乙型肝炎疫苗远期免疫效果研究及慢性感染后HBeAg血清学转换

发布时间：2018-04-05 03:42

本文选题：乙型肝炎病毒　切入点：疫苗　出处：《复旦大学》2013年硕士论文

【摘要】：目的 1综合抗体衰减、免疫记忆以及保护感染等指标综合评价乙型肝炎疫苗的远期免疫效果。 2观察自然无干预状态下,HBsAg/HBeAg双阳性的病毒携带者HBeAg年血清转换率。 3应用meta分析估算有/无抗病毒治疗情况下,慢性乙肝患者HBeAg血清转换率。方法 1乙型肝炎疫苗的远期免疫效果研究 (1)对上海市南市区(现为黄浦区)1986年出生并全程及时接种乙肝疫苗的新生儿进行纵向队列研究,定期进行血清学随访,检测HBsAg.抗-HBs和抗-HBc,观察抗体衰减与保护感染效果。 (2)在乙肝疫苗免疫效果观察的河北省正定县监测点采集1986年出生的全程接种乙肝血源性疫苗人群的全血样本,同时进行疫苗加强与病毒性肝炎病史调查。采用美国雅培Architect i2000SR系统(Abbott,Abbott Park, IL, USA)检测乙型肝炎HBsAg、抗-HBs和抗-HBc,根据抗-HBs检测结果,分为抗体阳性与抗体阴性两组,采用流式细胞术和Fluorospot法检测免疫记忆细胞及其功能。 2乙型肝炎病毒携带者HBeAg自然血清转换率的纵向队列研究通过1999年、2005年、2006年对河北正定县两个乡8个村全体村民陆续进行的病毒性肝炎普查,筛选出HBeAg阳性慢性乙肝病毒携带者172人,建立HBsAg/HBeAg双阳性慢性乙肝病毒携带者研究队列。于2010年、2012年进行血清学随访,检测乙型肝炎两对半,以及转氨酶,并调查用药情况。 3慢性乙型肝炎患者HBeAg血清学转换的系统综述采用Meta分析方法,检索PubMed、SinoMed与CNKI数据库,纳入发表于2012年9月以前,提供HBeAg血清转换率数据的文献。由两名研究人员独立筛选文献,评价质量和提取数据,以HBeAg血清转换率为研究指标,采用meta方法,分别估计应用抗病毒治疗和无抗病毒治疗情况下,慢性乙型肝炎患者的HBeAg血清转换率。结果 1乙型肝炎疫苗的远期免疫效果研究 (1)持续随访南市区1986年出生队列23年,抗-HBs阳性率随免疫时间延长逐渐下降,自免后1年的89.0%降至免后23年的18.8%,但抗-HBc各年阳性率基本维持在2%以下,同时,HBsAg阳性率保持在1.0%(0.5-0.9%)以下。 (2)疫苗免后23年无论抗-HBs阳性或阴性,采用流式细胞术和Fluorospot法均可检测到特异性免疫记忆T细胞,但CD4+/IFN-γ+细胞水平在抗体阳性组为高。 2乙型肝炎病毒健康携带者HBeAg自然血清转换率的纵向队列研究经2010、2012年两次随访,检测到HBeAg阴转32例,平均人年阴转率为2%(95%CI：1.4-2.8%)；其中26例发生HBeAg血清学转换,平均人年转换率为1.6%(95%CI：1.1-2.4%)。 3慢性乙型肝炎患者HBeAg血清学转换的Meta分析共纳入501篇文献,其中中文305篇,英文196篇。研究地点分别在中国,美国等全球多个国家,发表语种为中文和英文。Meta分析结果显示,无抗病毒治疗组的HBeAg血清年自然转换率为7.9%(95%CI：6.3-9.5%)；不同抗病毒药物按标准疗程治疗1年的meta分析结果显示：阿德福韦治疗1年HBeAg血清转换率为14.3%(95%CI：13.0-16.1%),恩替卡韦治疗1年HBeAg血清年转换率为19.6%(95%CI：12.3-26.8%),拉米夫定治疗1年HBeAg血清年转换率为20.8%(95%CI：18.5-23.1%),替比夫定治疗1年HBeAg血清年转换率为26.5%(95%CI：22.8-30.1%),普通干扰素治疗1年HBeAg血清年转换率为29.3%(95%CI：25.3-33.3%),长效干扰素治疗1年HBeAg血清年转换率为36.0%(95%CI：30.0-42.0%)。结论 1乙肝血源性疫苗免后23年抗-HBs抗体逐渐衰减,但保护效果依旧,且无论抗体阳性或阴性,均能检测到功能性免疫记忆T细胞,因此,没有证据支持加强免疫。 2对于慢性病毒携带者,HBeAg血清学转换可以在无药物干预情况下自然发生,但发生率较低。HBeAg血清学转换伴随着HBV DNA水平下降、HBsAg载量降低和肝功能的正常。 3对于慢性乙肝患者,HBeAg血清学转换可以在无抗病毒治疗情况下自然发生,但发生率较低。对于慢性乙型肝炎的治疗,核苷类似物中以替比夫定疗效最好,其次是恩替卡韦；干扰素类以长效干扰素疗效为最佳。HBeAg血清学转换往往伴随着HBV DNA水平下降和肝功能的正常。
[Abstract]:objective
1 comprehensive antibody attenuation, immune memory and protection of infection and other indicators to evaluate the long-term immune effect of hepatitis B vaccine.
2 the serological conversion rate of HBsAg/HBeAg double positive virus carriers in HBeAg was observed in the state of natural non intervention.
3 meta analysis was used to estimate the HBeAg seroconversion rate of chronic hepatitis B patients with / without antiviral treatment.
Method
Study on the long-term immune effect of 1 hepatitis B vaccine
(1) a longitudinal cohort study was carried out on the neonates born in 1986 in the Southern District of Shanghai (now Huangpu District), who were vaccinated with hepatitis B vaccine in a timely manner. Regular serological follow-up was performed to detect HBsAg. anti -HBs and anti -HBc, and to observe the effect of antibody attenuation and protective infection.
(2) blood samples to observe the immune effect of hepatitis B vaccine in Zhengding County of Hebei province collected 1986 birth of vaccination of hepatitis B vaccine in the blood at the same time, strengthen the investigation and vaccine history of viral hepatitis. The Abbott Architect i2000SR system (Abbott Abbott, Park, IL, USA) detection of hepatitis B virus HBsAg, anti -HBs and anti -HBc, according to the detection results of anti -HBs antibody positive and negative antibody is divided into two groups by flow cytometry and Fluorospot assay for the detection of immune memory cells and its function.
Longitudinal cohort study of HBeAg natural serum conversion rate of 2 hepatitis B virus carriers
By 1999, 2005, 2006 census of viral hepatitis to all two townships Hebei Zhengding County, 8 villagers have been screened, HBeAg positive chronic hepatitis B virus carriers of 172 people, a cohort study of HBsAg/HBeAg positive chronic hepatitis B virus carriers. In 2010 2012, follow-up serological detection of hepatitis B, two and a half years, and transaminase the investigation, and medication.
