23价肺炎球菌多糖疫苗的规模化生产及质量控制

目的:扩大肺炎球菌发酵的培养规模,增加肺炎球菌多糖的收量,降低成品疫苗内毒素的含量,以提高肺炎球菌多糖疫苗的产能和质量;制备和标定企业用肺炎多糖参考品,及定性定量检测23价肺炎球菌多糖疫苗用的血清。方法:调整肺炎球菌培养参数及培养过程中糖、碱的补料方式、补料时间,放大肺炎球菌的发酵培养规模;在分段乙醇沉淀过程中添加速度和温度控制、调整乙醇浓度,在酚提过程中调控各种技术参数等,提高精制多糖的收量;控制加入生产过程中主要原辅材料的内毒素含量,并规范操作人员的行为习惯,降低肺炎球菌多糖疫苗成品的内毒素含量。标定自制多糖参考品以及用多糖免疫兔、鼠制备血清参考品。结果:肺炎球菌的发酵体积从500 L提高到1 000 L;精制多糖平均收量提高15%以上;内毒素平均含量控制在20 EU.mL-1以内;制备出23种型别的符合23价肺炎球菌多糖疫苗质量标准的多糖;获得3个型单抗和6个型的多抗。结论:23价肺炎球菌多糖疫苗的产量增加,疫苗质量得到了提升,自主化标准参考品研究进展迅速。     

疫苗0～2 ℃储存挑战性实验

目的  探讨冻干制剂乙型脑炎减毒活疫苗和液体制剂23价肺炎球菌多糖疫苗0～2 ℃条件下存放对其效价的影响。方法  将冻干制剂乙型脑炎减毒活疫苗和液体制剂23价肺炎球菌多糖疫苗存放于0～2 ℃条件下一定时间后,与存放于2～8 ℃规定条件的制品进行疫苗效价的比较。结果  1人份和5人份乙型脑炎减毒活疫苗在0～2 ℃条件下分别存放17 h 20 min和18 h 55 min,病毒滴度均符合5.7～7.1 lgPFU/ml的质量标准,且与存放于2～8 ℃规定条件的同批次疫苗比较,t值分别为0.26和0.28,P值均大于0.05,差异无统计学意义;23价肺炎球菌多糖疫苗在0～2 ℃条件下存放21 h 50 min,23个型别的多糖含量均符合35～65 μg/ml的质量标准,且与存放于2～8 ℃规定条件的同批次疫苗比较,t值为0.01~2.25,P值均大于0.05,差异无统计学意义。结论  冻干制剂乙型脑炎减毒活疫苗和液体制剂23价肺炎球菌多糖疫苗存放在0～2 ℃条件下的一定时间内,疫苗效价仍符合质量标准。     

动态浊度法检测23价肺炎链球菌多糖疫苗细菌内毒素的方法确认和应用

 目的  对动态浊度法检测23价肺炎链球菌多糖疫苗（23-valent pneumococcal polysaccharide vaccine,PPV23）细菌内毒素进行方法学确认并加以应用。 方法   按照《中华人民共和国药典》2010版三部中的动态浊度法操作,配制系列稀释的细菌内毒素标准品,验证动态浊度法的线性、准确度、重复性和中间精密度。根据2012年和2013年连续20批PPV23成品的细菌内毒素检测结果,分析PPV23对动态浊度法的影响。 结果   动态浊度法的标准曲线具有可靠性,细菌内毒素标准品的回收率为90%~129%,变异系数为6.2%~12.4%,均符合规定的标准,且操作人员（F=4.80,P=0.06）和时间（F=1.01,P=0.34）变化对检测结果没有影响。2012年和2013年各连续20批PPV23成品的细菌内毒素检测结果保持稳定,细菌内毒素均值分别为0.165和0.355 EU/ml,PPV23对动态浊度法没有影响（F=0.00,P=0.97）。 结论   动态浊度法有效可行,可用于PPV23细菌内毒素检测。     

