德清县成人乙肝疫苗接种和无应答者复种效果评价及其影响因素分析

发布时间：2018-03-02 16:20

本文选题：乙型肝炎疫苗　切入点：复种　出处：《浙江大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的乙型肝炎是由乙型肝炎病毒(Hepatitis B Virus,HBV)感染引起的可能危及生命的肝脏感染性疾病,是一个严重的全球卫生问题。我国自1992年乙肝疫苗纳入免疫规划后,在降低15岁儿童乙型肝炎表面抗原(Hepatitis B surface antigen,HBsAg)携带率方面取得了巨大的成就,但是成人HBsAg携带率仍然居高不下,成人已经成为乙型肝炎病毒(HBV)新发感染的主要人群。目前,仍然有大量的成人未接种乙肝疫苗,同时成人乙肝疫苗接种后仍有一部分人无应答。成人初次接种乙肝疫苗无应答可能和年龄、性别、(肥胖)BMI≥25 kg/m2、成人伴随疾病等有关,而关于成人无应答人群复种效果及影响因素的独立研究不多。本研究通过对浙江省德清县开展成人乙肝疫苗接种,观察乙肝疫苗初次免疫效果,分析无应答的影响因素,评价成人无应答人群复种1剂次60μg重组乙型肝炎疫苗后的抗体产生水平及疫苗安全性,探讨复种效果的影响因素。为今后制定更加合理的成人乙肝疫苗免疫政策和无应答人群复种措施提供依据。研究方法选取德清县西部莫干镇、中部乾元镇和东部新安镇三个乡镇,每个乡镇各选2个村,选择年龄为16～49周岁,既往未接种过乙肝疫苗者为调查对象。在取得当事人书面知情同意后,由经统一培训的乡镇防保人员按照统一的调查表对调查对象进行询问调查,主要内容包括性别、出生年月和乙肝暴露情况等。调查对象采静脉血5 mL,分离血清后,置低温保存、送检,检测血清乙肝病毒表面抗原(HBsAg)、乙肝病毒表面抗体(抗-HBs)、乙肝病毒核心抗体(抗-HBc)。HBsAg和抗-HBs两项均阴性者纳入为初种对象。研究对象分三组进行乙肝疫苗初次免疫,分别采用:A组0、1、3月免疫程序,B组0、1、6月免疫程序和C组0、1、12月免疫程序,研究对象按免疫程序在上臂三角肌处肌内注射3剂次重组(酵母)乙型肝炎疫苗(简称10 μg乙肝疫苗),在第3剂次乙肝疫苗接种后一个月,采静脉血5 mL检测抗-HBs。乙肝疫苗初次全程接种后1个月检测抗-HBs滴度10.00 mIU/mL者判定为免疫无应答。在知情同意的前提下,初次免疫无应答者纳入为复种研究对象。复种对象在初次免疫完成后一年,在上臂三角肌处肌内注射1剂次60 μg重组乙型肝炎疫苗(酿酒酵母)(简称60μg乙肝疫苗),并在接种现场测量复种对象的身高和体重,接种后1个月采集复种研究对象外周静脉血3ml,检测抗-HBs。乙肝疫苗由浙江省疾病预防控制中心提供,血清-20℃冷冻保存送至杭州市艾迪康医学检验中心检测,采用化学发光法定量检测,应用美国ABBOTT公司ARCHITETi2000化学发光免疫分析仪。血清学检测判定标准:HBsAg≥0.05 mIU/mL为阳性,抗-HBs≥10.00 mIU/mL为阳性,乙肝核心抗体(抗-HBc)≥1.00 mIU/mL为阳性。采用EPiData软件建立数据库,双录入数据,应用SPSS 19.0统计软件对数据进行处理和分析,率的比较采用χ2检验,如果其中有格子的期望频数5采用Fisher精确检验。两组的风险采用多元logistic回归计算OR值及其95%CI来评价。几何平均滴度(geometric means of titer,GMT)比较采用非参数 Mann-Whitney U 检验,GMT趋势检验采用Pearson相关分析;无应答危险因素分析采用非条件Logistic回归分析。研究结果1、乙肝疫苗初次免疫完成初次全程免疫接种689人,抗-HBs阳转率为82.29%(567/689),无应答122人,无应答率17.71%,抗-HBs GMT为75.19 mIU/mL。男女性阳转率分别为82.33%和82.27%,差异无统计学意义(χ2=0.001,P=0.982),男女性的GMT分别为 82.44 mIU/mL 和 70.52 mIU/mL,差异无统计学意义(Z=-0.02,P=0.988)。不同年龄组16～岁、25～岁、30～岁、35～岁、40～49岁抗-HBs阳转率分别为83.02%、85.42%、81.36%、79.69%和81.43%,各年龄组阳转率差异无统计学意义(χ2=1.76,P=0.780);GMT 分别为 107.43 mIU/mL、122.60 mIU/mL、61.48 mIU/mL、53.94mIU/mL、48.67mIU/mL,随着年龄的增高GMT有随之下降的趋势(r=-0.13,P0.001)。多因素Logistic回归分析显示,C组发生乙肝疫苗无应答的危险性是B组的2.09倍(95%CI:1.26～3.46,P=0.004),单项乙肝核心抗体(抗-HBc)阳性发生初次免疫无应答是抗-HBc阴性者的1.73倍(95%CI:1.07～2.80,P=0.026),有手术史发生无应答的危险性是无手术史的1.56倍(95%CI:0.96～2.53,P=0.070)。2、乙肝疫苗复种初次免疫无应答者122人,剔除外出或不愿意接种人群,最终有89人完成1剂次60μg乙肝疫苗接种和免疫后采血。复种1个月后,抗-HBs阳转率为95.51%(85/89),抗-HBs GMT 为 585.39 mIU/mL。其中抗-HBs 滴度≥100 mIU/mL 者占74.16%(66/89)。经χ2检验分析发现,成人再次免疫无应答与BMI有关(P=0.029),BMI≥25kg/m2是危险因素。多因素Logistic回归分析,随着BMI的增加,复种无应答风险有随之增加的趋势,OR值为1.20(P=0.133)。结论成人3剂次10μg乙肝疫苗初次接种可获得较好的免疫应答,但随着年龄的增高GMT有随之下降的趋势。抗-HBc单阳性者初次接种乙肝疫苗免疫应答水平低于抗-HBc阴性人群,复种可以提高其抗体应答率;成人乙肝疫苗接种0、1、3月程序和0、1、6月程序阳转率高于0、1、12月程序,其长期效果需进一步随访。成人常规乙肝疫苗免疫无应答者复种1剂次60μg重组乙型肝炎疫苗,可获得良好的免疫应答,控制体重可能会提高乙肝疫苗的复种免疫效果。
[Abstract]:Hepatitis B is caused by the hepatitis B virus (Hepatitis B, Virus, HBV) infection caused by potentially life-threatening liver infection is a serious global health problem. Since 1992 China's hepatitis B vaccine into immunization programs, 15 year old children in reducing hepatitis B surface antigen (Hepatitis B surface antigen, HBsAg) carrying rate has made great achievements, but the adult HBsAg carrying rate is still high, has become the adult hepatitis B virus (HBV) infection of the main population. At present, there are still a lot of adults without inoculation of hepatitis B vaccine, and adults after hepatitis B vaccination remains a part of non responders. Adult