肠道病毒71型灭活疫苗(Vero细胞)安全性分析

目的观察6月龄～3周岁儿童人群接种肠道病毒71型灭活疫苗(Vero细胞)(以下简称EV71疫苗)的安全性。方法通过主动监测与被动监测相结合的方式,观察受种者EV71疫苗接种后30d内发生的不良事件,采用描述性流行病学方法分析其特征。结果 4 077名儿童受种者,接种7 952剂EV71疫苗,其中第1剂4 077人,第2剂3 875人,共观察到接种后30d内发生的不良事件102例,总体不良事件发生率1.28/100剂,其中第1剂1.55/100剂,第2剂1.01/100剂,剂次间差异无统计学意义(χ~2=4.555,P=0.033)。接种局部可出现红、痛、疹、硬结、肿,发生率间差异无统计学意义,全身不良事件以发热、疲倦乏力、食欲下降、上呼吸道感染占优势,全身不良事件较局部发生率为高,不良事件发生与接种时间间隔以24h内(85.53%)多见,所有不良事件以1、2级(92.11%)为主,3级不良事件以发热(83.33%)为主,未发现致残致死或并发症等严重危及受种者身体健康的不良事件,所有不良事件经对症处理后均在7d内痊愈。结论在6月龄～3周岁儿童中实施EV71灭活疫苗接种具有较好的安全性。     

8-20月龄儿童接种肠道病毒71型灭活疫苗的免疫原性和持久性北大核心

目的观察8-20月龄儿童接种2剂次肠道病毒71型(Enterovirus 71,EV-71)灭活疫苗的免疫原性和持久性。方法于2017年10-12月在上海市静安区招募8-20月龄儿童,按0d、30d程序接种2剂次EV-71疫苗,采集免疫前和免疫后60d、365d、730d血标本,采用细胞病变法测定血清EV-71中和抗体,分析抗体阳转率和几何平均滴度(Geometric mean titer,GMT)。结果受试者EV-71疫苗免疫前EV-71中和抗体阳性率、GMT分别为3.25%(4/123)、1:4.17,免疫后60d、365d、730d抗体阳转率分别为96.15%(100/104)、90.20%(92/102)、90.80%(79/87),GMT分别1:41.76、1:28.44、1:43.41。结论8-20月龄儿童对EV-71疫苗具有良好的免疫原性和2年免疫持久性。     

甲型肝炎灭活疫苗（Vero细胞）人体接种的安全性和免疫原性研究

目的 研究在中国儿童和成人中接种江苏延申生物科技股份有限公司研制的甲型肝炎灭活疫苗(Vero细胞)的安全性和免疫原性.方法 在广西蒙山县筛选甲型肝炎病毒易感者,采用随机、盲法,同类疫苗对照方法,对600名1.5～15岁儿童和600名成人按照2:1比例,各400人接种试验疫苗(儿童或成人剂量甲型肝炎灭活疫苗)和200人接种对照疫苗(市售同类儿童或成人剂量甲型肝炎灭活疫苗),免疫程序为0、6月;观察接种后局部反应和全身反应;采用EIA竞争抑制法检测免疫前后的甲型肝炎抗体,以WHO甲肝免疫球蛋白(含100IU/ml)标准品进行标定,计算免疫后的甲型肝炎抗体阳转率和抗体几何平均滴度(mIU/ml).结果 两剂量组试验疫苗与对照疫苗的局部反应和全身反应相似,局部反应以注射部位疼痛多主,全身反应以轻度发热反应较常见.试验疫苗儿童剂量组和成人剂量组甲肝抗体阳转率分别为98.53%和97.55%,甲肝抗体几何平均滴度分别为10 332.32 mIU/ml和9 473.65 mIU/ml,与对照组比较均无显著差异.结论 新型甲肝灭活疫苗(Vero细胞)儿童剂量(800EU/ml)和成人剂量(1 600EU/ml)对儿童或成人接种的安全性良好,并可诱导高度的抗HAV阳转率和抗体水平.     