23价肺炎球菌多糖疫苗定量检定质量趋势分析

目的:统计分析2006-2011年生产的140批23价肺炎球菌多糖疫苗的5项定量检定指标,为疫苗的质量评价和质量监督提供依据。方法:对2006-2011年生产的140批23价肺炎球菌多糖疫苗的多糖含量、苯酚含量、氯化钠含量、pH值、细菌内毒素检查等5项指标的检定结果进行统计分析;对各单型多糖的含量进行移动标准偏差分析;对苯酚含量、氯化钠含量、pH值测定、细菌内毒素检查指标进行移动平均值总体趋势分析。结果:6年来,23价肺炎球菌多糖疫苗的多糖含量批间差异逐渐缩小;苯酚含量、氯化钠含量、细菌内毒素检查均值逐渐下降并趋于稳定;pH值一直较为稳定。结论:2006-2011年生产的23价肺炎球菌多糖疫苗质量逐步提高并保持稳定。     

23价肺炎球菌多糖疫苗质量控制现状和展望

目的：探讨23价肺炎球菌多糖疫苗质量控制标准。方法：对《中国药典》三部（2020年版）、《欧洲药典》（European Pharmacopoeia ,EP） 10.0、《美国药典》（United States Pharmacopoeia, USP）和WHO指南（Recommendations to assure the quality, safety and efficacy of pneumococcal conjugate vaccines, Annex 3.）中的23价肺炎球菌多糖疫苗质量标准进行比较研究。结果：《中国药典》2020年版三部23价肺炎球菌多糖疫苗质量标准比较全面,方法可行、适用。结论：《中国药典》2020年版三部中关于23价肺炎球菌多糖疫苗质量标准适用于该疫苗工艺的质量控制。     

23价肺炎球菌多糖疫苗稳定性考察

目的:考察23价肺炎球菌多糖疫苗在2～8℃条件存放24,27个月的稳定性,以及在(37±2)℃和(25±2)℃条件下存放的加速稳定性。方法:选取2008年生产的3批23价肺炎球菌多糖疫苗在2～8℃存放24,27个月后进行外观检查、鉴别试验、多糖含量、pH值、苯酚含量、氯化钠含量、无菌检查、热原检查、异常毒性检查;选取2011年生产的3批23价肺炎球菌多糖疫苗在(37±2)℃条件分别存放1,2,3,4周和在(25±2)℃条件分别存放1,2,3个月后进行鉴别试验和多糖含量测定、外观检查、pH值和苯酚含量测定。结果:疫苗2～8℃存放24,27个月,检定结果均符合质量标准的要求;疫苗(37±2)℃和(25±2)℃存放分别从第3周和第2个月开始,个别型别的多糖含量低于质量标准要求,其余各项检测指标均符合质量标准的要求。结论:23价肺炎球菌多糖疫苗在2～8℃条件存放至24个月的有效期质量是稳定的;在(37±2)℃和(25±2)℃条件存放的加速稳定性表明合格的疫苗分别最多能存放2周和1个月。     

23价肺炎球菌多糖疫苗研究进展

肺炎球菌是导致成人和儿童罹患肺炎疾病住院甚至死亡的重要原因。肺炎球菌的91个血清型中有20种血清型与各年龄组超过85%的侵袭性肺炎球菌感染有关。根据23种引起85%～90%的引起肺炎球菌感染疾病的血清型研制而成的23价肺炎球菌多糖疫苗,具有很好的安全性,成人和>2岁儿童接种后会产生可靠的免疫力,在人群中保护率达50%～80%,具有较好的成本效益比,是儿童和成人预防肺炎球菌感染的有效措施,推荐用于60岁以上老年人和2岁以上体弱儿童和慢性疾病患者。本文主要对23价肺炎球菌多糖疫苗的安全性、免疫反应、保护率及成本效益、对特殊健康状况人群的保护效果和免疫策略作一综述。     

