【作者】 刘倩；

【导师】 朱凤才；

【作者基本信息】 东南大学 ， 公共卫生与预防医学， 2024， 硕士

【摘要】 研究目的:本研究旨在分析和比较5种不同技术路线的2019冠状病毒病(Coronavirus disease 2019,COVID-19)疫苗的不良反应特征,主要探讨COVID-19疫苗类型、人口学特征与不良反应发生率之间的联系,探索不同COVID-19疫苗不良反应的发生模式,综合评估不同技术路线COVID-19疫苗的安全性。研究方法:本研究数据来自江苏省疾病预防控制中心主持的9项COVID-19疫苗临床试验的安全性数据,共包括5种不同技术路线的COVID-19疫苗,即灭活疫苗,重组蛋白疫苗,鼻喷流感病毒载体疫苗,腺病毒载体疫苗(肌注)以及腺病毒载体疫苗(吸入)。(1)通过统计描述,展现不同COVID-19疫苗试验组的不良反应发生类型、发生率和严重程度。(2)根据监管活动医学词典(Medical Dictionary for Regulatory Activities,Med DRA)26.1版本对不良反应编码,从系统器官分类(System Organ Class,SOC)层面上对5种COVID-19疫苗的不良反应特征进行描述。(3)根据性别、年龄、身体质量指数(Body Mass Index,BMI)以及有无合并疾病等人口学特征,比较不同人群的不良反应发生率。(4)建立logistic回归模型,校正不良反应的发生剂次,评估人口学特征对不良反应发生风险的影响,计算相对危险度(Relative Risk,RR)及其95%置信区间(Confidence Interval,CI)。(5)分别选取5种COVID-19疫苗中发生率最高的前10种不良反应类型,计算各不良反应类型在每种疫苗接种后24小时内、1-7天内的每天以及第7天以后的不良反应发生率,应用主成分分析识别不良反应类型与疫苗类型之间的关联。(6)采用关联规则探索“不良反应类型→不良反应类型”、“不良反应类型→性别”、“不良反应类型→年龄组”之间的发生模式。研究结果:(1)本研究共纳入13341名COVID-19疫苗受试者,包括灭活疫苗组1184人,重组蛋白疫苗组925人,鼻喷流感病毒载体疫苗组485人,腺病毒载体疫苗(肌注)组454人以及腺病毒载体疫苗(吸入)组10293人。共2240名受试者报告了107种(5535例次)不良反应。其中,82.47%的不良反应分级为1级。总体不良反应发生率为16.79%(95%CI,16.16%-17.44%),5种疫苗不良反应发生率分别为22.55%(95%CI,20.20%-25.04%)、20.65%(95%CI,18.08%-23.40%)、21.03%(95%CI,17.49%-24.93%)、76.65%(95%CI,72.48%-80.47%)和16.79%(95%CI,16.16%-17.44%)。(2)总体不良反应主要集中在5大系统器官分类上,即全身性疾病及给药部位各种反应(2112;38.16%),呼吸系统、胸及纵隔疾病(1280;23.13%),胃肠系统疾病(860;15.54%),各类神经系统疾病(605;10.93%)与各种肌肉骨骼及结缔组织疾病(381;6.88%)。以肌肉注射为免疫途径的COVID-19疫苗,全身性疾病及给药部位各种反应发生率最高。以鼻喷和雾化吸入为免疫途径的COVID-19疫苗,呼吸系统、胸及纵隔疾病类不良反应发生率最高。(3)单因素分析结果显示,在接种疫苗的总人群中,女性不良反应发生率高于男性(18.35%vs 15.46%,P<0.05);划分适当年龄区间,不良反应发生率随年龄的增加而下降(P<0.001);以BMI小于18.5 kg/m~2为偏瘦,18.5～25 kg/m~2为正常,大于等于25 kg/m~2为超重,不良反应发生率随BMI等级的增加而下降(P<0.001);有合并疾病的人群发生不良反应风险与没有合并疾病的人群相似(16.54%vs 15.81%,P>0.05)。(4)Logistic回归结果显示,5种COVID-19疫苗中以灭活疫苗为参照,接种腺病毒载体疫苗(肌注)的受试者不良反应发生率最高,RR值为11.405(95%CI,8.820-14.747),接种腺病毒载体疫苗(吸入)的受试者发生不良反应的风险最低,RR为0.569(95%CI,0.489-0.662)。在接种COVID-19疫苗的总人群中,以男性为参照,女性不良反应发生率更高,RR值为1.177(95%CI,1.069-1.295);以18～59岁人群为参照,60岁及以上人群不良反应发生率较低,RR值为0.707(95%CI,0.632-0.791);以BMI偏瘦人群为参照,正常和超重人群发生不良反应的风险较低,RR值分别为0.700(95%CI,0.499-0.984)和0.633(95%CI,0.450-0.889);以没有合并疾病的人群为参照,有合并疾病的人群不良反应发生风险更高,RR为1.587(95%CI,1.412-1.783)。(5)主成分分析显示,前3个主成分解释了88.43%的总方差,这3个主成分所代表的不良反应合并发生率在不同免疫途径的COVID-19疫苗中发生率不同。第一主成分涵盖了以下不良反应类型:疫苗接种部位疼痛、红斑、肿胀、瘙痒、咳嗽、口咽疼痛、恶心、腹泻、头痛、发热、关节痛、食欲减退、肌痛及疲劳。这些不良反应的合并发生率在以肌肉注射为免疫途径的COVID-19疫苗中发生率较高。第二主成分捕捉到的不良反应类型包括“鼻塞、喷嚏、头晕和流涕”,这4种不良反应类型在鼻喷流感病毒载体疫苗中发生率最高;第三主成分则显示了雾化吸入方式接种的腺病毒载体疫苗中独有的不良反应类型“咽部肿胀和口干”。(6)关联规则结果显示,不同COVID-19疫苗不良反应类型之间发生模式各有不同。在灭活疫苗和重组蛋白疫苗中均发现“疫苗接种部位硬结→疫苗接种部位红斑”,其提升度分别为17.12和13.37。腺病毒载体疫苗(肌注)中发现“疫苗接种部位硬结→疫苗接种部位肿胀”,其提升度为3.35。腺病毒载体新冠疫苗(吸入)中发现“流涕→喷嚏”和“咽部肿胀→口咽疼痛”,其提升度分别为5.44和4.11。探索不良反应类型与性别之间的关联模式时,在新冠灭活疫苗和重组蛋白新冠疫苗中均发现“疫苗接种部位硬结→女性”和“疫苗接种部位红斑→女性”。在新冠灭活疫苗中发现“腹泻→男性”,提升度为1.78。在重组蛋白新冠疫苗中发现“腹痛→男性”,提升度为2.48。探索不良反应类型与不同年龄层人群之间的关联模式时,在以肌肉注射为免疫途径的新冠灭活疫苗、重组蛋白新冠疫苗和腺病毒载体新冠疫苗(肌注)中均发现“疫苗接种部位红斑→18～59岁”、“疫苗接种部位肿胀→18～59岁”、“疫苗接种部位硬结→18～59岁”。研究结论:本研究通过分析5种不同技术路线的COVID-19疫苗不良反应特征,发现相对于其他COVID-19疫苗,腺病毒载体疫苗(肌注)表现出更高的不良反应发生率,而腺病毒载体疫苗(吸入)不良反应发生率较低。女性、年龄低于60岁、BMI小于18.5kg/m~2和存在合并疾病是不良反应发生的危险因素。此外,本研究通过主成分分析揭示了不良反应类型与COVID-19疫苗类型之间潜在联系,通过关联规则探索了不良反应的发生模式,为COVID-19疫苗的安全性评估和监测提供了新的参考价值。更多还原

