中华流行病学杂志  2014, Vol. 35 Issue (10): 1091-1094   PDF    
http://dx.doi.org/10.3760/cma.j.issn.0254-6450.2014.10.003
中华医学会主办。
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文章信息

刘甲野, 吕静静, 颜丙玉, 冯艺, 张丽, 徐爱强. 2014.
Liu Jiaye, Lyu Jingjing, Yan Bingyu, Feng Yi, Zhang Li, Xu Aiqiang. 2014.
乙型肝炎病毒核心抗体单项阳性及健康的成年人乙肝疫苗免疫效果配对比较研究
Matching study on immune response between single anti-HBc positivity and healthy adults after primary immunization and revaccination of hepatitis B vaccine
中华流行病学杂志, 2014, 35(10): 1091-1094
Chinese Journal of Epidemiology, 2014, 35(10): 1091-1094
http://dx.doi.org/10.3760/cma.j.issn.0254-6450.2014.10.003

文章历史

投稿日期:2014-4-8
乙型肝炎病毒核心抗体单项阳性及健康的成年人乙肝疫苗免疫效果配对比较研究
刘甲野, 吕静静, 颜丙玉, 冯艺, 张丽, 徐爱强     
250014 济南, 山东省疾病预防控制中心山东省传染病预防控制重点实验室
摘要目的 探讨单项乙型肝炎(乙肝)病毒核心抗体(抗-HBc)阳性成年人接种乙肝疫苗(HepB)的免疫效果。方法 筛选出HBsAg、抗-HBs阴性及抗-HBc阳性,既往无HepB免疫史的18~49 岁者组成抗-HBc单项阳性组(单阳组),并按1:1 匹配原则选择对照组。依照“0-1-6”免疫程序对单阳组和对照组接种HepB,对两组无应答者再次按该免疫程序接种HepB,比较两组人群抗-HBs 阳转率及其滴度。结果 两组人群共调查228 对。对照组和单阳组初次免疫抗体阳转率分别为91.23%和91.67%,差异无统计学意义(χ2=0.00,P>0.05)。对照组无应答率、低应答率、正常应答率和高应答率分别为8.77%、11.84%、31.14%和48.25%,单阳组分别为8.33%、30.70%、35.96%和25.00%,对照组低应答率低于单阳组(χ2=22.28,P<0.01),高应答率高于单阳组(χ2=24.43,P<0.01)。初次免疫后对照组抗-HBs 几何平均浓度(534.07 mIU/ml)高于单阳组(183.99 mIU/ml),差异有统计学意义(u=4.42,P<0.01);再次免疫1 针后,对照组应答率(82.35%)高于单阳组(41.18%)(P<0.05),再免疫3 针后两组应答率分别达到90.00%和82.35%(P=1.00)。结论 抗-HBc 单阳者HepB 初次免疫可获得较好的免疫应答,但低于一般人群;初次免疫无应答的抗-HBc单阳者3 剂次再免疫可获得较高阳转率。
关键词乙型肝炎疫苗     乙型肝炎病毒核心抗体     抗体应答     成年人    
Matching study on immune response between single anti-HBc positivity and healthy adults after primary immunization and revaccination of hepatitis B vaccine
Liu Jiaye, Lyu Jingjing, Yan Bingyu, Feng Yi, Zhang Li, Xu Aiqiang     
Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan 250014, China
Abstract: Objective To compare the antibody response between adults with hepatitis B virus(HBV)core antibody(anti-HBc)single positivity and healthy adults after primary immunization and revaccination of hepatitis B vaccine(HepB). Methods Adults aged from 18 to 49 who were both negative for HBV surface antigen(HBsAg)and antibody to HBsAg(anti-HBs),but positive for anti-HBc and narrated no history of HepB immunization by themselves,were selected as single anti-HBc positive group(‘anti-HBc alone').Adults who were negative for HBsAg,anti-HBs and anti-HBc,with age differences within 2 years,and same gender under the 1:1 matching program,were selected to form the control group. Both groups were vaccinated on 0-1-6 schedule with the same HepB. Those who were non-response to HepB at primary immunization were revaccination on 0-1-6 schedule. Response rates and geometric mean concentrations(GMC)between the two groups were compared. Results In total,the number of anticipants were 228 pairs. Rates on non-response,low-response,normal-response and high-response after the primary immunization were 8.77% ,11.84%,31.14% and 48.25% in the control group respectively. The corresponding rates were 8.33%,30.70%,35.96% and 25.00% in the‘anti-HBc alone'. The rate of low-response in the control group was lower than that in the‘anti-HBc alone' χ2=22.28,P<0.01),while the rate of high-response was higher than that in the control group(χ2=24.43,P<0.01). GMC of anti-HBs in the control group (534.07 mIU/ml)was higher than that in the‘anti-HBc alone'(183.99 mIU/ml)(u=4.42,P<0.01). The anti-HBs conversion rates were 82.35% and 41.18% in the control group and in the ‘anti-HBc alone'respectively after the first-dose revaccination,but increased to 90.00% and 82.35% after the third-dose revaccination. The anti-HBs conversion rates in the control group were higher than that in the‘anti-HBc alone' after the first-dose revaccination (P<0.05),while there was no difference seen between the two groups after the third-dose revaccination(P>0.05). Conclusion Immune response in the anti-HBc positive adults after primary immunization was weaker than that in common adults. However,immune response induced by HepB was enough to prevent them from infecting HBV. The rates of response showed an obvious increase after revaccination,hence the same HepB immunization strategy could be used.
Key words: Hepatitis B vaccine     Hepatitis B virus core antibody     Antibody response     Adult    

