming mice suffered from peritoneal stimulation in Aimmugen group and influenza vaccine group, and the symptoms occurred in 1-5 min and lasted for 8-10 min. All mice suffered from peritoneal stimulation in hepatitis A vaccine group, post-adsorbed hepatitis A vac- cine group, aluminum hydroxide adjuvants group and positive control group, and the symptoms occurred in 1-5 min and lasted for 12 min except for positive control group. No other abnormal reaction was found in all mice and they were normal in body weight. CONCLUSIONS： Perhaps aluminum hydroxide adjuvant is the main reason of the mice peritoneal stimulation symptom.