新工艺制备Hib结合疫苗原液长期稳定性试验

目的在前期开发的b型流感嗜血杆菌(haemophilus influenzae type b,Hib)荚膜多糖提取新工艺及利用1-氰基-4-二甲基氨基吡啶·四氟化硼(1-cyano-4-dimethylaminopyridinium tetrafluoroborate,CDAP)活化的疫苗制备新方法的基础上,评价利用新方法生产的Hib结合疫苗原液的稳定性。方法将疫苗原液在2～8℃条件下放置36个月,根据实验设计,不同时间取样并按照《中国药典》中相应的检测指标、检测方法进行评价。结果新工艺制备的Hib结合疫苗原液在2～8℃储存条件下,大部分指标保持相对稳定,只有分子量大小、高分子结合物含量及效力结果下降,但保存30个月仍符合2010年《中国药典》的相关要求。结论新方法与传统方法生产的Hib结合疫苗原液稳定性基本相同,证明了利用新方法制备Hib结合疫苗的新工艺可以用于扩大生产规模。     

GBSⅢ荚膜多糖-精制破伤风类毒素结合疫苗的制备及其免疫原性研究

目的研究和制备B群链球菌Ⅲ荚膜多糖-破伤风类毒素结合疫苗,并对其免疫原性进行评价.方法用亲和层析法纯化荚膜多糖抗原,用获得的结合疫苗皮下注射免疫小鼠,间接ELISA方法检测小鼠血清内型特异性的IgG抗体.结果结合疫苗在小鼠体内诱导产生的免疫反应远比单纯的荚膜多糖强烈.结论破伤风类毒素作为荚膜多糖抗原的载体,能显著提高荚膜多糖的免疫原性.     

提高疫苗接种率降低Hib感染危害

b型流感嗜血杆菌(Hib)是引起5岁以下婴幼儿侵袭性感染的重要致病菌。脑膜炎和肺炎是Hib感染的两种主要疾病。目前使用的多糖-蛋白结合疫苗,对预防儿童Hib有一定效果。本文通过预防保健工作人员对开展b型流感嗜血杆菌相关疾病危害性和防治知识的宣教,提高了Hib疫苗的免疫效果,降低了Hib感染的危害。     

B型流感嗜血杆菌疫苗的研究进展

B型流感嗜血杆菌(Haemophilus influenzae type b,Hib)是小儿细菌性感染的主要元凶之一。据世界卫生组织(WHO)2012年4月统计报道,2008年全世界因Hib感染死亡的5岁以下儿童人数为20.3万,而目前预防Hib最有效的措施是接种Hib疫苗。本文回顾了Hib疫苗的发展,对现有Hib结合疫苗的免疫原性、结合方式、结合策略进行综述。     

接种b型流感嗜血杆菌结合疫苗偶合急性咽炎二例

b型流行性感冒嗜血杆菌结合疫苗,简称Hib疫苗,是用来预防b型流感嗜血杆菌引起的感染性疾病,如脑膜炎、肺炎、蜂窝组织炎、关节炎、会厌炎、败血症等,但对其它病原体引起的感染无效.Hib疫苗在中国接种的时间不长,开始用的是进口疫苗, 2004年以后,才有国产Hib疫苗投产[1].该疫苗副作用少,接种安全,出现异常反应的报道不多.近年来曾有个别接种Hib疫苗后偶合血小板减少性紫癜、幼儿急疹、多发性神经炎等疾病的报道[2-4].     

B型流感嗜血杆菌结合疫苗纳入肯尼亚儿童计划免疫的效果

背景：迄今为止，非洲国家未将B型流感嗜血杆菌（Haemophilus influenzae Type b，Hib）结合疫苗列为首要的公共卫生问题，其原因在于有关Hib疾病负担以及Hib疫苗效力的资料仍很稀缺。2001年，肯尼亚的婴儿开始接种Hib疫苗。     

