乙肝疫苗接种无（弱）应答者再接种后三年效果观察

乙肝疫苗接种无（弱）应答者再接种后三年效果观察徐慧文，隋秀芬，王学良，门伯媛，李东升，徐经武，刘蓬勃为了观察乙肝疫苗接种无（弱）应答者对疫苗再接种的反应，我们于１９８９年对原接种过３针血源性乙肝疫苗的１０名无（弱）应答者和１８名原应答良好者共计２８人...     

国产血源性乙肝疫苗复种的应答效果：附一年观察材料

对3年前接种过3针血源性乙肝疫苗的10名无应答和弱应答者以及52名应答良好者各复种1针血源性乙肝疫苗。无应答和弱应答者大部分抗-HBs阳转,其滴度明显升高,但持续时间较短。52名良好应答者复种后多数出现良好的回忆反应。1μg疫苗皮内注射显示了同10μg肌肉注射相似的应答效果。复种后的抗体应答水平与初种后的抗体应答峰值呈明显正相关。     

重组酵母乙型肝炎疫苗无（或弱）应答者复种远期效果观察

目的探讨重组酵母乙肝疫苗无（或弱）应答者复种远期效果。方法严格筛选无（或弱）应答者40名，分肌肉和皮内接种，用3针加倍剂量（每次10μg或20μg），以80名同期筛检人群正常应答者作对照，完成30个月随访观察。结果无（或弱）应答者复种后产生抗体应答；第30个月，肌肉和皮内组仍有64．7％和34．8％维持抗体阳性。但无（或弱）应答者抗-HBs阳性率和抗体阳性者的抗体几何平均滴度（GMT）均明显低于正常应答者（P〈0．01）。无（或弱）应答者HBV累积感染率（单项抗-HBe阳性）为25．0％（肌肉组17．6％，皮内组30．4％），显著高于正常应答者2．6％（P〈0．01）。结论肌肉接种好于皮内接种。无（或弱）应答者复种确实能起到改善应答并在一个相对较长时间里维持抗体水平的作用。     

重组酵母乙型肝炎疫苗无(或弱)应答者复种远期效果观察

目的探讨重组酵母乙肝疫苗无(或弱)应答者复种远期效果。方法严格筛选无(或弱)应答者40名,分肌肉和皮内接种,用3针加倍剂量(每次10μg或20μg),以80名同期筛检人群正常应答者作对照,完成30个月随访观察。结果无(或弱)应答者复种后产生抗体应答;第30个月,肌肉和皮内组仍有64.7%和34.8%维持抗体阳性。但无(或弱)应答者抗-HBs阳性率和抗体阳性者的抗体几何平均滴度(GMT)均明显低于正常应答者(P<0.01)。无(或弱)应答者HBV累积感染率(单项抗-HBc阳性)为25.0%(肌肉组17.6%,皮内组30.4%),显著高于正常应答者2.6%(P<0.01)。结论肌肉接种好于皮内接种。无(或弱)应答者复种确实能起到改善应答并在一个相对较长时间里维持抗体水平的作用。     

乙型肝炎疫苗无/弱应答者复种远期效果

目的　探讨乙肝疫苗无 /弱应答者复种远期效果。方法　严格筛选无 /弱应答者 40名 ,分肌肉和皮内接种 ,用 3针加倍剂量 (每次 1 0 μg或 2 μg) ,以 80名同期筛检人群正常应答者作对照 ,完成 30个月随访观察。 结果　无 /弱应答者复种后 39人产生抗体应答 ;第 30个月 ,肌肉与皮内组仍有 64 7%和 34 8%维持抗体阳性。但无 /弱应答者抗 -HBs阳性率和抗体阳性者GMT均明显低于正常应答对照 (P <0 0 1 )。无 /弱应答者HBV累积感染率 (单项抗 -HBc阳性 )为 2 5 0 % (肌肉组 1 7 6 % ,皮内组 30 4% ) ,显著高于正常应答对照 2 6 % (P <0 0 1 )。结论　肌肉接种好于皮内接种。无 /弱应答者复种确实能起到改善应答 ,并在一个相对较长时间维持抗体水平的作用 ,但效果不容乐观。最终结论还需结合免疫记忆的研究做进一步追踪观察     