单项乙型肝炎(乙肝)病毒核心抗体(抗-HBc) 阳 性 是 指 血 清 学 检 测抗-HBc阳 性,HBsAg和 抗-HBs均为阴性。单项抗-HBc阳性可能为乙肝急 性感染窗口期、慢性感染、慢性感染恢复期等。有研 究认为不同地区一般人群中单项抗-HBc阳性检出 率约为0.1%~8.9% [1]。目前关于抗-HBc单项阳性 者接种乙肝疫苗(HepB)免疫效果的研究较少,为此 本研究对抗-HBc单项阳性者HepB初次免疫和无应 答者再次免疫的抗体应答进行观察。 对象与方法

1. 研究对象:选择山东省章丘市人口流动性较 小的3个乡(镇)为研究现场,以满足如下条件者作 为初筛对象:①当地常住年龄18~49周岁汉族人 口;②自述既往未接种过HepB;③无乙肝患病史与 HBsAg阳性史;④无HepB接种禁忌症;⑤接受知情 同意。对初筛对象进行问卷调查,包括年龄、性别、 住址、身高、体重、吸烟史、饮酒史和慢性病史等;同 时采集静脉血标本5ml,检测HBsAg、抗-HBs和 抗-HBc。其中HBsAg、抗-HBs阴性,抗-HBc阳性 者组成单项抗-HBc阳性组(单阳组),按照1∶ 1比 例从HBsAg、抗-HBs和抗-HBc全阴者中选择与单 阳组同乡镇、同性别、年龄相差<1岁、BMI相差< 2kg/m2者组成对照组。

2.研究方法:

(1)疫苗接种:所有研究对象初次免疫按照 “0-1-6”免疫程序接种10μg重组乙肝疫苗(酿酒酵 母)(北京天坛生物制品股份有限公司产品,批号 20090406,有效期至2012年5月4日),初次免疫无 应答者使用上述疫苗按照同样免疫程序再次免疫。 于初次免疫和再次免疫第3剂次1个月后,采集静脉 血3~5ml,分离血清-20℃冷冻待检。

(2)标本检测:初筛血标本采用ELISA(瑞士 TECAN公司Freedom EVO全自动酶免工作站)检测 HBsAg、抗-HBs,试剂为英科新创(厦门)技术有限 公 司 产 品;采 用 化 学 发 光 微 粒 子 免 疫 分 析 法 (Chemiluminescence Microparticle Imunoassay,CMIA) (雅培ARCHITECT-i2000免疫发光检测仪,美国雅 培公司试剂,下同)检测抗-HBc。初次免疫血标本 采用CMIA方法检测抗-HBs,抗-HBs阴性者采用 CMIA方法检测HBsAg,HBsAg阴性者采用巢式 PCR方法检测HBV DNA;再次免疫血标本仅采用 CMIA方法检测抗-HBs。

3. 判定标准:免疫后血清学检测抗-HBs< 10mIU/ml且HBsAg、HBV DNA均阴性判断为无应 答,10mIU/ml≤抗-HBs<100mIU/ml为低应答, 100mIU/ml≤抗-HBs<1000mIU/ml为正常应答, 抗-HBs≥1000mIU/ml为高应答。抗体阳转指免 疫后抗-HBs≥10mIU/ml。

4. 统计学分析:采用EpiData数据库进行数据双 录入和比对。采用SAS9.13软件进行数据分析,不 同组间应答率比较采用配对χ2检验;抗-HBs几何平 均浓度(GMC)比较采用配对u检验。 结 果