柳州市儿童b型流感嗜血杆菌多糖抗体水平调查分析

目的了解b型流感嗜血杆菌（141b）最易感人群体内Hib的特异性荚膜多糖（PRP）自然抗体水平。为Hib疫苗的推广使用提供依据。方法从柳州市常住3～59月龄健康婴幼儿中,抽取未接种过Hib疫苗的婴幼儿708名,采集血清标本,用ELISA方法检测Hib—PRP自然抗体水平。结果3～59月龄婴幼儿体内Hib—PRP自然抗体水平（0．1840．016）mg／L;3—35月龄婴幼儿体内Hib—PRP抗体水平与36—59月龄幼儿体内Hib—PRP抗体水平间差异有统计学意义（P〈0．05）。各月龄儿童体内抗-PRP水平的保护程度间差异有统计学意义（P〈0．05）。幼儿园儿童抗-PRP水平高于散居儿童（P〈0．05）;性别对婴幼儿体内Hib—PRP抗体水平没有影响（P〉0．05）。结论对最易感人群接种Hib疫苗,提高体内Hib—PRP抗体水平,预防Hib感染性疾病是非常必要的。     

新药研究与开发

FDA批准葛兰素史克公司的B型流感嗜血杆菌强化疫苗为应对美国预防婴儿B型流感嗜血杆菌(Hib)强化疫苗短缺,葛兰素史克公司收到FDA的加速批准函,允许其B型流感嗜血杆菌疫苗Hiberix(Hib与破伤风类毒素结合疫苗)用于15月龄至4岁婴儿免疫强化,作用可持续4年.     

美国加拿大限制对幼儿接种流感嗜血杆菌b型结合疫苗

加拿大多伦多消息:要求批准年龄小于18月的儿童接种流感嗜血杆菌(Haemophilus influenzae)b型(Hib)结合疫苗的压力,在美国和加拿大在增加着。新的结合型疫苗似乎对18个月的婴儿就有致免疫原性,比过去不结合型PRP疫苗批准在24～60个月对婴儿接种是一进步。在美国每年约有近20000例Hib脑膜炎发生,在加拿大每年可能有多至1000例发生,80％病例发生在2岁以下儿童。洛杉矶加利福尼亚大学(UCLA)医学中心流行病学主任Joel Ward博士说:“若要预     

Hib多糖衍生物中残余CDAP检测方法的建立

目的 在b型流感嗜血杆菌结合疫苗生产过程中有效监控1-氰基-4-二甲基氨基-吡啶四氟化硼（CDAP）的残留量。方法 在已有针对流脑多糖衍生物的基于强阳离子交换层析检测法的基础上进行改进。结果 该法具有良好的专属性、准确度、精密度,最低检出限为6μg/L,且在20~100μg/L的范围内线性良好。结论 建立了一种针对b型流感嗜血杆菌多糖衍生物中CDAP的检测方法。     

潍坊市健康人群A、C群脑膜炎奈瑟菌抗体水平调查

目的了解潍坊市健康人群A、C群脑膜炎奈瑟菌(Nm)抗体水平,为制定预防控制流行性脑脊髓膜炎(流脑)措施提供依据。方法采用分层随机抽样方法,在5个县市区共采集1125名健康人群血清标本,应用酶联免疫吸附试验检测A、C群Nm抗体。结果调查的1125名健康人群中,A群Nm抗体阳性率22.58%(254/1125),几何平均滴度(GMP)为1:1.70;C群Nm抗体阳性率11.73%(132/1125),(GMP)为1:1.30。结论潍坊市健康人群A、C群Nm抗体水平均较低。     

Immunoglobulin deficiency and idiotype expression in children developing Haemophilus influenzae type b disease after vaccination with conjugate vaccine. The Collaborative Study Group

OBJECTIVE.--Haemophilus influenzae type b (Hib) conjugate vaccines are effective in preventing Haemophilus disease in most children. The reasons why the vaccination fails in some children are unknown. This study investigated host factors in children who developed the disease despite conjugate vaccination. DESIGN, PATIENTS, OUTCOME MEASURES.--A convenience sample of 23 patients in whom Hib disease developed 14 days or more after conjugate vaccination was investigated for the presence of subnormal serum immunoglobulin concentrations and anticapsular antibody responses to Hib disease. We also investigated expression of the Hib idiotype 1 (Hibld-1), a serological marker of a VKII chain that comprises a major portion of the normal variable region repertoire of the antibody response to Hib polysaccharide. The results were compared with those of 149 patients in whom the unconjugated Hib polysaccharide vaccine failed and of 90 unvaccinated patients who developed the disease. RESULTS.--Compared with children in whom the unconjugated polysaccharide vaccination failed, the relative risk of a subnormal serum concentration of IgM, IgA, IgG, and/or IgG2 in the children in whom the conjugate vaccination failed was 4.9 (95% confidence interval [CI], 1.8 to 14; P less than .003) and of IgG2 was 22 (95% CI, 3.5 to 146; P less than .001). With the exception of the children with subnormal serum immunoglobulin concentrations, most of the children with conjugate vaccination failure showed normal or high anticapsular antibody responses to the disease, whereas the children with polysaccharide vaccination failure showed impaired responses. The Hibld-1 was expressed by the majority of the children in both vaccination failure groups and of the unvaccinated patients. CONCLUSIONS.--In most patients, vaccination failure is not attributable to lack of expression of the variable region gene encoding Hibld-1. However, children in whom conjugate vaccination has failed frequently have subnormal serum immunoglobulin concentrations and should be evaluated for immunodeficiency.     