primary inoculation of hepatitis B no vaccine response may and age, gender, BMI = 25 kg/m2 (obesity), with adult diseases, and the effect on adult population and non response cropping due to not many independent research elements. Based on the study of Zhejiang in Deqing County province to carry out adult hepatitis B vaccine, immune effect of hepatitis B vaccine first, analysis of influence factors of non response, and the level of vaccine safety evaluation of adult non response group multiple antibody 1 doses of 60 g after Recombinant Hepatitis B Vaccine, to investigate the factors affecting the effect of cropping. And provide evidence for developing adult hepatitis B vaccination policy more reasonable and non response measures. Methods of multiple cropping populations in Western Deqing County Mo Zhen, Gan Yuan Zhen central and Eastern Xin'an town three townships, each township 2 village, aged 16~49 years of age, who had not been vaccinated with hepatitis B vaccine as the subjects. In obtaining written informed consent after the parties and by the trained personnel of township to survey questionnaire according to the questionnaire, the main contents include gender, year of birth April and exposure. The survey of hepatitis B 5 mL venous blood, serum separation after the cryopreservation, inspection, detection of serum hepatitis B virus surface antigen (HBsAg), hepatitis B virus surface antibody (anti -HBs), hepatitis B virus core antibody (anti -HBc) and anti.HBsAg -HBs two were negative into early the object of study. Subjects were divided into three groups of hepatitis B vaccine immunization, immunization programs were carried out: A group 0,1,3 month, 0,1,12 month B immunization program immunization program and C group 0,1,6 group, the research object according to the immune program in the upper arm deltoid intramuscular injection of 3 doses of heavy group (yeast) hepatitis B vaccine (referred to as 10 g, a month) of hepatitis B vaccine in third doses of hepatitis B vaccine, venous blood 5 mL detection of anti -HBs. vaccine of hepatitis B vaccination in 1 months after the initial detection of anti -HBs titer of 10 mIU/mL were judged as no immune response. On the premise of informed consent, without immunization The respondents included as the research object. The object in multiple cropping a year after the completion of the first immunization, 1 doses of 60 g Recombinant Hepatitis B Vaccine injection in the upper arm deltoid muscle (Saccharomyces cerevisiae) (referred to as 60 g of hepatitis B vaccine), and height and weight measurements in multiple cropping object inoculation site, venous blood 3ml after inoculation of 1 collected cropping on peripheral -HBs., detection of anti hepatitis B vaccine provided by the Zhejiang Provincial Center for Disease Control and prevention, serum -20 C cryopreservation to ADICON clinical laboratories in Hangzhou detected by chemiluminescence quantitative detection, using the United States ABBOTT company ARCHITETi2000 chemiluminescence immunoassay analyzer. Standard serological detection: HBsAg = 0.05 mIU/mL positive anti -HBs was greater than 10 mIU/mL positive, hepatitis B core antibody (anti -HBc) for more than 1 mIU/mL respectively. The database was established by EPiData software, the double input data, using SPSS 19 .0 statistical software for