麻疹-腮腺炎-风疹联合减毒活疫苗无菌生产工艺风险评估

目的 评价国产麻疹-腮腺炎-风疹联合减毒活疫苗(麻腮风疫苗)的无菌生产工艺风险。方法 应用质量风险管理的原则,使用失效模式和效果分析的风险管理工具评估确定麻腮风疫苗生产工艺中所有可能存在的质量问题和潜在风险。采用定量方法,计算风险系数,对此进行风险评估。结果 风险评估后各工艺环节的风险系数均小于40。结论 麻腮风疫苗无菌生产工艺风险可控,可不采取措施。     

两种不同取样方式测定麻腮风类减毒活疫苗病毒滴度的评价

目的：比较麻腮风类减毒活疫苗的两种取样方式测定疫苗各组分滴度是否存在差异。方法：采用多支疫苗混合滴定和单支疫苗滴定两种方法对国内上市的麻腮风类疫苗进行检测，对两种方法测定的结果平行比对。结果：单支疫苗滴定后的均值与多支疫苗混合后的检测结果基本一致； 腮腺炎疫苗的支间滴度差异略高，麻疹、风疹疫苗的支间滴度差异较小。结论：目前使用的多支混合滴定的检测方法能够满足对麻腮风类疫苗质控的要求，但单支滴定法对工艺改进更有指导意义。     

麻疹-腮腺炎-风疹联合减毒活疫苗生产场地变更的质量可比性研究

目的  比较生产场地变更前后生产的麻疹-腮腺炎-风疹联合减毒活疫苗（麻腮风疫苗）的关键质量指标及其变化趋势。 方法   新老车间同步各生产3批麻腮风疫苗,比较新老车间生产的疫苗的关键指标及其变化趋势,同时对新老车间生产的疫苗进行稳定性和安全性比较研究。 结果   新老车间生产的疫苗成品的关键质量指标均符合相关规定的要求,其中新车间生产的疫苗的水分为1.6%~1.8%,其麻疹、腮腺炎和风疹病毒滴度分别为4.1~4.3、4.8~5.0 和3.9~4.1 lgCCID₅₀/ml,与老车间生产的疫苗（水分为1.6%~2.1%,麻疹、腮腺炎和风疹病毒滴度分别4.0~4.3、4.8~5.0和4.1~4.2 lgCCID₅₀/ml）相似。新老车间生产的疫苗成品的稳定性和安全性实验结果均符合相关规定的要求,且新老车间生产的疫苗的稳定性实验结果相似,新老车间生产的疫苗的抗生素残留量（t＝3.46,P>0.05）和牛血清白蛋白残留量（t＝2.00,P>0.05）间的差异无统计学意义。 结论   麻腮风疫苗生产场地变更未对其制品质量产生影响。     

麻疹、腮腺炎、风疹和水痘联合疫苗在健康儿童中的安全性和免疫原性

将水痘疫苗加入现有的麻疹-腮腺炎-风疹疫苗（MMR）作为健康儿童的常规免疫是理想的。作者对麻疹-腮腺炎-风疹-水痘四联疫苗和不同部位同时接种的MMR和水痘疫苗在接种后6周和1年的安全性、细胞和体液免疫应答进行了评价。     

不同类型麻疹、腮腺炎、风疹疫苗及初免年龄对抗体水平的影响

作者以加拿大魁北克省作为试验基地,用MMRⅡ和Trivirix两种不同配方的麻疹、腮腺炎、风疹（MMR）疫苗对468名12～24月龄儿童进行接种。其中241人接种MMRⅡ疫苗,其余接种Trivirix疫苗。此两种疫苗中,风疹疫苗均用RA27/3株制备,且含量相同〔1000半数组织培养感染量（TCID_(50)）〕,但在麻疹和腮腺炎病毒和含量上有所差别,MMRⅡ疫苗含Enders Edmonston麻疹病毒1000 TCID_(50),Teryl Lynn腮腺炎病毒5000TCID_(50),Trivirix疫苗含Schwarz麻疹病毒1000 TCID_(50),Urabe Am 9腮腺炎病毒20000TCID_(50)。初免后5～6年,取静脉血,分别用蚀斑减少中和（PRN）试验、酶免疫试验和血凝抑制（HI）试验检测麻疹、腮腺炎和风疹抗体。     