23价肺炎球菌多糖疫苗体外诱导人气道上皮细胞hBD-2表达的机制

目的探讨23价肺炎球菌多糖疫苗在体外诱导人气道上皮细胞人防御素2（human β-defensin2,hBD-2）表达的机制。方法0．5μg/ml的23价肺炎球茵多糖疫苗刺激原代人气道上皮细胞12h,电泳迁移率变动分析法（electrophoretic mobility shift assay,EMSA）检测原代人气道上皮细胞中NF-KB的活性。激光扫描共聚焦显微镜技术检测原代人气道上皮细胞内钙离子浓度的变化情况。结果23价肺炎球菌多糖疫苗刺激原代人气道上皮细胞24h后．细胞内NF-KB活性增高;静息状态下人气道上皮细胞内钙离子浓度为（38．4±1．21）nmol／L,随着刺激时间的延长,钙离子的浓度逐渐上升,20、30、40min分别为（50．5±3．26）、（51±2．83）、（48±3．47）nmol／L,与对照组相比,差异具有统计学意义（P〈0．05）。结论23价肺炎球菌多糖疫苗诱导hBD-2表达上调是通过激活NF-κB信号通路介导的,细胞内钙离子浓度增高可能是NF-κB激活的重要因素之-。     

4种评价方法对广东省常规免疫报告接种率可靠性的评价分析

目的了解广东省常规免疫数据报告质量,为指导今后常规免疫接种率监测工作和制定策略提供科学依据。方法收集广东省2010-2012年儿童卡介苗(BCG)、乙肝疫苗(HepB)、脊灰疫苗(PV)、百白破疫苗(DPT)、含麻疹成分疫苗(MCV)、乙脑疫苗(JE)、A群流脑疫苗(MenA)和甲肝疫苗(HepA)常规免疫接种数据,采用D值法、R值法、脱漏率以及与疫苗用量比较法对报告接种率的可靠性进行评价。结果 2010-2012年广东省8种免疫规划疫苗报告接种率在91.31%~99.71%之间,估算接种率在39.38%~106.18%之间。各年HepB、PV、DPT、MCV的D值评价均为可信,HepA的D值评价均为不可信,JE的D值评价均为可疑,2011、2012年BCG和MenA的D值评价均为可疑。HepB、PV和JE的R值评价均为可信,HepA的R值评价均为不可信,2011、2012年BCG和MenA的R值评价为可疑。各年流动儿童HepB和MenA的脱漏率,以及2010年本地儿童MenA的脱漏率均超过10%。DPT和JE的估算损耗系数与参考损耗系数较为接近,而HepA的估算损耗系数与参考损耗系数有较大差别。结论广东省常规免疫报告接种数据存在漏报和虚报情况,报告接种率不能真实反映实际接种情况,数据报告质量有待提高。     

Antibody concentration and clinical protection after Hib conjugate vaccination in the United Kingdom

