冻干人用狂犬病疫苗(Vero细胞)非临床安全性研究  

Non-clinical safety of freeze-dried rabies vaccine (Vero cell) for human use

作　　者：梁婧 刘佐兵 田义超 杨莹 徐晓 王玲 王玥 林弦 曹烨 刘翠丽 金文芳 杜洪桥 Liang Jing;Liu Zuobing;Tian Yichao;Yang Ying;Xu Xiao;Wang Ling;Wang Yue;Lin Xian;Cao Ye;Liu Cuili;Jin Wenfang;Du Hongqiao(Research and Development Department,Wuhan Institute of Biological Products Co.,Ltd,Wuhan 430207,China;Hubei Topgene Biotechnology Co.,Ltd.,Wuhan branch,Wuhan 430075,China)

机构地区：[1]武汉生物制品研究所有限责任公司科研开发部,武汉430207 [2]湖北天勤生物科技有限公司武汉分公司,武汉430075

出　　处：《国际生物制品学杂志》2023年第6期307-314,共8页International Journal of Biologicals

摘　　要：目的对冻干人用狂犬病疫苗(Vero细胞)进行动物肌内单次给药毒性、肌内重复给药毒性伴随局部刺激性和免疫原性、主动全身过敏性评价,以考察其安全性。方法采用ICR小鼠肌内注射单次给药毒性试验评价制品的急性毒性;采用SD大鼠和食蟹猴肌内注射6周重复给药毒性伴随局部刺激性、免疫原性试验评价制品的长期毒性;采用豚鼠主动全身过敏试验评价制品的致敏性。结果ICR小鼠单次肌内注射,所有动物未见与疫苗相关的异常反应,疫苗的最大耐受量>125国际单位(international unit,IU)/kg,为临床拟用剂量的3472.2倍,等效剂量的268.8倍;除伴随的轻度局部刺激反应外,SD大鼠6周重复给药毒性伴随局部刺激试验和免疫原性试验的安全剂量为37.5 IU/kg,为临床拟用剂量的1041.7倍,等效剂量的182.0倍;食蟹猴最大无毒性反应剂量为1.875 IU/kg,是临床拟用剂量的52.1倍,等效剂量的18.0倍;疫苗剂量为0.1剂(0.05 ml/只)和1剂(0.5 ml/只)时,豚鼠主动全身过敏反应结果均为阳性。结论冻干人用狂犬病疫苗(Vero细胞)显示出良好的安全性,但肌内给药可能引起过敏反应,临床应用需密切关注。Objective To evaluate the safety of freeze-dried rabies vaccine(Vero cell)for human use by animal single intramuscular administration toxicity,repeated intramuscular administration toxicity accompanied by local irritation and immunogenicity,and active systemic anaphylaxis test.Methods Acute toxicity was evaluated by single intramuscular injection in ICR mice.Long-term toxicity was evaluated by 6-weeks repeated dose toxicity test accompanied by local irritation and immunogenicity tests in SD rats and cynomolgus monkey by intramuscular injection.Allergenicity of the vaccine was evaluated by the active systemic anaphylaxis test in guinea pigs.Results After a single intramuscular injection,no abnormality associated with the vaccine was observed in all ICR mice,and the maximum tolerated dose was>125 international unit(IU)/kg,which was 3472.2 times of the clinical intended dose and 268.8 times of the equivalent dose.Regardless of the accompanying mild local stimulus response,the safe dose for SD rats in 6-week repeated dose toxicity test accompanied by local irritation and immunogenicity test was 37.5 IU/kg,which was 1041.7 times of the clinical intended dose and 182.0 times of the equivalent dose.The no observed adverse effect level of the vaccine in cynomolgus monkey was 1.875 IU/kg,which was 52.1 times of the clinical dose,and 18.0 times of the equivalent dose.Both 0.1 dose(0.05 ml per guinea pig)and 1 dose(0.5 ml per guinea pig)of the vaccine caused positive results of active systemic anaphylaxis in guinea pigs.Conclusion Freeze-dried rabies vaccine(Vero cell)for human use have good safety,but muscle administration may cause anaphylaxis which needs close attention in clinical application.

关 键 词：狂犬病疫苗 VERO细胞 非临床安全性 肌内单次给药毒性 肌内重复给药毒性 主动全身过敏性 

分 类 号：R392-33[医药卫生—免疫学]