HBsAg阳性孕产妇其幼儿乙型肝炎疫苗免疫应答情况及其影响因素

目的  获取HBsAg阳性孕产妇其幼儿乙型肝炎(乙肝)疫苗无/弱应答的概率,分析其影响因素。 方法  对2016年1月至2017年4月在陕西省西北妇女儿童医院分娩的284对HBsAg阳性孕产妇及其幼儿进行研究,随访幼儿乙肝疫苗接种情况及血清学标志物产生情况。 结果  高危幼儿无/弱应答率为10.57%(28/237)。表面抗原(HBsAg)、e抗原(HBeAg)和核心抗体(HBcAb)均阳性的孕产妇其幼儿发生乙肝疫苗免疫无/弱应答率为19.64%,高于HBsAg、e抗体(HBeAb)和HBcAb均阳性的孕产妇的幼儿,其乙肝免疫无/弱应答率为9.89%(RR=1.99,95% CI：1.01~3.92,P＜0.001)。孕期有穿刺史者其幼儿发生无/弱应答的风险是无穿刺史者的6.72倍(RR=6.72,95% CI：2.79~16.19,P=0.049),幼儿发生乙肝疫苗无/弱应答的孕产妇白蛋白(ALB)低于强应答组(t=2.518,P=0.013),白球比(A/G)高于强应答组(t=-5.559,P＜0.001)。 结论  HBsAg阳性孕产妇幼儿是乙肝疫苗无/弱应答的重点人群,其又处于母亲为传染源的高危环境中,应重点进行抗体监测。其孕期有创检查可能会增加幼儿发生乙肝疫苗无/弱应答的概率。HBsAg、HBeAg和HBcAb均表现为阳性的孕产妇幼儿有较高的乙肝疫苗免疫无/弱应答率。     

Th1和Th2细胞因子的基因多态性与新生儿乙型肝炎疫苗低免疫应答的关联性研究北大核心

目的探讨Th1和Th2细胞因子基因多态性与新生儿乙型肝炎(乙肝)疫苗(HepB)低免疫应答的关系。方法在广西两家医院招募已完成HepB全程免疫的8-9月龄汉族儿童,采用微粒子酶联免疫测定法测定血清乙肝表面抗体(HBsAb),抗体浓度≥10mIU/L且<100mIU/L为低应答,≥1000mIU/L为高应答。采用SNPscanTM多重单核苷酸多态性(SNP)分型技术检测细胞因子,分析基因位点、基因型、等位基因与HepB免疫应答水平的关联性。结果本研究纳入HepB低应答儿童88名、高应答儿童132名;共筛选出Th1和Th2细胞因子12个基因52个位点。Logistic回归分析显示,IL18基因rs3882891位点T/T基因型、IL12A基因rs583911位点A等位基因、IFN-γ基因rs2069728位点C等位基因的低应答比例高[OR(95%CI):2.72(1.33-5.57);1.81(1.15-2.85);2.01(1.07-3.79)],IL1B基因rs16944位点A等位基因的低应答比例低[OR(95%CI):0.64(0.43-0.95)]。结论IL18基因rs3882891位点T/T基因型、IL12A基因rs583911位点A等位基因、IFN-γ基因rs2069728位点C等位基因可能与汉族儿童HepB初次免疫低应答有关,而IL1B基因rs16944位点A等位基因可能是其保护因素。     

北京市房山区291名儿童乙型肝炎疫苗免疫应答研究

目的了解房山区291例15岁以下儿童接种乙肝疫苗的低、无应答率,为探讨适合儿童人群乙肝疫苗低、无应答者的再免方案提供依据。方法多阶段整群系统随机抽样法抽取8个乡镇的在房山区居住半年以上且按照＂0-1-6程序＂完成乙肝疫苗接种的15岁以下儿童291人为本次调查对象,同时检测乙肝抗体。结果 15岁以下儿童无应答率9.28%,低应答率15.81%;随着年龄增加,无应答率逐渐上升、低应答率和正常应答率逐渐下降,各年龄段之间低、无应答率与正常应答率差异有统计学意义;男性无应答率9.09%,低应答率14.94%;女性无应答率9.49%,低应答率16.79%;男性与女性低、无应答率差异无统计学意义。结论对于处于低、无应答状态人群应何时进行乙肝疫苗复种,接种剂量和针剂有待于探索。     