婴幼儿乙型肝炎疫苗免疫失败者再免疫的初步研究

目的：探讨按标准免疫程序接种乙型肝炎疫苗后无抗体应答的对策。方法：采用放射免疫方法（RIA）检测乙肝病毒表面抗原（HBsAg）、乙肝病毒表面抗体（抗-HBs）和乙肝病毒核心抗体（抗-HBc），对3项指标均为阴性的120例研究对象接种1-3剂乙肝疫苗，2剂间隔1个月，分别在每剂接种1个月后采血检测HBsAg、抗-HBs和抗-HBc，判断抗体应答情况。结果：再免疫1剂乙肝疫苗后抗-HBs阳转率为75.8％（S/N≥2.0）和56.7％，（S/N≥10.0）；对再免疫1剂后仍无抗体应答者（29人）又接种第2剂乙肝疫苗，1个月后又有19例抗-HBs阳转，占总数的15.8％；对再免疫2剂后仍无抗体应答者（10人）继续接种第3剂乙肝疫苗，1个月后又有8例抗-HBs阳转，占总数的6.7％。再免疫3剂后抗体应答率达到98.3％。结论：按标准免疫程序接种乙型肝炎疫苗后无抗体应答者，再免疫可以诱导-HBs阳转，且效果比较满意。     

乙肝疫苗接种无免疫应答儿童复种后抗-HBs检测分析

目的探讨乙型肝炎疫苗接种无免疫应答儿童复种不同剂量乙肝疫苗的免疫效果,为乙型肝炎免疫预防工作提供依据。方法严格筛选无应答儿童46名,随机分为两组,每组23人。两组用不同剂量(每剂分别为20ug,5ug)乙肝疫苗,按0、1、6免疫程序进行肌肉接种。完成7个月随访观察。结果无应答儿童复种20ug组21人产生抗体应答;复种5ug组16人产生抗体应答。无应答儿童复种20ug组抗-HBs阳性率和抗体阳性水平(GMT)均明显高于复种5ug组(P<0.01)。结论无应答儿童复种能起到改善免疫应答。大剂量(20ug)接种好于小剂量(5ug)接种。     

国产血源性乙肝疫苗在健康儿童中全程接种后23年的效果

目的 评价国产血源性乙型肝炎疫苗（乙肝疫苗）接种23年后的免疫原性和预防感染的保护效果。方法 1986年在西安市两所乡村小学筛检了261名5～9岁学生,按照分层随机分为疫苗组（126名）和对照组（135名）。2009年进行随访,剔除自行接种者后,疫苗组和对照组分别有81名和75名。对乙型肝炎病毒表面抗体（抗-HBs）＜10 mIU/ml及乙型肝炎病毒表面抗原(HBsAg)、乙型肝炎病毒核心抗体（抗-HBc）和乙肝病毒(HBV) DNA阴性者复种1针5μg国产重组疫苗,复种后1个月再次采血检测抗-HBs。结果 消除早期复种和自行接种的影响后,在第23年时,疫苗组48.1％(39/81)的研究对象抗-HBs仍保持在10 mIU/ml以上,高于对照组的阳性率[34.7％(26/75)]。疫苗组中84.0％ (21/25)的抗-HBs和抗-HBc均阴性的研究对象复种后产生了较强的回忆应答,而对照组中相似的抗-HBs阳性率为7.5％ (3/40)。本次随访未发现乙肝临床病例,但疫苗组和对照组的抗-HBc阳性率分别为16.0％( 13/81)和30.7％ (23/75)(x2=4.687,P＜0.05)。结论 国产血源性乙肝疫苗在健康儿童中全程接种后23年,免疫效果仍维持良好或有免疫记忆;疫苗仍有较好的保护效果。     

60μg乙肝疫苗对某医院低/无应答医务人员免疫效果观察

目的探讨无(弱)应答的医院职工接种60μg乙肝疫苗后的抗体产生状况及其影响因素。方法在深圳市某医院既往接受过乙肝疫苗0、1、6程序接种而未产生保护性抗体的职工中,随机抽取研究对象,使用深圳康泰生物制品股份有限公司生产的60μg重组乙型肝炎(酿酒酵母)疫苗再次接种,5个月后采集接种者血清,采用化学发光免疫分析法(CLIA法)检测抗-Hbs水平。同时对接种者进行问卷调查,采用非条件Logistic回归分析,以了解影响乙肝疫苗免疫应答的因素。结果本次调查共发出问卷110份,收回有效问卷102份,有效回收率为92.73%。接种后,乙肝抗体阳转率达100.0%,乙肝保护性抗体阳转率达88.24%。非条件Logistic回归分析未发现影响接种乙肝疫苗无(弱)应答率的因素(P0.05)。结论低/无应答者接种一针高剂量60μg乙肝疫苗,可获得较好抗体应答。尚未发现影响接种乙肝疫苗无(弱)应答率的因素。     