金华市6-35月龄儿童肠道病毒71型灭活疫苗免疫原性监测北大核心

目的评价上市肠道病毒71型(Enterovirus 71,EV71)灭活疫苗的免疫原性。方法采用分层随机抽样方法选取金华市6-35月龄健康婴幼儿,接种2剂次EV71疫苗,检测免疫前和免疫后30-45d血清抗EV71中和抗体,分析免疫后抗体阳转率和几何平均滴度(Geometric mean titer,GMT)。结果受试者2剂次EV71疫苗免疫后抗EV71中和抗体阳转率为99.24%(362/364),GMT为1:117.06。6-11、12-23、24-35月龄儿童中和抗体阳转率分别为100%、98.39%、100%(Fisher精确概率法,P=0.244),GMT(1:)分别为103.28、123.95、163.61(F=0.32,P=0.728)。A、B、C生产企业EV71疫苗的中和抗体阳转率分别为100%、98.33%、100%(Fisher精确概率法,P=0.216),GMT(1:)分别为127.75、109.95、113.88(F=1.04,P=0.353)。结论金华市上市EV71疫苗在6-35月龄儿童中均具有良好的免疫原性;建议加强EV71疫苗接种宣传,提高适龄儿童接种率。     

小儿接种肠道病毒71型灭活疫苗预防效果研究

目的 探讨肠道病毒71型（Enterovirus 71,EV71）灭活疫苗对预防手足口病（hand-foot-mouth disease,HFMD）的预防作用及安全性。方法 选取2018年1—12月山东省广饶县大码头镇辖区内786例适龄儿童为研究对象,按照是否接种EV71疫苗分为研究组（接种疫苗）367例与对照组（未接种疫苗）419例。分析儿童接种EV71疫苗后的不良反应,并统计比较两组儿童2年内EV71型HFMD发生率及重症HFMD发生率。结果 研究组儿童接种EV71疫苗后30 d内不良反应发生率为3.54%(26/734);不同性别、不同年龄儿童接种EV71疫苗后全身不良反应、局部不良反应比较差异均无统计学意义（均P> 0.05）。随访2年,研究组EV71型HFMD发生率为0.27%,低于对照组的2.15%(P <0.05),两组重症HFMD发生率比较差异无统计学意义（P> 0.05）。结论 接种EV71疫苗,不良反应发生率低且症状轻微,具有较高安全性,可有效降低EV71型HFMD发病率。     

杭州市儿童肠道病毒71型灭活疫苗接种特征分析

目的分析杭州市2014-2017年出生儿童肠道病毒71型(EV71)疫苗接种情况,为今后EV71疫苗的接种实施提供依据。方法从杭州市儿童免疫规划信息管理系统中导出2014-2017年出生儿童EV71疫苗接种数据,运用描述流行病学方法进行分析。结果在550888名2014-2017年出生儿童中,第1剂次EV71疫苗接种率为29.15%,2014-2017年各年出生儿童接种率分别为11.55%、22.13%、37.93%和42.16%,城区、城乡结合部、郊县儿童接种率分别为43.85%、20.78%和27.87%。第2剂次接种率为26.59%,2014-2017年各年龄组儿童接种率分别为10.14%、20.03%、35.23%和38.31%,城区、城乡结合部、郊县儿童接种率分别为40.51%、18.59%和24.61%。EV71疫苗主要接种年龄为1岁,其中10~13月龄为接种高峰。结论杭州市EV71疫苗接种率虽逐年上升但有待进一步提高,接种月龄偏晚,需加强EV71疫苗接种宣传,使儿童尽早完成接种获得免疫保护。     

北京市朝阳区婴幼儿接种EV71疫苗的安全性调查

  目的  分析国产肠道病毒71型（EV71）灭活疫苗上市后在大人群（IV期临床试验）接种中的安全性,为国产EV71灭活疫苗的广泛接种提供参考。  方法  按自愿自费知情同意原则,在北京市朝阳区选取2016年8月 — 2017年12月按程序接种国产EV71疫苗的25 995名6～71月龄常住健康婴幼儿作为观察对象,于受种婴幼儿上臂三角肌肌内注射,共免疫2剂次,观察受种婴幼儿每剂接种后30 min的即时反应,并通过接种医生电话访视或法定监护人收集受种婴幼儿每剂接种后30 d内的全身、局部和其他不良事件记录在《不良事件主动监测登记表》上,参照国家食品药品监督管理局关于《预防用疫苗临床试验不良事件分级标准指导原则》对注射部位红肿、注射部位硬结、发热进行分级,同时统计不良事件发生率。  结果  观察的25 995名婴幼儿共计接种国产EV71疫苗52 260剂次,接种共发生总不良事件1 730例次,发生率为3.31 %。其中,全身、局部和其他不良事件分别为1 178、516和36例次,发生率分别为2.25 %、0.99 %和0.07 %;在注射部位红肿、注射部位硬结、发热等不良事件中,1、2和3级不良事件分别为362、537和36例次,发生率分别为0.69 %、1.03 %和0.07 %,未见 ≥ 4级及罕见和极罕见不良事件,所有不良事件均经药物或门诊治疗痊愈。  结论  国产EV71疫苗具有较好的安全性。     