CONTEXT: The schedule for Haemophilus influenzae type b (Hib) vaccination of infants in the United Kingdom consists of 3 doses given at 2, 3, and 4 months of age. Many countries include a fourth dose (booster) of Hib vaccine in the second year of life on the basis of declining Hib antibody concentrations after the primary series. Few data are available to show that this fourth dose is actually necessary. OBJECTIVE: To evaluate long-term clinical protection against Hib disease and Hib antibody concentrations following primary Hib vaccination without a booster dose. DESIGN, SETTING, AND SUBJECTS: Clinical protection study conducted between October 1992 and March 1999 in the United Kingdom, in which children developing invasive Hib disease despite vaccination in infancy with 3 doses of Hib conjugate vaccine were reported by pediatricians through an active, prospective, national survey. Separate antibody studies were conducted among 2 cohorts of children (n = 153 and n = 107) vaccinated at 2, 3, and 4 months of age with Hib conjugate vaccine and followed up to 43 and 72 months of age. MAIN OUTCOME MEASURES: Age-specific vaccine effectiveness, derived from the observed number of true vaccine failures after 3 Hib vaccine doses compared with the number of cases expected based on the age-specific rates of invasive Hib disease obtained prior to the introduction of Hib vaccines; and proportion of children in the 2 cohorts with Hib antibody concentrations of less than 0.15 and less than 1.0 microg/mL. RESULTS: Ninety-six true vaccine failures occurring after 3 vaccine doses were detected. During the study period, an estimated 4,368,200 infants in the United Kingdom received 3 doses of vaccine; therefore, the vaccine failure rate was 2.2 per 100,000 vaccinees (95% confidence interval, 1.8-2.7 per 100,000). Although vaccine effectiveness declined significantly after the first year of life (P<.001), it remained high until the sixth year of life (99.4% in children aged 5-11 months vs 97.3% in those aged 12-71 months). The proportion of cohorts 1 and 2 with anti-PRP antibody levels of less than 0.15 microg/mL increased between 12 and 72 months of age (6% at 12 months, 8% at 43 months, and 32% at 72 months; chi(2)(1) = 18.25; P<.001 for trend). CONCLUSIONS: Our results suggest that anti-PRP antibody levels and clinical protection against Hib disease wane over time after Hib vaccination at 2, 3, and 4 months of age without a booster dose at 2 years of age. The decline in clinical protection is minimal, however, suggesting that a booster dose of Hib vaccine following infant vaccination is not essential. JAMA. 2000;284:2334-2340.     

青岛市汉族群体ADH2和ALDH2基因多态性及其与乙醇代谢速率关系

目的了解青岛市汉族人群乙醇脱氢酶（ADH2）和乙醛脱氢酶（ALDH2）基因的多态性分布及其乙醇代谢速率。方法提取青岛市179例汉族健康人的DNA,用扩增片段长度多态性方法,设计特殊引物对ADH2和ALDH2基因的特定序列进行扩增,并检测不同ADH2基因型受试者的乙醇代谢速率。结果 ADH2基因的两种等位基因ADH2＊1和ADH2＊2频率分别为42.74%和57.26%,3种基因型ADH2＊1/＊1、ADH2＊1/＊2和ADH2＊2/＊2频率分别为15.08%、55.31%和29.61%;ALDH2基因的两种等位基因ALDH2＊1和ALDH2＊2频率分别为72.26%和23.74%,3种基因型ALDH2＊1/＊1、ALDH2＊1/＊2和ALDH2＊2/＊2频率分别为59.78%、39.96%和7.26%。ADH2＊1/＊1基因型的乙醇代谢速率为（113.6±3.6）mg/（L·h）,ADH2＊1/＊2为（85.9±6.0）mg/（L·h）,ADH2＊2/＊2为（60.6±4.0）mg/（L·h）,差异有显著性（F=95.22,P〈0.01）。结论青岛市汉族群体ADH2和ALDH2存在基因多态性,ADH2基因多态性与乙醇代谢的快慢有关。     

义乌市2012年疑似预防接种异常反应监测情况分析

目的分析2012年义乌市疑似预防接种异常反应（Adverse Events Following Immunization,AEFI）的监测资料,评价AEFI监测系统运行状况,探讨监测中可能存在的问题。方法采用描述性流行病学方法分析2012年义乌市AEFI监测资料。结果 2012年义乌市AEFI监测系统共报告病例54例,其中一般反应21例（38.89%）,异常反应29例（53.70%）,偶合症4例（7.41%）。AEFI总报告发生率为6.59人次/10万剂;48 h报告及时率及调查率均为100%。病例报告数较多的是百白破疫苗（10例）和麻风疫苗（6例）,而报告发生率较高的为乙脑（灭活）疫苗（124.44人次/10万剂）、流脑A＋C结合疫苗（98.89人次/10万剂）及7价肺炎疫苗（40.05人次/10万剂）。结论 2012年义乌市AEFI监测系统总体运转情况良好。但由于多种因素的影响,异常反应的报告比重大于一般反应,部分二类疫苗的报告发生率也较高,提示需强化人员监测意识,提高监测敏感性。     