乙肝疫苗无应答复种免疫效果观察

目的 观察接种乙肝疫苗无应答者复种不同剂量乙肝疫苗后的免疫效果,为进一步提高乙肝疫苗保护率提供依据.方法 将全程接种后无应答的173名一～三年级小学生随机分成2组,按“0-1-2-12”程序分别接种重组酵酶乙肝疫苗（5 μg组91人、10 μg组82人）,于第13个月、36个月时检测HBsAg、抗-HBs、HBeAg、抗-HBe、抗-HBc,观察其免疫效果.结果 在第13个月,抗-HBs阳性率为60.12%,弱阳性率为20.23%,阴性率为19.65%,2组差异有统计学意义（P＜0.01）,无人感染乙肝病毒;在第36个月,抗-HBs阳性率为33.53%,弱阳性率为30.63%,阴性率为35.84%,2组差异有统计学意义（P＜0.01）,有7名学生出现乙肝两对半异常,5 μg组已有2名学生感染乙肝病毒（HBsAg阳性）.结论 无应答者均按“0-1-2-12”免疫程序复种酵酶乙肝疫苗,10 μg组较5 μg组免疫效果好.第36个月表面抗体阳性率水平明显低于第13个月,提示对无应答者复种后,在出现表面抗体阴性或弱阳性时应及时进行加强免疫.     

健康人群中乙肝疫苗无（低）应答者再免疫效果研究

目的探讨不同年龄段健康人群中乙肝疫苗免疫后无（低）应答者接种不同类型乙肝疫苗的再免疫效果。方法采用分层随机抽样方法，按地域分布选取东莞市五镇区2～4岁、6～8岁、13～15岁和16～40岁四个年龄组健康人群，用ELISA法筛查HBcAb、HBsAg、HBsAb均为阴性且有3针乙肝疫苗免疫史的人员作为再免疫研究对象。采用5μg酵母、10μg酵母、10μgCHO、10μg汉逊酵母、20μgCHO和20μg酵母乙肝疫苗按0、1、6月程序再免疫3剂。结果各种疫苗在人群中的再免疫成功率和抗体水平中位数（mIU／m1）分别为：5μg酵母94．34％和226．53，10μg酵母86．46％和175．36，10μgCHO97．39％和331．44，10μg汉逊酵母91．30％和439．01，20μgCHO99．20％和386．66，20μg酵母89．04％和372．97。各年龄组的再免疫成功率和抗体水平中位数（mIU／m1）分别是：2～4岁组98．25％和353．42，6～8岁组96．80％和320．31，13～15岁组94．67％和262．12，16～40岁组87．76％和305．24。结论年龄、疫苗种类和接种剂量是影响无（低）应答者再免疫效果的主要因素，随年龄的增长再免疫效果下降，更换疫苗种类可提高再免疫效果。     

Increment of recombinant hepatitis B surface antigen-specific T-cell precursors after revaccination of slow responder children

The aim of the study was to investigate the in vitro T-cell response to recombinant hepatitis B (rHBsAg) in a group of children (defined as "slow responders") vaccinated at birth, presenting antibody levels < 10 mIU/ml after the vaccination schedule, and developing anti-rHBs antibodies after revaccination. T-cell mediated immune response towards rHBsAg was evaluated in 35 healthy children in "bulk" culture experiments (19 responders and 16 slow responders) and by limiting dilution analysis (nine responders and five slow responders) to quantify the frequency of proliferating T lymphocyte-precursors (PTL-p). Before the booster dose, lymphocytes from slow responder children failed to proliferate to rHBsAg, while a normal proliferation was observed in all responders. A statistically significant difference in rHBsAg-specific PTLp frequencies was observed between the two groups. Among the slow responder group, a significant increase of PTLp was observed after the supplementary vaccine dose.Nevertheless, PTLp frequencies remained significantly lower than those measured in responders. These results suggest a role for follow-up of slow responder children over time, in order to perform booster vaccination when inadequate anti-HBs titre is present.     