乙型肝炎患者血清IL-18水平与HBV感染的关系

探讨IL-18在乙型肝炎病毒(HBV)感染中的作用。方法用ELISA法测定62例HBV感染者和10例健康者血清中IL-18水平，免疫荧光PCR法测定肝炎患者血清中HBV DNA的含量。结果重型肝炎组患者血清中IL-18水平升高，低病毒量组血清中IL-18浓度高于高病毒量组。结论IL-18可能参与慢性乙型肝炎的免疫应答，在清除感染的HBV的同时也造成肝细胞的损伤。     

不同免疫程序和IL-18对乙型肝炎病毒PreS2-S基因DNA疫苗免疫效果的影响

目的探讨不同免疫程序对表达乙型肝炎病毒(HBV)PreS2-S基因的DNA疫苗免疫效果的影响。方法分别采用重组质粒DNA疫苗单独免疫、重组MVA(r MVA)载体疫苗单独免疫、DNAprime/r MVAboost、DNAprime/r MVAboost并以表达鼠IL-18(mIL-18)的真核表达质粒为佐剂的程序免疫C57BL/6小鼠,通过ELISA检测抗-HB-sAb及ELISPOT检测IFN-γ评价体液免疫和细胞免疫的水平。结果表达PreS2-S抗原的各组疫苗在抗体产生的时间和滴度方面差异均无统计学意义,用ELISPOT检测IFN-γ的产生可知,所有免疫组均可引起针对特异性抗原的细胞免疫,r MVA单独免疫组强于DNA疫苗单独免疫组,弱于DNAprime/r MVAboost和DNAprime/r MVAboost+mIL-18组,DNAprime/r MVAboost和DNAprime/r MVAboost+mIL-18之间差异无统计学意义。结论携带HBV保护性抗原基因的重组MVA病毒可以诱导针对抗原的特异性细胞免疫和体液免疫,将其与表达相同抗原的DNA疫苗联合,采用DNAprime/rMVA boost的免疫方案,可以诱导比两者单独应用更强的细胞免疫反应。IL-18对免疫效果无明显影响。     

MicroRNA基因单核苷酸多态性和DNA甲基化与儿童乙型肝炎疫苗无或低免疫应答的关联性

目的探讨MicroRNA基因单核苷酸多态性(SNP)和DNA甲基化与儿童乙型肝炎疫苗(HepB)无或低免疫应答的关联性。方法选取广西壮族自治区三家医院出生且已完成3剂HepB接种的8-9月龄儿童,采集血标本,开展乙型肝炎病毒(HBV)DNA含量和血清标志物检测、MicroRNA基因位点的基因型/等位基因SNP检测和DNA甲基化检测;比较HepB无/低应答和正常/高应答儿童MicroRNA基因位点的基因型/等位基因分布和DNA甲基化β值(中位数)。结果 miR196A2基因rs11614913位点的基因型(C/C、C/T、T/T)和等位基因(C、T)、miR499基因rs3746444位点的基因型(G/G、G/A、A/A)和等位基因(G、A)的分布在110名无/低应答和391名正常/高应答儿童之间均无显著性差异。miR196A2_2基因204位点、miR499B基因44、80、162位点的DNA甲基化β值在104名无/低应答和159名正常/高应答儿童之间均有显著性差异(0.028 vs 0.024,Z=-2.12,P=0.017;0.963 vs 0.956,Z=-2.43,P=0.007;0.965 vs 0.958,Z=-1.92,P=0.028;0.976 vs 0.973,Z=-1.93,P=0.027)。结论本研究中儿童HepB无/低免疫应答与MicroRNA基因SNP无显著性关联,而可能与miR196A2_2基因204位点、miR499B基因44、80和162位点的DNA甲基化存在关联。     