麻疹、腮腺炎、风疹和水痘疫苗的联合应用

作者在15～17月龄的健康儿童中,比较了麻疹、腮腺炎、风疹和水痘四联疫苗(MMRV)与麻疹、腮腺炎和风疹三联疫苗(MMR)接种后6周再给予水痘疫苗(MMR+V)的免疫效果。水痘疫苗系Merck药厂应用Oka株制备,MMRV组和MMR+V组所用的Oka株剂量分别为2300和1900蚀斑形成单位(pfu)。每个接种者均记录接种后每天的体温和皮疹等临床反应,并通过各种调查方法调查他们免疫后1年内接触水痘自然感染的情况。     

国产麻腮风联合减毒活疫苗的稳定性观察

目的  观察国产麻腮风联合减毒活疫苗（麻腮风疫苗）的稳定性。方法  取24批上海生物制品研究所有限责任公司（上海公司）2008－2017年生产的麻腮风疫苗,按照国家食品药品监督管理局批准的麻腮风疫苗注册标准和中国药典的要求进行各项检定：在0个月进行热稳定性试验;在0和18个月进行鉴别试验,外观、水分、无菌、异常毒性检查,牛血清白蛋白残留量、抗生素残留量（2010年10月以后）、细菌内毒素（2013年12月以后）、pH值和渗透压摩尔浓度检测（2015年12月以后）;在0、6、12、18个月进行病毒滴定。同时对新、老车间生产的各3批疫苗进行加速稳定性与长期稳定性试验,重点考察水分和病毒滴度。结果  麻腮风疫苗在有效期内各项指标检定结果均符合注册标准和药典要求。质量可比性研究结果显示新老车间生产的疫苗质量相似。疫苗中水分都不高于3.0%,麻疹、腮腺炎、风疹病毒滴度分别为3.3～4.3 、4.6～5.6 、3.3～4.3 半数细胞培养感染量/ml。结论  上海公司10年间生产的麻腮风疫苗质量稳定、安全有效。     

接种风疹、麻疹及腮腺炎疫苗儿童的抗体随访

最近研究指出,13个月以下接种麻疹疫苗的儿童血清抗体阴性率显著高于13个月以上的接种者。风疹和腮腺炎尚无类似的资料,但疫苗产生的免疫力是持久的。风疹疫苗接种4一9年后的调查证明,90%以上的受试对象抗体为阳性。研究腮腺炎疫苗的报告亦指出,     

以往罹患血小板减少性紫癫的儿童接种MMR疫苗的指征

Rollan医生问:我的1名11岁女患儿目前应接种第2剂麻疹-腮腺炎-风疹(MMR)疫苗,这是西班牙推荐的常规接种疫苗.然而,她在15月龄接种第1剂MMR疫苗后13天,因罹患严重的血小板减少性紫癜而需住院观察4周.目前,她的血清抗风疹IgG滴度提示她对风疹易感.那么,考虑到西班牙当前罹患风疹的危险性是15/10万,她应接种第2剂MMR疫苗吗?血小板减少症复发的危险排除了免疫接种的裨益吗?Pool等(美国疾病控制和预防中心)答:血小板减少性紫癜是儿童期感染较常见的并发症,每1500～3000例麻疹或风疹感染中约有1例,而腮腺炎和水痘感染中则较少见.因此,尽管MMR减毒活疫苗接种引起血小板减少症较为少见,发病率约为2.4万～4万名接种者中1例(根据主动监测的研究结果),但并不出乎意外.疫苗相关血小板减少症似与天然麻疹或风疹感染引起的相似,无法与急性儿童期特发性血小板减少性紫癜相区别,而后者与疫苗接种无关.     

感染AIDS病毒的儿童的免疫接种

问:有症状的AIDS病毒感染儿童可接种哪些疫苗? 答:对具有与AIDS或AIDS病毒感染的其他临床表现相关的免疫抑制儿童和青少年不应接种活菌苗和疫苗,如麻疹、腮腺炎和风疹三联疫苗(MMR)、口服脊髓灰质炎疫苗(OPV)和BCG。他们应以脊髓灰质炎灭活疫苗(IPV)作常规免疫接种,由于医学上的原因,不应将麻疹、风疹和/或腮腺炎疫苗作为常规接种。人们担心,接种灭活疫苗对上述儿童和青少年免疫系统的刺激可能会引起免疫功能衰退,     

Measles,mumps, rubella vaccine (Priorix; GSK-MMR): a review of its use in the prevention of measles,mumps and rubella