成人乙型肝炎疫苗无应答者大剂量再免疫效果评价

摘要:目的　探讨2种大剂量乙型肝炎（乙肝）疫苗对无应答成人再免疫的效果,为60 μg/1.0 ml乙肝疫苗的临床应用提供依据。方法　将有乙肝疫苗全程接种史、乙肝表面抗原（HBsAg）及乙肝表面抗体（抗-HBs）阴性的健康成人,根据知情同意、随机原则分为2组,1组为20 μg组,即接种3针20 μg乙肝疫苗,按“0、1、6”程序;1组为60 μg组,即接种1针60 μg乙肝疫苗。完成免疫程序后3个月内检测乙肝5项指标。结果　无应答成人再免疫后,20 μg组和60 μg组2组抗-HBs阳转率约为88%,且正常应答者,2组抗-HBs几何平均滴度（GMT）水平相近,差异无统计学意义（P＞0.05）,低应答者,60 μg组抗-HBs GMT高于20 μg组（P＜0.05）。男性抗-HBs阳转率较女性低（P＜0.05）,不同年龄组间抗-HBs阳转率差异无统计学意义（P＞0.05）。结论　1针60 μg/1.0 ml乙肝疫苗和3针20 μg/ml乙肝疫苗疗效相当,可根据个体实际情况选择免疫方案。     

Persistence of antibody in healthcare workers vaccinated against hepatitis B

A cross-sectional serological survey was undertaken in 82 randomly selected high-risk healthcare workers previously vaccinated with the hepatitis B vaccine. The study design allowed for the identification and testing for hepatitis B surface antibody in equal numbers of employees in six-month intervals up to five years after vaccination. The results showed a consistent decline in antibody level with time, and an increasing proportion of participants with antibody levels below the commonly accepted protective level of greater than or equal to 10 S/N (sample counts/negative control counts) radioimmunoassay units. The percent of vaccinees whose S/N ratio was greater than 10 fell from 10% at one year, to 25% at two years, to over 50% at four years. Based on these figures, as well as the financial costs of hepatitis B in employees and the predictability of booster immunization, it was possible to assess the cost benefit of a hospital policy for reimmunization. At our institution, a strategy of revaccination at fixed intervals could save up to $200,000 over a ten-year period if revaccination was not offered and vaccine efficacy declined. The information obtained should help determine the need for revaccination and the advantages and disadvantages of alternative revaccination strategies.     

Duration of response to intramuscular versus low dose intradermal hepatitis B booster immunization

OBJECTIVE: To determine the duration of the immune response to plasma-derived hepatitis B vaccine among healthcare workers responding to booster doses of intradermal (ID) or intramuscular (IM) vaccine in 1986 and those with protective levels of antibody to hepatitis B surface antigen (anti-HBs) in 1986 without booster vaccine. Both groups received a primary hepatitis B vaccine series 24 to 36 months earlier. DESIGN: Cross-sectional follow-up study two years later of an inception cohort defined in 1986. SETTING: An academically affiliated metropolitan county hospital. PARTICIPANTS: Group 1: Hospital employees responding to booster doses of hepatitis B vaccine given ID or IM in 1986 due to low anti-HBs levels. Forty-one (82%) of 50 eligible persons were evaluated. Group 2: Persons not receiving booster vaccine in 1986 due to protective levels of anti-HBs. A random sample of 95 persons was drawn from a pool of 152 participants with protective levels in 1986. Sixty-five (68%) of 95 contacted persons were restudied. RESULTS: In 1988, 14 (64%) of 22 previous ID responders had anti-HBs levels greater than or equal to 10 milli-international units (mIU)/mL, compared with 17 (89%) of 19 IM responders (p = .055). The 1988 geometric mean titer of IM recipients was 66.4 +/- 4.5 mIU/mL and of ID recipients was 20.7 +/- 7.4 (p = .04). None of 65 Group 2 subjects' anti-HBs titers dropped below 10 mIU/mL by 1988. CONCLUSIONS: Plasma-derived hepatitis B vaccine recipients with anti-HBs levels greater than or equal to 10 mIU/mL at 24 to 36 months after primary immunization are likely to maintain these levels two years later. The diminished durability of the antibody response together with the increased rate of local side effects associated with the ID injection route may limit its applicability as an alternative to using IM booster doses of hepatitis B vaccine.     