【Abstract】 Objective:This study aims to analyze and compare the adverse reaction characteristics of five different technological platforms of Coronavirus disease 2019(COVID-19)vaccines.It primarily explores the connections between vaccine types,demographic characteristics,and adverse reaction rates.The study seeks to investigate the patterns of adverse reactions associated with different COVID-19 vaccines and comprehensively assess the safety of COVID-19 vaccines developed through various technological platforms.Methods:This study utilizes safety data from nine COVID-19 vaccine clinical trials conducted by the Jiangsu Provincial Center for Disease Control and Prevention,involving five different technological platforms:inactivated vaccines,recombinant protein vaccines,intranasal influenza-vectored vaccines,adenovirus type-5 vector-based vaccines(intramuscular injection),and adenovirus type-5 vector-based vaccines(aerosolized inhalation).(1)Descriptive statistics is used to present the types,incidence rates,and severity of adverse reactions in different COVID-19 vaccine groups.(2)Adverse reactions are coded according to the Medical Dictionary for Regulatory Activities(Med DRA)Version 26.1,and described at the System Organ Class(SOC)level for all five types of COVID-19 vaccines.(3)Compare the incidence rates of adverse reactions among different demographics,including gender,age,Body Mass Index(BMI),and comorbidities.(4)A logistic regression model is used to adjust the incidence doses of adverse reactions,evaluate the effects of various demographic factors on the risk of adverse reactions,and compute the relative risks(RR)along with their 95%Confidence Intervals(CI).(5)The top ten most frequent adverse reactions for each of the five types of vaccines are selected to calculate the incidence rates of these reactions within 24 hours,1-7days daily,and beyond the 7th day post-vaccination,using principal component analysis to identify associations between vaccine types and adverse reactions.(6)Association rule mining is used to explore the patterns between"adverse reaction type→adverse reaction type","adverse reaction type→gender",and"adverse reaction type→age group".Results:(1)This study includes 13341 COVID-19 vaccine recipients,1184 in the inactivated vaccine group,925 in the recombinant protein vaccine group,485 in the intranasal influenza-vectored vaccine group,454 in the adenovirus type-5 vector-based vaccine(intramuscular injection)group,and 10,293 in the adenovirus type-5 vector-based vaccine(aerosolised inhalation)group.A total of 2240 participants reported 107 types of adverse reactions(5535instances),with 82.47%classified as Grade 1.The overall incidence rate of adverse reactions is 16.79%(95%CI,16.16%-17.44%).The incidence rates of adverse reactions for the vaccines were as follows:22.55%(95%CI,20.20%-25.04%),20.65%(95%CI,18.08%-23.40%),21.03%(95%CI,17.49%-24.93%),76.65%(95%CI,72.48%-80.47%)and 16.79%(95%CI,16.16%-17.44%).