A Preliminary Study On Post-marketing Safety Of Preventive Human Papillomavirus Vaccine

Objective: Human Papilloma Virus(HPV)vaccination is an important measure to prevent diseases caused by HPV,especially in preventing cervical cancer in women.Vaccines,as special medicines,also have safety problems.This study intends to research the safety of preventive HPV vaccine by the methods of evidence-based medicine,data mining and causality assessment,to provide the reference in Vaccine Pharmacovigilance.Methods: 1.According to the evidence-based medicine method of PICOS,we search literatures about preventive HPV vaccination safety in Pubmed,Springer,Web of science,China National Knowledge Infrastructure(CNKI)and Wanfang Data from the establishment to December 2019.We screen the literatures according to the exclusion criterias,extract the data about adverse event(AE)and analysis these AE data in literatures.2.(1)Based on the AEs reported in these literatures,we used the Bayesian Confidence Propagation Neural Network(BCPNN)algorithm to detecte signals about these AEs in the Vaccine Adverse Event System(VAERS),which covers the period from the time of marketed to 2019.(2)From different levels of the Standard MedDRA query(SMQ)and preferred term(PT),we focuse on the common signals of various preventive HPV vaccines.3.The signal correlation intensity evaluation was performed on the new verify the signal stability and association strength.We select a known ADR to verify the method of CISA.As for strong association signal,we assessed the causality by the method of The Clinical Immunization Safety Assessment(CISA)collaboration network.Results: 1.In our research,there were 53 articles included,which were 48 observational researches,and 5 post marketing clinical trails.In addition,there were 20 literatures for HPV2,30 literatures for HPV4,1 literature for HPV9,4 literatures for unknown vaccine types.We found 254 kinds of AEs including: myasthenia gravis,systemic lupus erythematosus,tubulointerstitial nephritis,uveitis syndrome,fibromyalgia-like disease,acquired nerve rigidity,premature menopause,hair loss,idiopathic thrombocytopenia Purpura,interstitial lung disease,erythema polymorpha,autoimmune disease,spontaneous abortion,Guillain-Barre syndrome,congenital abnormalities,etc.2.(1)In the VAERS database,from 2006 to 2019,VAERS received a total of 481 265 AE reports,in which 36 693 were AE reports for HPV4.From 2009 to 2019,VAERS had a total of 405 965 reports,and HPV2 was 253.From 2015 to 2019,VAERS received 225,403 reports,and HPV9 had 12,118 reports.There was no " bivalent human papilloma virus vaccine " AE report.HPV2 detected 7 safety signals,which involved 4 system organ classes(SOC).There are 4 signals were included in the table,which including headache,dizziness,dysmenorrhea,etc.HPV4 detected a total of 51 signals,23 of which are included in the manual and related to 18 SOCs.The signals covered syncope,irregular menstruation,amenorrhea,blurred vision etc.HPV9 detected a total of 24 safety signals,involving 8 SOCs.Five signals were included in tabel,which were syncope,dizziness,dysmenorrhea,vomiting,abdominal pain.(2)Presyncope and vision blurred were the common signals for HPV2,HPV4 and HPV9.And retinal disorders detected as a signal for them in the level of SMQ.3.Signal intensity analysis showed that HPV4-amenorrhea was a strong association signal,and time scan map indicated that the signal was stable and strong association.We choose the repoerts of syncope associated with HPV4 to verify CISA.The results indicated that 85.19% of "HPV4-syncope" reports with a " consistent with " relationship,suggesting the method was reliable.Among the 162 adverse event reports about HPV4-amenorrhea,2 reports were "consistent with" relationship,2 were " inconsistent with " relationship,and 158 was " indeterminate " relationship.Conclusion: This study evaluated the safety of preventive HPV vaccine in post-marketing experience from three levels,which were safety literature analysis,data mining and signal detection evaluation,and preliminary causality evaluation.Literature analysis found that HPV had 254 kinds of AEs and 82 safety signals.We should focus on these signals,especially strong association signal.We found amenorrhea as a strong association signal for HPV4,and two case with a "consistent with" relationship.Moreover,further study is suggested to research the causality between preventive HPV vaccine and signals.This study provides a new evidence for the safety information update of preventive HPV vaccine and provides a new direction and ideas for the safety research of vaccines after marketing.