江苏省儿童家长肠道病毒71型灭活疫苗接种意愿和影响因素北大核心

目的掌握江苏省家长为儿童接种肠道病毒71型(EV71)灭活疫苗的意愿和影响因素。方法采样分层随机抽样方法,抽取江苏省三个市6月龄-5岁儿童家长进行面对面在线问卷调查,采用多因素Logistic回归分析EV71疫苗接种意愿的影响因素。结果65.9%(593/900)的家长愿意为孩子接种EV71疫苗。多因素Logistic回归分析显示,居住在苏州市或盐城市、愿意为孩子接种水痘疫苗、手足口病认知高、认为疫苗价格能接受的儿童家长为孩子接种EV71疫苗的意愿率高;而家庭有医学背景者接种意愿率低。结论江苏省儿童家长为孩子接种EV71疫苗的意愿率较高,需进一步加强对儿童家长的EV71疫苗相关知识宣传。     

精制甲型肝炎灭活疫苗(Vero细胞)维罗信TM的安全性和免疫原性随机对照研究

目的评价精制甲型肝炎灭活疫苗(Vero细胞)的安全性和免疫原性。方法2005年1～8月在广西恭城县选择1507名健康人群,以随机、双盲、平行对照方法,观察该疫苗的不良反应,抗体阳转率和抗体水平(GMT),应用EIA竞争抑制法检测血清抗甲型肝炎抗体(抗-HAVIgG)。结果成人剂量组试验疫苗全身、局部反应发生率分别为8.80%、2.67%,与对照疫苗(分别为12.41%、4.41%)相比,无显著差异;儿童剂量组试验疫苗全身、局部反应发生率分别为10.60%、2.28%,与对照疫苗(10.71%、2.86%)相比,亦无显著性差异。维罗信首针免疫后1个月,儿童剂量组和成人剂量组的阳转率分别为88.2%、93.8%,两针全程免疫1个月后两组抗体阳转率均达到100%,抗体滴度分别为16447、8555mIU/ml,对照疫苗分别为1946、5881mIU/ml,儿童剂量组抗体滴度与对照组相比有显著性差异。结论精制甲型肝炎灭活疫苗(Vero细胞)在儿童和成人中应用具有良好的安全性,采用0,6个月免疫程序免疫后抗体阳转率达100%,并有高的抗体滴度。     

肠道病毒71型灭活疫苗上市后安全性主动监测

目的 初步评价肠道病毒71型（EV71）灭活疫苗（EV71疫苗）上市后常规接种的安全性,比较疑似预防接种不良反应（AEFI）主动及被动监测的差异。方法 2016年8-11月在北京市朝阳区对3 162名儿童开展EV71疫苗上市后安全性监测,其中对770名受种儿童采用手机应用（APP）信息化平台进行主动监测AEFI,对2 392名受种儿童通过家长上报方式进行被动监测AEFI。结果 主动监测组AEFI总发生率为42.33%（326/770）,以全身反应为主,未见罕见和极罕见不良反应;被动监测组AEFI总发生率为0.67%（16/2 392）,明显低于主动监测组（χ²=51 274.285,P<0.001）,主要表现为一般反应。结论 该EV71疫苗安全性良好;主动监测能够更敏感地获得疫苗接种后不良反应,可为疫苗的安全性评价提供可靠的数据支持。     

Similar protective immunity induced by an inactivated enterovirus 71 (EV71) vaccine in neonatal rhesus macaques and children

During the development of enterovirus 71 (EV71) inactivated vaccine for preventing human hand, foot and mouth diseases (HFMD) by EV71 infection, an effective animal model is presumed to be significant and necessary. Our previous study demonstrated that the vesicles in oral regions and limbs potentially associated with viremia, which are the typical manifestations of HFMD, and remarkable pathologic changes were identified in various tissues of neonatal rhesus macaque during EV71 infection. Although an immune response in terms of neutralizing antibody and T cell memory was observed in animals infected by the virus or stimulated by viral antigen, whether such a response could be considered as an indicator to justify the immune response in individuals vaccinated or infected in a pandemic needs to be investigated. Here, a comparative analysis of the neutralizing antibody response and IFN-γ-specific T cell response in vaccinated neonatal rhesus macaques and a human clinical trial with an EV71 inactivated vaccine was performed, and the results showed the identical tendency and increased level of neutralizing antibody and the IFN-γ-specific T cell response stimulated by the EV71 antigen peptide. Importantly, the clinical protective efficacy against virus infection by the elicited immune response in the immunized population compared with the placebo control and the up-modulated gene profile associated with immune activation were similar to those in infected macaques. Further safety verification of this vaccine in neonatal rhesus macaques and children confirmed the potential use of the macaque as a reliable model for the evaluation of an EV71 candidate vaccine.     