健康人群乙型肝炎疫苗再免疫抗体应答

目的探讨不同年龄组健康人群接种不同类型、不同剂量乙型肝炎（乙肝）疫苗（Hepatitis B Vaccine,HepB）的再免疫抗体应答。方法采用分层随机抽样方法,按地域分布选取东莞市5个镇2～4、6～8、13～15、16～40岁4个年龄组健康人群,用酶联免疫吸附试验筛查乙肝病毒核心抗体、乙肝病毒表面抗原和乙肝病毒表面抗体均为阴性,且有3剂HepB免疫史的人作为再免疫研究对象。采用5μg重组HepB（酵母）（HepB Made by Recombinant DNA Techniques in Yeast,HepB-Y）、10μg HepB-Y、10μg重组HepB（中国仓鼠卵巢细胞）（HepB Made by Recombinant DNA Techniques in CHO Cell,HepB-CHO）、10μg重组HepB（汉逊酵母）（HepB Made by Recombinant DNA Techniques in Hansenula Yeast,HepB-HY）、20μg HepB-CHO和20μg HepB-Y,均按0、1、6个月程序再免疫3剂。结果不同类型不同剂量HepB在人群中的再免疫成功率和抗体水平中位数[毫国际单位/毫升（mIU/ml）]分别为：5μg HepB-Y94.34%和226.53,10μg HepB-Y86.46%和175.36,10μg HepB-CHO97.39%和331.44,10μg HepB-HY91.30%和439.01,20μg HepB-CHO99.20%和386.66,20μg HepB-Y89.04%和372.97。各年龄组的再免疫成功率和抗体水平中位数（mIU/ml）分别是：2～4岁98.25%和353.42,6～8岁96.80%和320.31,13～15岁94.67%和282.12,16～40岁87.76%和305.24。结论年龄、疫苗种类和剂量是影响再免疫抗体应答的主要因素,随年龄的增长再免疫抗体应答下降,更换疫苗种类可提高再免疫抗体应答。     

儿童对乙型肝炎疫苗加强接种的免疫应答

观察了经乙型肝炎疫苗初免的38名儿童对乙型肝炎疫苗加强接种的免疫效果。疫苗加强接种后97.4%(37/38)儿童产生了免疫应答,接种后3周、3月及6月的抗-HBs水平由接种前的33.6IU/L,分别增至824.1、407.7及193.6IU/L,平均增高24.5、12.1和5.8倍,加强接种后3周抗-HBs水平达到高峰,3月及6月时抗-HBs水平比3周时分别下降50.5%和76.5%。加强免疫的应答效果主要由初免的免疫应答状态所决定。本文显示,儿童用10μg乙型肝炎疫苗加强接种能获得良好的免疫应答效果。     

Immunogenicity of hepatitis B vaccine among hemodialysis patients: effect of revaccination of non-responders and duration of protection

Background

Hepatitis B vaccination is recommended for patients on hemodialysis, however, seroprotection after a primary vaccine series is suboptimum. Limited data are available on the effect of revaccination of non-responders and on persistence of immunity in this population.

Methods

Hepatitis B vaccine (40 μg/dose) was given to 77 susceptible patients on hemodialysis (0, 1, and 6 month schedule). Levels of hepatitis B surface antibody (anti-HBs) were tested ≥28 days after the third dose was administered, and non-responders revaccinated with an additional 3-dose series. Vaccine responders (anti-HBs ≥10 mIU/mL) were re-tested every 6 months and booster doses given as needed. Kaplan-Meier survival curve was used to estimate the probability of maintaining protective antibody level. Cox-proportional hazards models were used to assess the association between time to loss of protective antibody levels and certain explanatory variables.

Results

Overall primary vaccine-induced response was 79.2% (95% CI 68.2%, 87.3%), including 49/77 (63.6%; 95% CI 51.8%, 74.7%) patients who received the initial primary hepatitis B vaccine series and 12/21 (57.1%; 95% CI 34.4%, 77.4%) non-responders who were revaccinated with an additional series. Among weak responders (anti-HBs level 10.0-99.9 mIU/mL), protective antibody levels persisted in 44% for 12 months post-vaccination; whereas among strong responders (anti-HBs level ≥100 mIU/mL), protective antibody levels persisted in 92% for 12 months, and 68% for 24 months post-vaccination. A weak post-vaccination response increased the risk of losing protective antibody levels (adjusted hazard ratio, 9.7; 95% confidence interval, 3.5-28.5; p < 0.0001).

Conclusion

Revaccinating patients undergoing hemodialysis who do not respond to a primary vaccine series substantially increases the pool of protected patients. The threshold for defining hepatitis B vaccine-induced immunity should be revisited in this patient population to maximize the duration of protection.