水痘减毒活疫苗(SV-1细胞)在食蟹猴体内的长期毒性试验

Long-term toxicity test on live attenuated varicella vaccine(SV-1 cells)in Macaca fascicularis

目的评价水痘减毒活疫苗(SV-1细胞)在食蟹猴体内的长期毒性。方法将50只食蟹猴随机分为5组,分别为阴性对照组(0. 9%氯化钠,2. 5 mL/只)、细胞基质对照组(SV-1细胞基质,5剂/只)、市售疫苗对照组(5剂/只)、供试品低剂量组(1剂/只)和高剂量组(5剂/只),每组10只,雌雄各半。经动物单侧或双侧后肢皮下注射,每点注射量不超过2 mL,每3周给药1次,共3次。观察动物临床表征,并进行体重、体温、心电、血细胞计数、凝血功能、血液生化、尿液、眼科、免疫指标、大体解剖、主要脏器称重、组织病理学等检查。结果各组动物临床表征、体重、体温、心电图参数、眼科检查、血液学、凝血功能、血液生化、尿液分析、T淋巴细胞亚群、细胞因子和PBMCs分泌IFNγ的淋巴细胞斑点数等指标均未见具有毒理学意义的规律性改变。ELISA法测定血清水痘-带状疱疹病毒(varicella-zoster virus,VZV)特异性IgG抗体结果表明,给药后市售疫苗对照组、供试品低剂量组和高剂量组所有动物均可检测到抗体,最高抗体滴度为1∶800,该结果与荧光抗体膜抗原(fluorescent antibody to membrance antigen,FAMA)法检测结果具有可比性。各组动物脏器重量和脏器系数均未见与给药相关改变,组织病理学检查均未见与给药相关的系统毒性病理改变。结论水痘减毒活疫苗(SV-1细胞)在食蟹猴体内未见与其相关的全身毒性反应,安全剂量为5剂/只。

Objective To evaluate the long-term toxicity of live attenuated varicella vaccine in Macaca fascicularis.Methods Fifty M.fascicularis were divided into five groups randomly,ten for each and equal in genders,including negative control(0.9%sodium chloride,2.5 mL),cell matrix control(SV-1 cell matrix,5 doses),commercial vaccine control(5 doses),low dose test vaccine(1 dose)and high dose test vaccine(5 doses)groups.The animals were injected subcutaneously in unilateral or bilateral hind limbs every 3 weeks for 3 times,while the injection volume in each site was not more than 2 mL.The animals were subjected to clinical observation,measurements of bodyweight,body temperature and ECG parameters,blood cell counting,coagulation function,blood biochemical and urine tests,ophthalmic examination,immune index test,gross anatomy,weighing of major organs and histopathological examination.Results No regular changes of toxicological significance were observed in all the groups during the test,including those in clinical observation,body weight,body temperature,ECG parameters,ophthalmic examination,hematology,blood coagulation function,blood biochemistry,urine analysis,T lymphocyte subsets,cytokines and number of spots formed by lymphocytes secreting IFNγin PBMCs.The determination results of specific serum anti-VZV IgG by ELISA showed that antibodies were detected in commercial vaccine control as well as low and high dose test vaccine groups,with the highest of 1∶800,which was consistent with the determination results by FAMA.No changes associated with administration were found in the organ weight or organ coefficient in various groups.Conclusion No systemic toxicity associated with live attenuated varicella vaccine was observed in M.fascicularis,while safe dose was 5 doses per animal.