A systematic review of serological conversion of HBeAg in patients with chronic hepatitis B (3)
By using the method of Meta analysis, PubMed SinoMed and CNKI database retrieval, and included in the published before September 2012, HBeAg seroconversion rate data in the literature. By two researchers independently screened literature, quality assessment and data extraction with HBeAg serum conversion rate as the study index, using meta method, respectively, estimated by the antiviral treatment and no antiviral in case of chronic hepatitis B patients with HBeAg seroconversion rate.
Result
Study on the long-term immune effect of 1 hepatitis B vaccine
(1) continuous follow-up in the southern urban area in 1986, the birth cohort was 23 years. The positive rate of anti -HBs decreased gradually with the prolongation of immunization time. The rate of anti -HBc in 1 years decreased to 89% in 23 years, but the positive rate of anti -HBc in all years was basically below 2%. Meanwhile, the positive rate of HBsAg remained below 1% (0.5-0.9%).
(2) 23 years after the vaccine was released, no matter the anti -HBs was positive or negative, the specific immune memory T cells could be detected by flow cytometry and Fluorospot, but the level of CD4+/IFN- + cells was high in the antibody positive group.
Longitudinal cohort study of HBeAg natural serum conversion rate of 2 HBV healthy carriers
After 20102012 years and two follow-up visits, 32 cases of HBeAg negative conversion were detected, with an average annual negative conversion rate of 2% (95%CI:1.4-2.8%), of which 26 cases had HBeAg serological conversion, with an average annual conversion rate of 1.6% (95%CI:1.1-2.4%).
3 Meta analysis of serological conversion of HBeAg in patients with chronic hepatitis B
A total of 501 articles were included, of which 305 Chinese, English 196. The study sites were in Chinese, the United States and other countries worldwide, and the language was published Chinese English.Meta analysis showed no antiviral treatment group serum HBeAg natural conversion rate was 7.9% (95%CI:6.3-9.5%); different antiviral drugs according to the standard procedure for the treatment of meta analysis of 1 years showed that: A Duff Vee 1 years of treatment HBeAg seroconversion rate was 14.3% (95%CI:13.0-16.1%), entecavir for 1 years HBeAg years serum conversion rate was 19.6% (95%CI:12.3-26.8%), conversion rate of 20.8% years 1 years of lamivudine serum HBeAg (95%CI:18.5-23.1%), telbivudine treatment for 1 years HBeAg serum conversion rate of 26.5% years (95%CI:22.8-30.1%), interferon treatment for 1 years HBeAg years serum conversion rate was 29.3% (95%CI:25.3-33.3%), interferon treatment for 1 years HBeAg years serum conversion rate was 36% (95% CI:30.0-42.0%).
conclusion
1, 23 years after the release of hepatitis B blood derived vaccine, the anti -HBs antibody gradually declined, but the protective effect remained. No matter the antibody was positive or negative, all the functional immune memory T cells could be detected. Therefore, there was no evidence to support the enhancement of immunity.
2, for chronic viral carriers, serological conversion of HBeAg can occur naturally without drug intervention, but the incidence is low..HBeAg serological conversion is accompanied by decreased HBV DNA level, reduced HBsAg load and normal liver function.
3 for patients with chronic hepatitis B, HBeAg seroconversion can occur naturally in the absence of antiviral therapy, but the occurrence rate is low. The treatment for chronic hepatitis B, nucleoside analogues with telbivudine best effect, followed by entecavir; interferon with long-term interferon efficacy is often accompanied by a decrease in HBV DNA level and liver function the normal for the best.HBeAg seroconversion.

【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.62

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