Willingness and influential factors of parents to vaccinate their children with novel inactivated enterovirus 71 vaccines in Guangzhou,China

Hand, foot and mouth disease (HFMD) primarily affects children younger than 5 years of age. Recently, HFMD has ranked as the top notifiable infectious disease in China. In December 2015, China approved two novel inactivated enterovirus 71 vaccines (EV71 vaccines) for HFMD. Parents’ acceptance is often essential for vaccination program success. The goal of this study was to identify willingness and influential factors to vaccinate among parents of kindergarteners in Guangzhou, China. A cross-sectional survey of face-to-face interviews was conducted from March to July 2016. Fifty-five kindergartens were randomly selected from 11 districts of Guangzhou. An anonymous self-designed questionnaire was used to investigate awareness, knowledge and attitude towards HFMD and EV71 vaccines. A total of 868 parents participated in the survey. Mean(±standard deviation) knowledge score of HFMD was 6.32(±1.70). Approximately 32.03% of parents had heard of the EV71 vaccines with 22.58% receiving information before this study. Nearly 44.24% of parents showed willingness to vaccinate their children. Previously receiving EV71 vaccine-related information [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.04–2.11], no fear of adverse effects (aOR = 4.25, 95%CI: 2.77–6.53), perceived susceptibility of children to HFMD (aOR = 2.15, 95%CI: 1.42–3.25) and children not previously diagnosed with HFMD (aOR = 1.56, 95%CI: 1.07–2.27) were positively associated with EV71 vaccination acceptability. However, parental education background (aOR = 0.54, 95%CI: 0.37–0.80) was negatively correlated with vaccination acceptability. Our study provides baseline information for future vaccination campaigns to help improve the EV71 vaccine uptake rate. Special efforts are urgently needed to improve the awareness and knowledge of EV71 vaccines in China.     

儿童肠道病毒71型和柯萨奇病毒A16型感染血清流行病学研究进展

  目的  了解广东省2016 — 2017年肠道病毒71型（EV71）灭活疫苗接种水平及接种期间手足口病的流行情况。  方法  从“中国免疫规划信息管理系统”提取EV71灭活疫苗接种情况报表资料;从“中国疾病预防控制信息系统”收集手足口病普通病例疫情数据、重症及死亡病例疫情数据;在广东省8家哨点医院开展手足口病普通病例EV71感染病原学监测,结合EV71哨点监测结果和网络直报疫情数据来估算EV71感染手足口病发病情况。  结果  2016年9月 — 2017年12月,广东省共报告接种EV71灭活疫苗2 304 456剂次,其中2017年5 — 9月为接种高峰,月平均接种量为198 315剂次。全省平均估算接种率2016年为3.82 %、2017年为10.07 %。21个地市中深圳估算接种率最高,2016年为6.05 %、2017年为19.76 %;汕头估算接种率最低,2016年0.78 %、2017年1.39 %。2017年广东省EV71感染手足口病发病率比2016年下降39.97 %,EV71感染手足口病重症及死亡数下降53.33 %。  结论  广东省2016年启动EV71灭活疫苗接种项目以来,疫苗接种水平逐渐增加,但仍处于较低水平;2017年EV71感染手足口病发病率、重症与死亡数比2016年有所下降。     

肠道病毒71型灭活疫苗滴度的酶联免疫吸附检测方法

目的 建立肠道病毒71型(EV71)灭活疫苗滴度的检测方法,用于疫苗研制及生产过程中抗原含量的测定.方法 以兔抗EV71多克隆抗体为包被抗体,小鼠抗EV71单克隆抗体为检测抗体,以夹心ELISA方法测量我们制备的EV71疫苗抗原参照品,建立抗原标准曲线,确定定量限度及最佳定量范围,同时验证该方法的特异性和可重复性.结果...     

Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys

A number of commonly recognized public health issues are associated with EV71 infection, including the induction of severe cases of hand-foot-and-mouth disease (HFMD). Because of such issues, research and development of EV71 vaccine candidates is of growing importance. In the present study, an experimental EV71 inactivated vaccine was prepared, and its corresponding immunogenicity was analyzed. The immune responses and immunoprotective effect induced by the vaccine in mice and rhesus monkeys are described, and the two animal models are compared to evaluate the potential of assessing the inactivated vaccine's immunogenicity in these two species. In addition to assessing the vaccine's efficacy in mice, our data further elucidate the significance and value of assessing the immunogenicity and immunoprotection of vaccine candidates in rhesus monkeys by relying on a range of analyses, including pathological, etiological and lethal challenge analyses.     

Immunogenicity and safety of the inactivated enterovirus 71 vaccine administered concomitantly with the measles-rubella vaccine in infants aged 8 months in China: A noninferiority randomized controlled trial

BackgroundTo evaluate the immunogenicity and safety of simultaneous administration of the enterovirus 71 (EV71) vaccine with the measles and rubella (MR) combined vaccine.MethodsIn this phase 4, randomized, open-label and noninferiority study, a total of 680 infants aged 8 months were enrolled and assigned to the simultaneous administration group (infants received the first dose of EV71 vaccine and MR vaccine on Day 0, and the second dose of EV71 vaccine on Day 28), or the separate administration groups (EV71 group: infants received two doses of EV71 vaccine on Day 0 and Day 28, respectively; MR group: infants received MR vaccine on Day 0). Blood sample was obtained on Day 0 and Day 56 to measure antibody responses to each of the antigens in terms of antibody titer or concentration, respectively. Local and systemic adverse reactions (ARs) and other adverse events (AEs) following each dose were monitored and compared among groups.ResultsAfter vaccination, simultaneous administration group showed similar seroconversion rates of antibody against EV71(97.9%), measles (97.4%), and rubella (94.3%) compared to EV71 group (99.6% for anti-EV71) or MR group (98.4% for anti-measles and 98.9% for anti-rubella, respectively). Noninferiority was demonstrated for all antibodies as the lower limits of two-sided 97.5% confidence intervals (CIs) of the difference in seroconversion rates between simultaneous administration group and separate administration groups were above the predefined margin of ?10%. Additionally, the adverse reaction rates were comparable among groups (54.4% in the simultaneous group versus 43.9% in the MR group versus 52.6% in the EV71 group).ConclusionAntibody responses induced by simultaneous administration of EV71 vaccine with MR vaccine were robust and noninferior to those by single administration alone. Like the previous findings by single administration alone, simultaneous administration demonstrated comparable reactogenicity and safety profiles.     

Immunogenicity,safety, cross-reaction,and immune persistence of an inactivated enterovirus A71 vaccine in children aged from two months to 11 years in Taiwan

Background

To fight against enterovirus A71 (EV-A71)-associated diseases, vaccine development was initiated in Taiwan focusing on two-month-old infants.

Immunogenicity to poliovirus type 2 following two doses of fractional intradermal inactivated poliovirus vaccine: A novel dose sparing immunization schedule

IntroductionThe polio eradication endgame strategic plan calls for the sequential removal of Sabin poliovirus serotypes from the trivalent oral poliovirus vaccine (tOPV), starting with type 2, and the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV), to maintain an immunity base against poliovirus type 2. The global removal of oral poliovirus type 2 was successfully implemented in May 2016. However, IPV supply constraints has prevented introduction in 21 countries and led to complete stock-out in >20 countries.MethodsWe conducted a literature review and contacted corresponding authors of recent studies with fractional-dose IPV (fIPV), one-fifth of intramuscular dose administered intradermally, to conduct additional type 2 immunogenicity analyses of two fIPV doses compared with one full-dose IPV.ResultsFour studies were identified that assessed immunogenicity of two fIPV doses compared to one full-dose IPV. Two fractional doses are more immunogenic than 1 full-dose, with type 2 seroconversion rates improving between absolute 19–42% (median: 37%, p < 0.001) and relative increase of 53–125% (median: 82%), and antibody titer to type 2 increasing by 2–32-fold (median: 10-fold). Early age of administration and shorter intervals between doses were associated with lower immunogenicity.DiscussionOverall, two fIPV doses are more immunogenic than a single full-dose, associated with significantly increased seroconversion rates and antibody titers. Two fIPV doses together use two-fifth of the vaccine compared to one full-dose IPV. In response to the current IPV shortage, a schedule of two fIPV doses at ages 6 and 14 weeks has been endorsed by technical oversight committees and has been introduced in some affected countries.