GSK-MMR (Priorix) is a trivalent live attenuated measles, mumps and rubella (MMR) vaccine which contains the Schwarz measles, the RIT 4385 mumps (derived from the Jeryl Lynn mumps strain) and the Wistar RA 27/3 rubella strains. GSK-MMR as a primary vaccination demonstrated high immunogenicity in clinical trials in >7500 infants aged 9-27 months, and was as immunogenic as Merck-MMR (MMR II). However, antimumps seroconversion rates and geometric mean titres (GMTs) were significantly higher in infants receiving GSK-MMR compared with Berna-MMR (Triviraten trade mark ) recipients. Coadministration of GSK-MMR with a varicella vaccine (Varilrix; GSK-MMR/V) did not significantly affect the immunogenicity of GSK-MMR. A persistent immune response to GSK-MMR has been demonstrated in follow-up data from several randomised trials. GMTs for measles, mumps and rubella antibodies remained high in GSK-MMR recipients 1-2 years post-vaccination and were similar to those in Merck-MMR recipients. The immunogenicity of GSK-MMR was high, and similar to that of Merck-MMR, when used as a second dose in children aged 4-6 or 11-12 years who had received a primary vaccination with Merck-MMR in their second year of life. Although there are no protective efficacy data concerning the GSK-MMR vaccine to date, the rubella Wistar RA 27/3 rubella and Schwarz measles strains have well established protective efficacy; the new RIT 4385 mumps strain is expected to afford similar protection from mumps to that achieved with mumps vaccines that contain the Jeryl Lynn mumps strain (e.g. Merck-MMR). GSK-MMR was well tolerated as a primary or secondary vaccination, and in most clinical studies comparing GSK-MMR with Merck-MMR as a primary vaccination in infants, GSK-MMR was associated with significantly fewer local adverse events (e.g. pain, swelling and redness). The incidence of local adverse events with GSK-MMR, GSK-MMR/V or Berna-MMR was similar. GSK-MMR and Merck-MMR were associated with similar rates of fever, rash and parotid gland swelling, but Berna-MMR was associated with a lower incidence of fever. In conclusion, GSK-MMR is a highly immunogenic MMR vaccine with good tolerability. In clinical trials, the immunogenicity of GSK-MMR was similar to that of Merck-MMR, and the mumps component was more effective at eliciting seroprotection than that of Berna-MMR. Furthermore, GSK-MMR causes fewer injection-site adverse events than Merck-MMR. As such, GSK-MMR is an attractive alternative for immunisation against measles, mumps and rubella.     

Swedish experience of two dose vaccination programme aiming at eliminating measles, mumps, and rubella.

In 1982 a two dose regimen was introduced in Sweden for the combined vaccination against measles, mumps, and rubella of children aged 18 months and 12 years. Since 1977 about half of the preschool children were vaccinated against measles annually, and since 1974 about 80% of 12 year old girls were vaccinated against rubella. During the period 1982 to 1985 90-93% of the eligible age cohorts of 18 month old children and 88-91% of the 12 year old children were immunised with the new combined vaccine. A study in 1982 of about 140 18 month old children who were nearly all seronegative before vaccination showed that 96%, 92%, and 99% seroconverted against measles, mumps, and rubella, respectively. A second study was carried out in 1983 of 247 12 year old children, of whom 11% lacked antibodies to measles, 27% to mumps, and 45% to rubella. This showed seroconversion in 82% and 80% against measles and mumps, respectively, and all children seroconverted against rubella. In the latest study in 1985 of 496 12 year olds 9% and 13% were seronegative against measles and mumps before vaccination, and 41% against rubella. Of these, 88% seroconverted to measles and 80% to mumps, and all converted to rubella when sera were tested by the haemolysis in gel method. After a neutralisation test against measles as well all children showed immunity to the disease. A low incidence of measles and declining figures for mumps and rubella were reported in 1984 to 1986. An outbreak of rubella during 1985 affected mainly boys in age cohorts in which only the girls had been vaccinated during the 1970s.     

Live attenuated measles, mumps, rubella, and varicella zoster virus vaccine (Priorix-Tetra)

The live attenuated tetravalent vaccine against measles, mumps, rubella, and varicella zoster viruses (MMRV) is a combination of the measles, mumps, and rubella (MMR) vaccine and the varicella zoster virus vaccine. The immunogenicity after each dose of a two-dose vaccination course of MMRV vaccine was generally similar to that of two doses of separately administered MMR plus varicella zoster vaccines, or a single dose of separately administered MMR plus varicella zoster vaccines followed by a dose of MMR vaccine, in infants aged 9-24 months. In infants aged 9-24 months administered a two-dose course of MMRV vaccine, geometric mean titers for antibodies against all vaccine antigens increased after the second dose relative to the first dose, with the increase being most pronounced for varicella zoster virus antibodies (10- to 21-fold). MMRV as the second vaccination was immunogenic in children aged 5-6 years who had previously received either MMRV or MMR as the first vaccination at 12-24 months of age. The immunogenicity for measles, mumps, rubella, and varicella zoster viruses, in terms of seropositivity and antibody titers, was not altered when MMRV was coadministered with a booster dose of diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b conjugate vaccine in infants aged 12-23 months. Nor was the immunogenicity of the latter vaccine altered by coadministration. The tolerability profile of MMRV vaccine was comparable to that of separately administered MMR plus varicella zoster vaccines or of MMR vaccine alone. Injection-site redness and fever (rectal temperature > or =38degreesC or axillary temperature > or =37.5degreesC) were the most frequent adverse events in both groups.     