A day care-based study of the efficacy of Haemophilus b polysaccharide vaccine

To assess the efficacy of the Haemophilus b polysaccharide vaccine following licensure and to evaluate the risk of Haemophilus influenzae type b (Hib) disease in the week following vaccination, we conducted a day care-based case-control efficacy study using cases of invasive Hib disease ascertained through active surveillance in areas with a total population of 34 million. For each patient 18 to 59 months old, up to three 18- to 59-month-old controls were chosen from the same day care classroom. Using conditional logistic regression, the vaccine efficacy was estimated to be 45% (95% confidence interval = -1% to 70%) and did not change significantly after accounting for potential biases. In addition, three (3%) of 104 patients vs five (2%) of 207 controls were vaccinated within seven days before the patients' dates of admission (odds ratio = 1.8, 95% confidence interval = 0.3 to 10.2), which does not suggest an increased risk of Hib disease in the week following immunization. This study suggests that the efficacy of the currently used HBPV is less than expected from previous studies and points out the usefulness of case-control studies for monitoring vaccine efficacy following licensure.     

活性维生素D3在大鼠肾间质纤维化中的保护作用

目的探究活性维生素D3[1,25-（OH）2D3]对大鼠肾间质纤维化的保护作用。方法选取体质量在200~220 g的清洁级大鼠60只,随机分为3组,假手术组（20例）、UUO组（20例）,UUO＋活性维生素D3组（20例）。肾间质模型采用单侧输尿管结扎法（unilateral ureteral obstruction,UUO）。造模后UUO＋活性维生素D3组给予骨化三醇（商品名罗钙全）灌胃[3 ng/（100 g·d）],其他两组给予生理盐水灌胃,在给药15 d后,30 d后分两批处死,并取造模侧肾脏,采用HE染色法观察造模肾脏组织的纤维化程度,测定各组大鼠结缔组织生长因子（connective tissue growth factor,CTGF）（免疫组织化学法）在造模侧肾脏的表达情况。结果 UUO组、UUO＋活性维生素D3组其CTGF表达水平均较假手术组有提高,而UUO＋活性维生素D3组其结缔组织表达水平明显低于UUO组。结论活性维生素D3可以有效地抑制CTGF的表达,有减轻UUO大鼠的肾脏组织纤维化程度的作用。     

ADH活性对绞窄性肠梗阻大鼠早期肠缺血预测作用

目的探讨乙醇脱氢酶（ADH）活性对绞窄性肠梗阻大鼠早期肠缺血的预测作用。方法成年健康Wistar大鼠72只,随机分为假手术组（A组,n=8）,单纯性肠梗阻（S组,n=32）,绞窄性肠梗阻组（I组,n=32）。A组仅开腹翻动肠管后关腹;S组在盲肠末端以上10cm处结扎小肠;I组结扎肠系膜上动脉根部。S、I组分别于造模成功后O．5、1．0、3．0、6.0h下腔静脉取血测定血清乙醇脱氢酶（ADH）、天冬氨酸氨基转氨酶（AST）、丙氨酸转氨酶（ALT）水平,并与肝、小肠损伤病理评分做相关性分析。结果I组各时间点ADH活性与A组比较差异均有显著性（F=37．27,q=5．53～16．31,P＜0．05）;S组与I组各对应时间点ADH活性比较差异均有显著性（q：5．025～12．20,P＜0.05）;S组各时间点各指标与A组比较差异均无显著性（F=15．24～37．27,P＞0．05）;与A组比较,I组ALT、AST分别在6．0h和3．0h明显升高,差异有显著意义（F=15．24、16．69,q=12．32、12．81,P＜O．05）。I组ADH、AI。T、AST与小肠、肝脏病理评分均呈正相关（r=O．696～0．795,P＜0．05）。结论ADH水平在绞窄性肠梗阻早期即开始升高,与肠损伤程度呈正相关,可能成为预测早期肠绞窄的指标。