病毒感染与DNA甲基化

基因表达的表观遗传学调控,在多种疾病的起始和发展中起到重要作用,DNA甲基化是表观修饰方式之一。病毒感染能够调节宿主细胞的表观遗传模式,这种可遗传变化有利于病毒的复制,进而促进疾病的发展。本文简要综述了几种病毒感染对宿主细胞DNA甲基化修饰的影响,以及相关联的致病机制,旨在为疾病的预防和治疗提供新的思路。     

TLR基因多态性对广西汉族儿童乙型肝炎疫苗初次免疫应答水平的影响

  目的  探讨Toll样受体(toll-like receptors,TLR)基因多态性与广西汉族儿童乙型肝炎(以下简称乙肝)疫苗初次免疫应答水平的关联。  方法  收集2014-2016年到广西自治区妇幼保健院、南宁市妇幼保健院儿科就诊的8~9月龄汉族儿童513例为研究对象。采集外周血标本,采用微粒子酶免疫法检测乙肝血清标志物"两对半",用套式聚合酶链式反应法检测乙肝病毒DNA,应用SNPscanTM多重SNP分型技术检测TLR基因10个位点的基因多态性。采用非条件Logistic回归分析TLR等位基因、基因型与儿童乙肝疫苗免疫后应答的关联。  结果  TLR3基因rs13126816的基因多态性与广西汉族儿童初次乙肝疫苗免疫后应答情况有关(OR=1.79,95% CI:1.11~2.89,P=0.018);A/A基因型[238.04(519.75) mIU/L]和G/A基因型[347.96(619.68) mIU/L]儿童的乙肝病毒表面抗体(hepatitis B surface antibody,抗-HBs)水平明显低于G/G基因型[489.08(854.76) mIU/L]的儿童,差异均有统计学意义(均有P < 0.05);携带等位基因A[317.20(608.72) mIU/L]儿童的抗-HBs水平也明显低于携带等位基因G[457.01(852.66) mIU/L]的儿童,差异有统计学意义(Z=-3.055,P < 0.05)。TLR基因其余位点均与乙肝疫苗免疫应答无关(均有P>0.05)。  结论  TLR3基因rs13126816位点等位基因A可能是汉族儿童产生初次乙肝疫苗免疫低应答的影响因素。     

CTLA-4融合基因免疫策略增强DNA疫苗的免疫应答效应

DNA疫苗具有较大的临床应用前景,但其免疫效力还不够强大,尤其在大动物和人类中.CTLA-4融合基因免疫能同时增强机体的特异性体液和细胞免疫应答,在抗感染、抗肿瘤中显示巨大的应用前景,并且其免疫增强效应已在部分大动物体内得到证实.     

乙型肝炎病毒感染人群T细胞对其抗原蛋白免疫应答的特征分析

目的 研究不同类型的乙型肝炎病毒(HBV)感染者的HBV抗原特异性T细胞免疫应答水平,为临床免疫调节治疗HBV感染提供诊断依据.方法 回顾性分析2010年1月-2011年1月医院就诊并且符合纳入标准的受试者80例,按照慢性乙型肝炎类型分为3组,分别是肝炎肝硬化(LC)组、无症状慢性HBV携带者(ASC)组、慢性乙型病毒性肝炎(CHB)组,所有患者均采取酶联接免疫吸附剂测定的方法(ELISA法)测定T细胞因子的免疫应答水平.结果 LC组、ASC组、CHB组的一般资料,组间比较差异无统计学意义,具有可比性；LC组和CHB组的INF-r细胞因子表达水平(1.21±0.16)、(1.57±0.21)明显高于ACS组(1.13±0.12),在INF-r、TGF-β-1、IL-17、IL-10 4个细胞因子代表的T细胞亚组CHB平均水平最高,分别为(1.57±0.21)、(3.55±0.25)、(1.36±0.12)、(32.66±11.22),差异有统计学意义(P＜0.05).结论 不同HBV感染者的抗原特异性T细胞的免疫应答不同,在一定程度上,对临床免疫调节治疗有指导意义.     

