Toxicity of human papillomavirus vaccines for Wistar rats following repeated intramuscular administration

ZHOU Xiao-bing; LIN Zhi; WANG Ya-jun; XU Lan; WANG Chao; HUANG Ying; JIANG Hua; MIAO Yu-fa; YANG Yan-wei; WANG Xue; YIN Fei; LIU Yong-jiang; CHEN Jian-ping; LI Bo

Abstract：Objective:To evaluate the preclinical safety of human papillomavirus vaccines (HPV) for preventing cervical cancer.Methods:Rats were randomly divided into four groups according to bodyweight,including control,aluminum adjuvant,low-and high-dose HPV vaccine groups.The animals were intramuscularly given vehicle or test articles on day 1,22,43 and 64 with 4-week recovery.The toxicological parameters were determined on different time points before and after administration.Results:Following repeated intramuscular administration of test articles,there were no obvious abnormalities in clinical symptom,weight,food consumption,temperature,and urinalysis in all groups.Mild increase of neutrophil and WBC counts were found in HPV vaccine-treated groups at the end of dosing period,but they returned to normal levels in the recovery period.No antinuclear antibody was detected in all groups.Three antigen component proteins induced high antibody responses in rats,suggesting these proteins had good immunogenicity.Histopathological examination showed that test article-related findings mainly concentrated at the injection site,sciatic nerve,muscle (skeletal muscles) and inguinal lymph nodes,which were characterized by different levels of granulomatous inflammation,interstitial fibrous tissue hyperplasia,edema,and inflammatory cells infiltration.All histopathological changes were gradually reduced over time.Conclusion:Repeated intramuscular dosing of HPV vaccines was well tolerated in rats,and no obvious toxicological responses were found.The dose without observed adverse effects was two times of human dose.These data will facilitate HPV vaccines to enter into clinical trials.