A new combination vaccine for measles, mumps, rubella and varicella

ProQuad is a recently approved combination vaccine for simultaneous vaccination against measles, mumps, rubella and varicella in children aged 12 months to 12 years. It combines two well-established vaccines: Measles, Mumps, Rubella Virus Vaccine Live (M-M-R II) and Varicella Virus Vaccine Live (Varivax with higher varicella-zoster titer). Whereas vaccination against measles, mumps and rubella has almost 100% coverage, vaccination against varicella shows a significantly lower uptake of approximately 84%. Clinical studies on the immunogenicity and efficacy of ProQuad demonstrated seroconversion rates and a magnitude of antibody response similar to those observed after administration of its individual components, M-M-R II and Varivax vaccines. The incidence of local side effects (pain/tenderness/soreness, erythema, swelling, ecchymosis and rash) and systemic adverse effects (fever, irritability, rash, upper respiratory infection, viral exanthema and diarrhea) is similar to or lower than that observed in component vaccines. ProQuad is a highly immunogenic combination vaccine with a good safety profile. The use of ProQuad combination vaccine will simplify immunization delivery by providing protection against more diseases with fewer injections and less pain, improve timely vaccination coverage and reduce the health-care costs for additional health visits. The ProQuad combination vaccine facilitates implementation of varicella vaccination into routine childhood immunization schedules and will help to protect children against these four potentially serious diseases.     

A combination vaccine against measles, mumps, rubella and varicella

A new combination vaccine against measles, mumps, rubella and varicella (MMRV) from GlaxoSmithKline Biologicals has recently been approved in Europe. It combines the components from two well-established, live, attenuated vaccines against measles, mumps and rubella. This review presents a summary of the development of this MMRV vaccine from published clinical studies. Seroconversion rates and antibody titers after the first and second dose are similar to those observed after concomitant administration of the MMR and varicella vaccines. Furthermore, the clinical profile of this combination vaccine, in terms of injection- site and general tolerability, is similar to that of the component vaccines. A higher incidence of low-grade fever has been noted following the first dose of MMRV vaccine, although it is no different from component vaccines following the second dose. MMRV vaccines were recommended in Germany in 2006 for administration in two doses to children aged 11-14 months and 15-23 months. They offer a convenient way to implement varicella vaccination and to achieve high vaccine coverage rates mirroring those of MMR vaccines. For other countries considering introducing these vaccines, the advantages for children, parents and healthcare providers of protecting against four diseases in a single vaccine should be noted.     

病毒性疫苗渗透压摩尔浓度的质量控制

目的  通过检测6种病毒性疫苗成品的渗透压摩尔浓度,比较不同疫苗检测均值的差异,并观察同种疫苗检测值的批间稳定性,为增加病毒性疫苗质量控制手段提供依据。方法  采用冰点下降法检测麻疹减毒活疫苗、风疹减毒活疫苗、麻疹腮腺炎联合减毒活疫苗、麻疹腮腺炎风疹联合减毒活疫苗、水痘减毒活疫苗、流感病毒裂解疫苗的渗透压摩尔浓度,对检测值进行统计学处理,计算变异系数。以麻疹腮腺炎风疹联合减毒活疫苗的渗透压摩尔浓度检测均值作为对照,进行方差齐性检验及假设检验,比较各疫苗检测均值的差异。结果  麻疹腮腺炎联合减毒活疫苗与对照相比,均值差异无统计学意义（t=1.66,P>0.05）;麻疹减毒活疫苗、风疹减毒活疫苗、水痘减毒活疫苗及流感病毒裂解疫苗与对照相比,均值差异均有统计学意义（Z>1.96,P<0.001）。同种疫苗批间渗透压摩尔浓度较为稳定,变异系数均<3%,变化幅度能控制在90%~110%均值范围内。结论  6种病毒性疫苗渗透压摩尔浓度存在一定差异,但同种疫苗检测值批间稳定性较好,因此,应根据不同疫苗的渗透压摩尔浓度,分别制定质量控制标准。     