Th17细胞因子IL-17A与乙肝疫苗无/弱应答关联的研究

目的了解Th17细胞因子IL-17A水平与乙肝疫苗免疫无/弱应答发生的关联。方法在1 481名完成乙肝疫苗全程接种的年轻成人中筛选出无/弱应答者30人,根据无/弱应答者性别、年龄和BMI,分别选择抗-HBs抗体中滴度、高滴度正常应答者各30例与之匹配形成对照,检测、比较三组人群血清中IL-17A的浓度差异。并检测无/弱应答者,加强接种1剂次60μg乙肝疫苗后血清IL-17A变化情况。结果 IL-17A在无/弱应答组血清水平中位数为225.16pg/ml(QIR:176.91,287.13),中滴度组为237.37pg/ml(QIR:164.09,266.68),高滴度组为219.05pg/ml(QIR:194.62,261.82),三组间差异无统计学意义(x~2=0.072,P=0.965);无/弱应答组在加强一剂次后IL-17A浓度为241.64pg/ml(QIR:222.40,241.64),高于加强前水平,但差异无统计学意义(Z=-1.175,P=0.240)。结论本研究未能证明Th17细胞因子IL-17A与乙肝疫苗接种无/弱反应发生存在关联。     

Evaluation of immune responses to combined hepatitis A and B vaccine in HIV-infected children and children on immunosuppressive medication

Objective

A phase IV interventional study with a combined hepatitis A and B vaccine was conducted in HIV-infected children and children receiving immunosuppressive medication for treatment of rheumatic diseases to evaluate immune responses.

Methods

Both groups (1–16 years of age) received combined (inactivated) HAV and (rDNA) HBV vaccine Ambirix^® at months 0 and 6. Serum samples were taken at four time points and tested for anti-HAV and anti-HBs antibodies. Anti-HAV concentrations ≥20 mIU/mL or anti-HBs concentrations ≥10 mIU/mL were considered protective. Seropositivity percentages were calculated and geometric mean concentrations (GMCs) were compared by nonparametric Mann–Whitney U-test or Kruskal–Wallis one-way-analysis-of-variance.

Results

Of 80 HIV-infected children who completed the study, 67 were HAV-susceptible and 68 HBV-susceptible at enrolment. Of 80 children with rheumatic diseases who completed the study, 65 were HAV-susceptible and 74 HBV-susceptible at enrolment. Immune responses to HAV after first dose of vaccine in both study groups were low: 71% and 55% respectively, whereas immune responses after the second dose were 99% and 100% respectively. Immune response to HBV after first dose of vaccine in both groups was also low: 27% and 17% respectively. Immune responses after the second dose were 97% and 93%, respectively. A larger proportion of children on combination antiretroviral therapy (cART) and of children with viral load <50 copies/mL responded to HBV, and also showed a significantly higher GMC.

Conclusions

Although immune response after full series of combined HAV and HBV vaccine in both groups was excellent and comparable to healthy children, a substantial proportion of both groups was not protected for HAV after first dose of vaccine. This protection gap is especially important for HAV in travel health and postexposure prophylactic treatment: both groups of children should be serologically tested for anti-HAV prior to travel to ensure protection if there is no time to await second dose of vaccine.     