1. 一般情况:两组研究对象共调查228对。两 组人群性别、年龄、BMI、吸烟史和饮酒史等方面的 差异均无统计学意义(χ2或u值分别为0.00、0.60、 0.81、2.39、2.20,P值均>0.05)(表 1)。

表 1 对照组和单阳组均衡性比较

2. 初次免疫后抗-HBs应答率比较:对照组和 单阳组分别有20人和19人全程免疫后抗-HBs< 10mIU/ml,进一步检测HBsAg和HBV DNA均阴 性,判断为无应答,无应答率分别为8.77%和8.33%, 差异无统计学意义(χ2=0.00,P>0.05)。对照组抗 体阳转率为91.23%,其中低应答率、正常应答率和 高应答率分别为11.84%、31.14%和48.25%;单阳组 抗体阳转率为91.67%,其中低应答率、正常应答率 和高应答率分别为30.70%、35.96%和25.00%。对照组低应答率低于单阳组,高应答率高于单阳组,差异 有统计学意义(χ2值分别为22.28和24.43,P值均< 0.01);单阳组正常应答率略高于对照组,但差异无 统计学意义(χ2=1.25,P>0.05)(表 2)。

表 2 对照组和单阳组HepB初免后抗体应答率

3. 初次免疫后抗-HBs GMC水平比较:对照组 和单阳组初次免疫后,抗-HBs GMC分别为534.07 (95%CI:373.88~762.91)mIU/ml和183.99(95%CI: 133.31~253.94)mIU/ml,对照组高于单阳组,差异 有统计学意义(u=4.42,P<0.01)。

4. 再次免疫后抗-HBs应答率:对照组和单阳组 均 有17人 再 免 疫1针,抗-HBs应 答 率 分 别 为 82.35%(14/17)和41.18%(7/17),对照组高于单阳 组,差异有统计学意义(P=0.03);两组分别有10人 和17人完成3剂次再免疫,抗-HBs应答率分别为 90.00%(9/10)和82.35%(14/17),差异无统计学意义 (P=1.00)。 讨 论

人体感染HBV后抗-HBc可较早出现,即使 HBV清除后抗-HBc仍可持续较长时间。单项 抗-HBc阳性的意义尚不完全清楚[2,3,4,5,6,78]。崔富强等[9] 利用大样本血清学调查发现,我国1~59岁社区人 群单项抗-HBc阳性率约为3.75%,据此计算,我国 单项抗-HBc阳性者约为4300余万人。由于该部分 人群血清HBsAg、抗-HBs均为阴性,从血清学角度 认为其既非HBV现症感染者,亦无HBV保护性抗 体,是HepB的接种对象,但目前国内对该部分人群 接种HepB后的抗体反应研究较少。因此开展相关 研究对完善我国HepB免疫策略具有实际意义。

国外学者对单项抗-HBc阳性者接种HepB后的 免疫效果进行了观察。如Kabir等[10]研究结果显示, 单项抗-HBc阳性者按照“0-1-6”免疫程序接种3针 10μgHepB后无应答率为20.2%;而Gessoni等[11]对 单项抗-HBc阳性者采用相同免疫程序接种20μg HepB后无应答率为28%。本研究结果显示,单项 抗-HBc阳性者HepB免疫后无应答率为8.33%,显 著低于国外研究结果。分析发现,本文调查对象平 均年龄(39.03岁)明显低于Kabir等[10]和Gessoni等[11] 研究中的平均年龄(分别为43.8岁和52.8岁),推测 年龄可能是研究结果差异较大的原因之一[12]。本研 究中单阳组HepB免疫后低应答率明显高于对照组, 高应答率显著低于对照组,提示单项抗-HBc阳性者 接种HepB后免疫应答较一般人群差。本文单阳组 初次免疫后无应答者再免疫1针后抗-HBs阳转率 为41.18%,再免疫3针后提高到了82.35%,说明对 于初次免疫后无应答的单项抗-HBc阳性者进行3 剂次再次免疫,可明显提高其抗-HBs阳转率。

本研究结果表明,单项抗-HBc阳性者按照 “0-1-6”程序接种3剂次HepB可产生较好的免疫应 答,但抗体水平低于一般人群;初次免疫无应答的单 项抗-HBc阳性者经过3剂次再次免疫后可达到较 高的抗体阳转率。建议对单项抗-HBc阳性成年人 按照一般人群的免疫策略接种HepB。 本研究存在不足。如研究对象HepB免疫史仅 通过回忆获得,可能存在回忆偏倚;研究对象样本量 较小,导致再次免疫效果观察的单阳组和对照组均 仅有17名;未对两组人群进行长期随访,无法观察 到两组人群抗体持久性方面的差异。

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