data processing and analysis, were compared by the 2 test, if the expected frequency which has 5 lattice using Fisher's exact test. The risk of the two groups using multivariate logistic regression to calculate the value of OR and 95%CI. To evaluate the geometric mean titer (geometric means of titer, GMT) compared with non parametric Mann-Whitney U GMT test, trend test analysis using Pearson correlation analysis; Logistic regression analysis of risk factors of non response. Results: 1, hepatitis B vaccine immunization completed the initial vaccination of 689 people, the anti -HBs positive seroconversion rate was 82.29% (567/689), no response in 122, no response rate 17.71%, anti -HBs GMT 75.19 mIU/mL. and seroconversion rates were 82.33% and 82.27%, the difference was not statistically significant (2=0.001, P=0.982), and GMT were 82.44 mIU/mL and 70.52 mIU/mL, there was no statistically significant difference (Z=-0.0 2, P=0.988). Different age groups aged 16 ~ 25 years old, 30 years old ~ ~, ~ 35 years old, 40~49 years old, anti -HBs positive rates were 83.02%, 85.42%, 81.36%, 79.69% and 81.43%, the seroconversion rate of each age group showed no significant difference (2=1.76, P=0.780); GMT = 107.43 mIU/mL, 122.60 mIU/mL, 61.48 mIU/mL, 53.94mIU/mL, 48.67mIU/mL, GMT increased with age has decreased trend (r=-0.13, P0.001). Logistic regression analysis showed that C group had no response to hepatitis B vaccine risk is 2.09 times more than that of B group (95%CI:1.26 3.46, P= 0.004), single hepatitis B core antibody (anti -HBc) positive primary immune non response is 1.73 times the anti -HBc negative (95%CI:1.07 - 2.80, P=0.026), a history of operation risk of non response is 1.56 times of surgery (95%CI:0.96 - 2.53,.2, P=0.070) without response to hepatitis B vaccine in immunization in 122 people, excluding out or Not willing to receive the crowd, the final 89 people completed the 1 dose 60 g of hepatitis B vaccination and immune blood. In 1 months after the anti -HBs positive seroconversion rate was 95.51% (85/89), anti -HBs GMT 585.39 mIU/mL. the titer of anti -HBs was greater than 100 mIU/mL accounted for 74.16% (66/89) by 2. The analysis showed that the adult again no immune response associated with BMI (P=0.029), BMI = 25kg/m2 are risk factors. Multivariate Logistic regression analysis, with the increase of BMI, multiple non response to be increased risk, the value of OR was 1.20 (P=0.133). Conclusion the adult 3 doses of hepatitis B vaccine at 10 g vaccination can obtain better immune response, but with the increase of age GMT has decreased trend. Anti -HBc positive initial inoculation of hepatitis B vaccine immune response level was lower than that of anti -HBc negative population, multiple cropping can improve the antibody response rate; adult hepatitis B vaccination program 0,1,3 months and 0,1,6 months The positive conversion rate of program is higher than that of 0,1,12 month program, and its long-term effect needs further follow-up. Adults with routine hepatitis B vaccine immunization and non responders revaccination 1 doses of 60 g g can get good immune response. Controlling body weight may improve the immune effect of multiple vaccination of hepatitis B vaccine.

【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R186

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