Immune response to the hepatitis B vaccine among HIV-infected adults in Uganda

BackgroundCo-infection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is common in sub-Saharan Africa (SSA) and can rapidly progress to cirrhosis and hepatocellular carcinoma. Recent data demonstrate ongoing HBV transmission among HIV-infected adults in SSA, suggesting that complications of HIV/HBV co-infection could be prevented with HBV vaccination. Because HBV vaccine efficacy is poorly understood among HIV-infected persons in SSA, we sought to characterize the humoral response to the HBV vaccine in HIV-seropositive Ugandan adults.MethodsWe enrolled HIV-infected adults in Kampala, Uganda without serologic evidence of prior HBV infection. Three HBV vaccine doses were administered at 0, 1 and 6 months. Anti-HBs levels were measured 4 weeks after the third vaccine dose. “Response” to vaccination was defined as anti-HBs levels ≥ 10 IU/L and “high response” as ≥ 100 IU/L. Regression analysis was used to determine predictors of response.ResultsOf 251 HIV-positive adults screened, 132 (53%) had no prior HBV infection or immunity and were enrolled. Most participants were women [89 (67%)]; median (IQR) age was 32 years (27–41), and 68 (52%) had received antiretroviral therapy (ART) for > 3 months. Median (IQR) CD4 count was 426 (261–583), and 64 (94%) of the 68 receiving ART had undetectable plasma HIV RNA. Overall, 117 (92%) participants seroconverted to the vaccine (anti-HBs ≥ 10 IU/L), with 109 (86%) participants having high-level response (anti-HBs ≥ 100 IU/L). In multivariate analysis, only baseline CD4 > 200 cells/mm3 was associated with response [OR = 6.97 (1.34–34.71), p = 0.02] and high-level response [OR = 4.25 (1.15–15.69)], p = 0.03].ConclusionHBV vaccination was effective in eliciting a protective humoral response, particularly among those with higher CD4 counts. Half of the screened patients did not have immunity to HBV infection, suggesting a large at-risk population for HBV infection among HIV-positive adults in Uganda. Our findings support including HBV vaccination as part of routine care among HIV-positive adults.     

乙型肝炎疫苗与婴儿期常用疫苗同时接种的免疫应答与反应观察:Ⅰ.乙型肝炎疫苗与白百破混合疫苗、脊髓灰质炎活疫苗同时接种的免疫应答与反应观察

本文对HB疫苗与DPT、TOPV疫苗同时接种的免疫应答性作了研究。对0~5月龄的229名婴儿随机分为Ⅰ组单独接种HB疫苗,Ⅱ组接种DPT、TOPV疫苗,Ⅲ组HB疫苗与DPT、TOPV同时接种。三针间隔为0、1、5个月,均作免前和第三针后一个月的血清抗体测定,同时接种组的抗-HBs、白喉、破伤风、百日咳及Ⅰ、Ⅱ、Ⅲ型OPV抗体的阳转率、GMT与单独接种组无差别。未见异常反应,一般反应均很轻微,二组间无差别。表明上述几种疫苗同时接种是安全和有效的。     

贺州市1—6岁儿童乙型肝炎疫苗免疫效果分析

目的评价1～6岁儿童乙型肝炎重组酵母疫苗（HepB）的免疫效果。方法贺州市五县区,每个县区调查约150名儿童,检测乙型肝炎病毒表面抗原（HBsAg）和乙型肝炎病毒表面抗体（HBsAb）。结果HBsAg、HBsAb阳性率分别为0．51％、77．76％。男性HBsAg阳性率为0．50％,HBsAb阳性率为79．55％;女性HBsAg阳性率为0．53％,HBsAb阳性率为75．85％;不同性别之间的HBsAg、HBsAb阳性率比较,差异无统计学意义（P〉0．05）。各年龄组间HBsAb阳性率差异有统计学意义（x2=45．977,v=6,P〈0．01）;1岁组HBsAb阳性率95．62％,6岁组HBsAb阳性率67．42％,差异有统计学意义（P〈0．05）。完成基础免疫儿童的HBsAb阳性率75．77％,经过加强免疫的儿童HBsAb阳性率95．24％,两者之间差异有统计学意义（P〈0．05）。结论贺州市儿童接种Heps免疫效果显著,随着年龄的增长HBsAb阳性率呈下降趋势,在完成基础免疫的情况下进行加强免疫能使乙型肝炎疫苗的保护效果更好。     