(2)The majority of adverse reactions are concentrated within five major SOCs:systemic disorders and administration site conditions(2,112;38.16%),respiratory,thoracic,and mediastinal disorders(1,280;23.13%),gastrointestinal disorders(860;15.54%),nervous system disorders(605;10.93%),and musculoskeletal and connective tissue disorders(381;6.88%).Vaccines administered via intramuscular injection had the highest rates of systemic and administration site reactions,while those administered via nasal spray and aerosolised inhalation had the highest rates of respiratory,thoracic,and mediastinal disorders.(3)Univariate analysis results show in the overall vaccinated population,females experience a higher incidence rate of adverse reactions than males(18.35%vs 15.46%,P<0.05).Adverse reaction rates decrease with increasing age(P<0.001).According to the World Health Organization’s standards for adult BMI,those under 18.5 kg/m^2 are underweight,those between 18.5 and 25 kg/m^2 are normal weight,and those more than or equal to 25 kg/m^2 are overweight;the incidence rate of adverse reactions decreases with increasing BMI(P<0.001).The risk of adverse reactions in individuals with comorbidities is similar to those without comorbidities(16.54%vs 15.81%,P>0.05).(4)Logistic regression results show that among the five COVID-19 vaccines,participants receiving the adenovirus type-5 vector-based vaccine(intramuscular injection)face the highest risk of adverse reactions,with an RR of 11.405(95%CI,8.820-14.747).Those receiving the adenovirus type-5 vector-based vaccine(aerosolised inhalation)exhibit the lowest risk,with an RR of 0.569(95%CI,0.489-0.662).Comparing males to females,the latter show a higher incidence rate of adverse reactions,with an RR of1.177(95%CI,1.069-1.295).Comparing the 18-59 age group to those 60 and older,the older group has a lower incidence rate,with an RR of 0.707(95%CI,0.632-0.791).Comparing underweight individuals to those of normal weight and overweight,the latter groups face lower risks of adverse reactions,with RRs of 0.700(95%CI,0.499-0.984)and 0.633(95%CI,0.450-0.889),respectively.Comparing individuals without comorbidities to those with them,the latter group experiences a higher risk of adverse reactions,with an RR of 1.587(95%CI,1.412-1.783).