14型肺炎球菌多糖双抗体夹心ELISA检测方法的建立

目的  建立并验证测定14型肺炎球菌多糖（pneumococcal capsular polysaccharide serotype 14，PS14）浓度的双抗体夹心ELISA。方法  采用Protein G亲和层析纯化兔血清，得到兔抗PS14多克隆抗体（多抗）。以鼠抗PS14单克隆抗体（单抗）为捕获抗体，兔抗PS14多抗为检测抗体，碱性磷酸酶标记山羊抗兔IgG为二抗，PS14为参考品建立双抗体夹心ELISA法。确定鼠抗PS14单抗和兔抗PS14多抗的工作浓度，建立标准曲线，并验证该方法的准确性、精密度和特异性，考察佐剂对该方法的影响。结果  鼠抗PS14单抗的最适工作浓度为5 μg/ml，兔抗PS14多抗的最适工作浓度为1 μg/ml，标准曲线的范围为9.375 ~ 600.000 ng/ml，线性良好，相关系数为0.999。测定多糖样品的PS14回收率为110% ~ 140%，多糖蛋白结合物样品的PS14回收率为90% ~110%。平均批内和批间精密度分别是5.64%和7.14%。13价结合物混合样品的PS14回收率为85% ~100%；含有佐剂的疫苗样品的PS14回收率为85% ~110%。结论  成功建立了双抗体夹心ELISA法，该方法准确性、精密度、特异性良好，且检测结果不受佐剂的影响，具有一定耐用性。     

国产23价肺炎球菌多糖疫苗上市后不良反应浅析

目的:评价国产23价肺炎球菌多糖疫苗上市后的安全性。方法:从日常收集、市场调查、文献资料3个方面收集23价肺炎球菌多糖疫苗上市后的不良反应,对其进行类型分析及不良反应发生率分析。结果:上市6年共销售1 074万人份国产23价肺炎球菌多糖疫苗,收集不良反应2 519例;不良反应以一般反应为主,局部反应和发热较多,严重不良反应数量极少。结论:国产23价肺炎球菌多糖疫苗上市后广泛使用是安全的。     

某社区老年人接种23价肺炎球菌多糖疫苗的效果分析

目的探讨上海某社区老年人接种23价肺炎球菌多糖疫苗效果分析。方法随机抽取社区老年人接种23价肺炎球菌多糖疫苗100例为接种组和100例未接种为对照组,回顾性调查呼吸道感染发生情况、肺炎发生情况、抗菌药物使用情况以及住院情况分析。结果呼吸道感染发生情况、肺炎发生情况、抗菌药物使用情况以及住院情况分析发现,接种组显著低于对照组(P <0.05)。结论社区老年人接种23价肺炎球菌多糖疫苗,有效的降低老年肺炎的发生,同时还可降低呼吸道感染的发生率,显著地提升了社区居民生活质量。     

Immune response to pneumococcal conjugate vaccination in asplenic individuals

Asplenic individuals are at increased risk of infection with Streptococcus pneumoniae. The immune response to pneumococcal conjugate vaccine has not been investigated in this clinical risk group. We investigated immune responses to pneumococcal vaccination in asplenic individuals. Eligible subjects aged > or =4 years received one dose 7-valent pneumococcal conjugate vaccine (PCV7) and, if no prior 23-valent polysaccharide vaccine (PPV23) had been received within previous 5 years, one dose was given 6 months following PCV7. Pre- and post-vaccination blood samples were taken. Pneumococcal serotype-specific IgG levels were determined for 9 serotypes; the 7 in PCV7 plus serotypes1 and by standardized ELISA. One hundred and eleven asplenic individuals were recruited [median age 54.8 years, (18.1-81.8)]. Median age at splenectomy was 29.6 years (3.6-78.3); 108 (97.3%) individuals had previously received PPV23. Compliance with UK recommendations on immunization and prophylaxis in this group was poor, 91 (82%) subjects had received Haemophilus influenzae type b conjugate vaccine and only 68 (62%) had received meningococcal serogroup C conjugate vaccine. In total 61 (55%) subjects were taking antibiotic prophylaxis and 12 subjects had reported previous invasive pneumococcal disease, five episodes of which occurred post-splenectomy. High serotype-specific IgG concentrations were observed pre-PCV7, with significant increases (p < 0.01) in geometric mean concentrations pre- to post-PCV7 for the PCV7 serotypes. Post-PCV7, between 27% (serotype 14) and 69% (serotype 23F) of subjects had a > or =2-fold rise in IgG. Pre-PCV7, the percentage of individuals with levels > or =0.35 microg/mL ranged between 77% (serotype 4) and 97% (serotypes 14, 19F), whilst post-PCV7 this was 90% (serotype 6B) and 99% (serotype 14). No significant increases were observed post-PPV23. Asplenic individuals responded well to PCV7, though protective levels were demonstrated pre-PCV7 in majority of participants due to prior PPV23. Although immunogenic, there is insufficient evidence here to recommend routine PCV7 immunization over PPV23 immunization in adult asplenic individuals.     

Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed): in older adults

Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) [PCV13] is approved for protection against pneumococcal disease in children aged 6 weeks to 5 years and adults aged ≥50 years. In randomized trials in adults aged 60-64 years (not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine [PPV23]) and ≥70 years (previously vaccinated with PPV23), PCV13 was noninferior to PPV23 in opsonophagocytic assay (OPA) geometric mean titres (GMTs) for all 12 serotypes common to the two vaccines. More PCV13 than PPV23 recipients had ≥4-fold increases in serotype 6A OPA GMTs (serotype 6A is not included in PPV23). PCV13 recipients also had higher OPA GMTs and met superiority criteria for most serotypes. Adults aged 50-59 years had antibody responses to PCV13 that were noninferior to those in adults aged 60-64 years for all included serotypes. PCV13 administered concomitantly with trivalent inactivated influenza vaccine in adults aged 50-59 or ≥65 years produced antibody responses that were noninferior to those following sequential administration, except for influenza strain A/H3N2 and pneumococcal serotype 19F in those aged ≥65 years. Antibody responses were numerically higher with sequential administration, although the clinical significance of this is unknown. Adverse events within 14 days of vaccination were mostly of mild-to-moderate severity, with serious events occurring in 0.2-1.4% of PCV13 and 0.4-1.7% of PPV23 recipients.     

23价肺炎链球菌多糖疫苗和13价肺炎链球菌结合疫苗在成年人中的应用

 肺炎链球菌是引起全球不同年龄人群,尤其是幼儿和老年人肺炎、败血症和脑膜炎等严重疾病的重要病原菌,由肺炎链球菌导致的这些疾病可以通过疫苗进行预防。在将肺炎链球菌疫苗纳入国家免疫计划的国家,儿童肺炎链球菌病的发病率以及疫苗型肺炎链球菌的携带率大大降低,且可在未免疫人群中产生间接保护作用。此文对23价肺炎链球菌多糖疫苗和13价肺炎链球菌结合疫苗在成年人中的应用进行探讨。     

Epidemiology of invasive pneumococcal disease in the Arabian Peninsula and Egypt

Invasive pneumococcal disease (IPD) causes considerable morbidity and mortality among children worldwide. This review describes the burden of disease and pneumococcal serotypes/serogroups causing disease in children in the Arabian Peninsula and Egypt identified from a literature search from 1990 to 2007. The incidence of IPD in children aged 相似文献   

23价肺炎链球菌荚膜多糖疫苗的研制

目的  研制23价肺炎链球菌荚膜多糖疫苗。方法  大罐培养1、2、3、4、5、6B、7F、8、9N、9V、10A、11A、12F、14、15B、17F、18C、19A、19F、20、22F、23F、和33F型肺炎链球菌并进行各型荚膜多糖的纯化,制备23价肺炎链球菌荚膜多糖疫苗。 结果  经检定各型精制多糖主要质量指标均符合《欧洲药典》（2005 年版）要求。 结论  已建立起成熟的细菌培养和多糖纯化工艺。     

Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species

Pneumococcal infections elicited by Streptococcus pneumoniae (pneumococcus) (pneumonia, otitis media, sinusitis, meningitis) are frequently occurring diseases that are associated with considerable morbidity and mortality even in developed countries. Pneumococci colonise the nasopharynx of up to 50% of children, and up to 5% of adults are pneumococcal carriers. Two pneumococcal vaccines are currently in clinical use. One of them contains 23 capsular polysaccharides of the as yet known 91 different pneumococcal serotypes. Because polysaccharide vaccines primarily induce a B-cell-dependent immune response, this type of vaccine prevents bacteraemia but does not efficiently protect the host against pneumococcal infection. In 2000, a vaccination programme was launched in the USA making use of a novel pneumococcal conjugate vaccine containing capsular polysaccharides derived from the seven most frequent pneumococcal serotypes causing pneumococcal disease in children <2 years of age. Conjugation of capsular polysaccharides with a highly immunogenic protein, i.e. a non-toxic diphtheria toxoid, induces a B- and T-cell response resulting in mucosal immunity and thus effectively protects against vaccine serotypes that induce invasive pneumococcal disease, thereby at the same time reducing vaccine serotype carrier rates. Pronounced herd immunity resulted in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as reduced antibiotic resistance rates. However, recent studies report that serotypes eradicated by the vaccine are being replaced by non-vaccine pneumococcal serotypes. This so-called 'replacement' might soon threaten the success of vaccine use.     

安徽省2011年0～6岁儿童抗百日咳毒素抗体水平监测

 目的  了解安徽省≤6岁健康儿童抗百日咳毒素（pertussis toxin,PT）抗体水平,为评价疫苗接种效果提供依据。 方法   采用多阶段随机抽样方法,在全省16个市0～6岁7个年龄组人群中抽取健康儿童1 787人,用ELISA定量检测血清抗PT IgG抗体。各组之间抗体阳性率差异比较采用χ²检验,抗体几何平均浓度（GMC）差异比较采用F检验。结果   2011年安徽省0～6岁儿童中,几乎所有采集的血清均呈现不同的抗体水平,以0岁组最高（10.33 IU/ml）。抗体GMC随免疫后时间的延长有下降的趋势。不同年龄组之间抗体阳性率和GMC差异均有统计学意义（χ²=15.06,P＜0.05;F=7.96,P＜0.01）。不同性别之间抗体阳性率和GMC差异均无统计学意义（χ²=0.98,P＞0.05;Z=0.852,P=0.394）。 结论   安徽省0～6岁儿童抗PT IgG抗体水平随年龄的增加而降低,是否需要加强免疫需作进一步研究。     

13-valent pneumococcal conjugate vaccine (PCV13)

The thirteen valent pneumococcal conjugate vaccine (PCV13, Prevenar 13(TM)) is the broader coverage successor to the highly effective seven valent vaccine (PCV7, Prevenar(TM)) which has reduced rates of pneumococcal disease in many countries. Despite the success of PCV7, pneumococcal disease due to non-PCV7 serotypes remains a threat in many settings, in particular many developing countries with a high burden of pneumococcal disease where serotype 1 and 5 are among the most common serotypes. Disease due to certain non-PCV7 serotypes, in particular serotype 19A has also begun to increase in incidence in countries with widespread use of PCV7. PCV13 consists of thirteen pneumococcal capsular polysaccharides individually conjugated to the diphtheria-derived protein carrier CRM(197). In addition to serotypes 4, 6B, 9V, 14, 18C, 19F and 23F included in PCV7, PCV13 also includes serotypes 1, 3, 5, 6A, 7F and 19A. PCV13 was licensed on the basis of non-inferiority trials and has proved to be at least as safe and effective as PCV7. PCV13 replaced PCV7 in the childhood immunisation schedules of the USA and UK in 2010 and is being rolled out to an increasing number of developing countries during 2011. Here we review the current literature regarding this vaccine, describing safety, efficacy, global serotype coverage and use and future directions.