乙型肝炎疫苗与儿期常用疫苗同时接种的免疫应答与反应观察Ⅲ．乙型肝炎疫苗与卡介苗、A群流脑多糖菌苗同时接种的免疫应答与反应观察

本文对HBV与BCG、BAPV同时接种的免疫应答性和接种反应作了研究，对出生3天内的360名新生婴儿，随机分为I组单独接种三针10μgHBV，Ⅱ组分别接种BCGs及50μg MAPV，Ⅲ组HBV分别与BCGs、MAPV同时接种，Ⅳ组分别接种BCGi和MAPV，Ⅴ组HBV分别与BCGi、MAPV同时接种，三针间隔为0、1、5个月。均作免疫前后抗体测定或OT，同时接种组的抗－HBs及MAPV之BA抗体及OT的阳转率分别为100％、92．59％及81．82％－90．0％与单独接种组的96．49％、90．24％和79．25％－87．50％，无显著差异，未见异常反应，一般反应轻微，二组无显著性差异，表明HBV可与BCG、MAPV同时接种。     

Hepatitis B vaccine response in obesity: A meta-analysis

BackgroundHepatitis B vaccination is critical in preventing hepatitis B virus (HBV) infection and transmission. However, the impact of obesity on immune response to hepatitis B vaccine remains unclear.MethodsWe performed a meta-analysis of the literature and summarized the results of immune response to hepatitis B vaccine among persons with and without obesity. We used Pubmed, Embase, Web of Science and Cochrane Library to identify all related studies between January 1973 and November 2015. Unadjusted and adjusted pooled OR and 95% CI were calculated by fixed-effect model or random-effect model according to the heterogeneity of the selected studies.ResultsTotally, 16 studies contributed to the present meta-analysis. Fifteen of them provided absolute numbers of non-responders in obese group and non-obese group. Overall, we found that the obese population was significantly associated with non-response to hepatitis B vaccination (adjusted OR: 2.46, 95% CI: 1.50–4.03). Significant heterogeneity was present in most of the pooled analyses, but was markedly reduced when analyses were restricted to study reports with uniform criteria of obesity and restricted to study in adults. No publication bias was observed in the present analysis.ConclusionsThe present meta-analysis suggested that obesity is significantly associated with the decreased response to hepatitis B vaccines. Future studies should be performed to unravel this relationship in order to prevent HBV infection and transmission.     

学龄前儿童乙型肝炎疫苗无应答者HBV感染风险的前瞻性队列研究

目的  评估学龄前儿童乙肝疫苗无应答者未来感染乙肝病毒（hepatitis B virus,HBV）的风险。 方法  采用前瞻性队列研究的方法,选取南宁市江南区64家幼儿园内、已经按照0、1、6程序全程接种了三针乙肝疫苗的2~5岁儿童,在2015年3~5月期间抽血检测乙肝病毒表面抗原（hepatitis B surface antigen,HBsAg）和乙肝病毒表面抗体（hepatitis B surface antibody,抗-HBs）,HBsAg阴性儿童为本次研究对象。根据儿童抗-HBs是否阳性,分成暴露组（抗-HBs阴性）和对照组（抗-HBs阳性）。研究开始于2015年6月1日,结束于2016年6月1日,在2016年6月1~30日对儿童进行随访检测血清HBsAg阳性率,比较两个组的HBsAg阳性率。 结果  纳入队列的无应答组人数1 907名,排除随访期间再次接种乙肝疫苗的83人,该队列人数实际为1 824,研究结束时失访151人,实际随访到的人数是1 673人,期间共有5名小孩HBsAg转成阳性,感染率为0.30%（5/1673）;纳入队列的应答组人数2 054名,研究结束时失访140人,随访到人数为1914,他们均未检测出HBsAg;研究结束时无应答组HBsAg阳性率高于应答组（P=0.023）。 结论  乙肝疫苗无应答者未来存在感染HBV的风险。