(5)Principal component analysis reveals that the first three principal components explain 88.43%of the total variance,representing different rates of combined adverse reactions across various immunization routes for COVID-19 vaccines.The first principal component captures adverse reactions including"cough,pain,erythema,swelling and itching at the vaccination site,pharyngeal pain,nausea,diarrhea,headache,fever,joint pain,appetite loss,myalgia,and fatigue,"which are particularly prevalent in COVID-19 vaccines administered via intramuscular injection.The second principal component identifies"nasal congestion,sneezing,dizziness,and rhinorrhea,"with the highest occurrence in the intranasal influenza-vectored vaccine.The third component highlights unique adverse reactions"pharyngeal swelling and dry mouth"in the aerosolized adenovirus vector-based vaccine.(6)Association rule results demonstrate different patterns of adverse reactions among the COVID-19 vaccines.In the inactivated and recombinant protein vaccine groups,the rule"vaccination site induration→vaccination site erythema"is identified,with lift values of 17.12 and 13.37,respectively.In the adenovirus vector-based vaccine(intramuscular injection)group,"vaccination site induration→vaccination site swelling"is found,with a lift value of 3.35.In the adenovirus vector-based vaccine(aerosolised inhalation)group,"rhinorrhea→sneezing"and"throat swelling→sore throat"are discovered,with lift values of 5.44 and 4.11,respectively.This study also explores the patterns of association between adverse reaction types and gender,finding"vaccination site induration→female"and"vaccination site erythema→female"in both the inactivated and recombinant protein vaccine groups.Additionally,"diarrhea→male"is identified in the inactivated vaccine group with a lift value of 1.78,and"abdominal pain→male"in the recombinant protein vaccine group with a lift value of 2.48.When exploring the patterns of association between adverse reaction types and different age groups,"vaccination site erythema→18-59 years,""vaccination site swelling→18-59 years,"and"vaccination site induration→18-59 years"are found in the inactivated,recombinant protein,and adenovirus vector-based vaccine(intramuscular injection)groups.Conclusion:This study analyzes the characteristics of adverse reactions to five different technological platforms of COVID-19 vaccines and finds the adenovirus type-5 vector-based vaccine(intramuscular injection)exhibited a higher risk of adverse reactions compared to other vaccines,while the adenovirus type-5 vector-based vaccine(aerosolised inhalation)demonstrated a lower risk.Factors such as being female,under 60 years of age,and having a BMI<18.5 kg/m^2 were identified as risk factors for the occurrence of adverse reactions.Furthermore,principal component analysis reveals potential links between types of adverse reactions and vaccines and association rule mining explores patterns of adverse reactions,offering new insights for the safety assessment and monitoring of COVID-19 vaccines.更多还原