Aseptic meningitis following mumps vaccine. A retrospective survey by the French Regional Pharmacovigilance centres and by Pasteur-Mérieux Sérums & Vaccins

Since 1989 many case series and observational studies of aseptic meningitis (AM) associated with the use of live attenuated mumps vaccines containing the Urabe AM9 strain have been reported worldwide. The aim of this retrospective reported AM in France following mumps vaccination with monovalent or multivalent vaccines containing the Urabe strain. Fifty-four cases of AM were reported to the Regional Pharmacovigilance centres or to the manufacturer from the time each vaccine was launched up until June 1992. Twenty cases were temporally associated with the administration of a monovalent mumps vaccine and 34 with a trivalent measles, mumps and rubella vaccine (MMR). A mumps virus was isolated in four cases in the cerebrospinal fluid and an Urabe-like strain was characterized twice by polymerase chain reaction (PCR). A probable mumps origin was assumed in 17 other cases where the patients presented with other clinical or biological signs of mumps infection. The clinical outcome of AM, known in 87% of the population, was always favourable. The global incidence of mumps vaccine-associated AM was 0.82/100,000 doses, which is significantly lower than the incidence in the unvaccinated population. Even considering that the actual incidence of AM is much higher when assessed by active surveillance studies, the risk/benefit ratio of mumps vaccine remains in favour of vaccination.     

Evolution of the New Zealand childhood immunisation schedule from 1980: a personal view

A personal view of the evolution of the New Zealand immunisation schedule (from the perspective of someone who has been involved in the decision-making process since 1980) is presented in this article. The rationale behind changes to vaccination strategies to control pertussis, hepatitis B, polio, measles, mumps and rubella, and Haemophilus influenzae type b are presented. Finally brief comment is made on the National Immunisation Register and the likely vaccines to be introduced into the schedule in the foreseeable future.     

麻疹、腮腺炎、风疹、水痘联合减毒活疫苗的生产工艺研究

目的  建立麻疹、腮腺炎、风疹、水痘联合减毒活疫苗（combined live attenuated measles，mumps，rubella and varicella vaccine，MMRV）的生产工艺。方法  根据现有疫苗病毒原液生产工艺，将麻疹病毒沪-191纯化株、腮腺炎病毒S79株、风疹病毒BRD-Ⅱ株和水痘-带状疱疹病毒Oka株在原代鸡胚成纤维细胞或人二倍体细胞MRC-5株中制备高滴度病毒原液，并超低温保存。筛选无明胶冻干稳定剂配方。按国外已上市同类产品的病毒配比，研究MMRV中4种病毒的原液配制滴度及成品配制比例，建立最佳冻干工艺。结果  用筛选出的适合于MMRV的无明胶冻干稳定剂配方进行试验，确定病毒原液的配制滴度为，麻疹4.6 lg半数细胞培养感染量（50% cell culture infective dose，CCID₅₀）/ml、腮腺炎5.8 lgCCID₅₀/ml、风疹4.3 lgCCID₅₀/ml、水痘4.8 lg噬斑形成单位（plaque forming unit，PFU）/ml。使成品中腮腺炎病毒滴度至少达到麻疹和风疹和水痘病毒的10倍，水痘病毒滴度高于现有单价水痘疫苗。连续制备3批MMRV，平均病毒滴度为，麻疹4.5 lgCCID₅₀/ml、腮腺炎5.1 lgCCID₅₀/ml、风疹4.3 lgCCID₅₀/ml、水痘4.6 lgPFU/ml；平均水分为1.2%。其他项目检定均合格。结论  建立了MMRV的生产工艺，可以稳定生产出达到国外同类产品质量标准并符合我国4种单价减毒活疫苗国家标准的产品。     

Interindividual variations in the efficacy and toxicity of vaccines

A number of currently available vaccines have shown significant differences in the magnitude of immune responses and toxicity in individuals undergoing vaccination. A number of factors may be involved in the variations in immune responses, which include age, gender, race, amount and quality of the antigen, the dose administered and to some extent the route of administration, and genetics of immune system. Hence, it becomes imperative that researchers have tools such as genomics and proteomics at their disposal to predict which set of population is more likely to be non-responsive or develop toxicity to vaccines. In this article, we briefly review the influence of pharmacogenomics biomarkers on the efficacy and toxicity of some of the most frequently reported vaccines that showed a high rate of variability in response and toxicity towards hepatitis B, measles, mumps, rubella, influenza, and AIDS/HIV.