四联疫苗：DTaP-X, MMRV
基于百白破三联疫苗开发的四联疫苗（DTaP-X）：
多项研究结果显示，基于百白破三联疫苗开发的四联疫苗在免疫原性和安全性方面均不逊色于单价疫苗1,2。
2007年，为了对中国首个自主研发的DTaP-Hib四联疫苗进行评估，研究者在江苏省盐城市大丰区进行了一项随机、两阶段、平行对照、单中心的临床试验。该试验共有720名婴幼儿入组，并以2: 1的比例随机分配到两组。在第一阶段，干预组的480名受试者分别在3、4和5个月大时接种了3剂DTaP-Hib四联疫苗，而对照组的240名受试者则分别在相同的阶段分别接种的DTaP三联疫苗和Hib单价疫苗。在第二阶段，633名已接种的幼儿（干预组的31名和对照组202名）在18个月大时接种了加强针。研究团队分别在接种首剂疫苗前1周、接种第三针后的四周，接种第四剂加强针前，以及接种第四剂加强针四周后四个时间点采集血清样本。结果显示，干预组的抗百日咳类毒素、抗丝状血凝素、抗白喉类毒素、抗破伤风类毒素和抗多核糖核糖醇磷酸酯血清阳转率与对照组相当。在基础免疫和加强针免疫后，两组受试者几乎100%的受试者都达到了相似的血清保护性水平，两组中不良反应的发生率都很低3。
在瑞典、意大利、美国等进行的针对DTaP-IPV四联疫苗的随机试验也揭示了类似的结果，在血清保护率和针对每种抗原成分产生的平均抗体水平方面，接种DTaP-IPV四联疫苗组与接种DTaP三联疫苗和IPV单价疫苗的组合结果相当，研究者在两组之间观察到的反应原性也近乎一致4,5。
西班牙的研究者在1998年至1999年间进行了另一项试验，共有223名儿童被随机分到DTaP-Hib四联疫苗组和分开接种DTwP三联疫苗及Hib单价疫苗组。试验结果显示，接种DTaP-Hib四联疫苗产生的反应原性明显低于分开接种三联及单价疫苗组，分开接种组报告了更多例局部反应和发热现象，接种四联疫苗对于儿童来说具有更好的反应原性和安全性6。
基于麻腮风三联疫苗开发的四联疫苗（MMRV）：
已有的研究表明，接种麻腮风水痘四联疫苗与分开接种麻腮风三联及水痘单价疫苗组合相比，在免疫原性和安全性方面表现更优7或相当8,9；一项韩国的研究则发现，干预组仅在流行性腮腺炎抗体水平非劣效性上未达主要终点10。上述研究中，干预组和对照组的不良反应率相当。
2009年至2015年间，一项在欧盟十国进行的、入组超过5000名儿童的试验发现，分开接种麻腮风三联及水痘单价疫苗组与接种麻腮风水痘四联疫苗组在接种后第六年进行随访时，两种接种方式所产生的抗体均对预防水痘感染有效。接种两剂麻腮风水痘四联疫苗对预防所有水痘和中度或重度水痘的有效性分别为 95.0% (95% CI: 93.6-96.2) 和 99.0% (95% CI: 97.7-99.6)，接种一剂水痘疫苗对所有水痘和中度或重度水痘的有效性分别为 67.0% (95% CI: 61.8-71.4) 和 90.3% (95% CI: 86.9-92.8)。另外，在试验期间共有422名儿童报告了570例不良反应事件，但经过调查，这些不良反应事件被证实与接种疫苗无关11。
也有一些研究显示，麻腮风水痘四联疫苗会在接种初期增加发热惊厥12,13或发热的概率14,15,16。一项多中心、单盲、随机对照试验发现，在接种第一剂疫苗后，麻腮风水痘四联疫苗组有57.4%的受试者出现38℃以上的发热现象，这一比例在麻腮风三联及水痘单价疫苗组的比例是44.5%， 而在麻腮风三联疫苗组中，出现发热现象的受试者略低，为39.8%17。
五联疫苗：DTaP-IPV-Hib, DTaP-HepB-IPV
五联疫苗分为两种，一种是百日咳、白喉、破伤风、脊髓灰质炎和b型流感嗜血杆菌疫苗（DTaP-IPV-Hib），而另一类是百日咳、白喉、破伤风、脊髓灰质炎和乙型肝炎疫苗（DTaP-HepB-IPV）。目前的研究证明，接种这两种五联疫苗与分开接种含有相同抗原成分的低联及单价疫苗组合相比，产生的抗体反应相似18,19,20,21。一项纳入九项五联疫苗研究的荟萃分析显示，白喉、百日咳抗体单独接种较联合疫苗接种产生更高的抗体滴度，多数研究发现百日咳、流感嗜血杆菌、脊髓灰质炎、乙肝的免疫水平无差异22。研究也反映接种五联疫苗组注射部位反应较少18,19,21，但研究显示接种联合疫苗后局部反应增加，或在第一剂接种后联合疫苗组发红率更高22。
韩国的研究人员进行了一项开放标签多中心研究，42-69天的健康婴儿（1:1随机分组）分别在2、4、6月龄时接种三剂五联疫苗（DTaP-IPV/Hib）或分别接种DTaP-IPV和Hib疫苗。研究表明五联疫苗相比于分别接种，免疫原性无显著差异23。
来自中国的研究者进行了一项针对百日咳、白喉、破伤风、脊髓灰质炎和b型流感嗜血杆菌疫苗（DTaP-IPV-Hib）的随机、开放标签的临床试验，共有962名儿童参加试验，并于2017年发表实验结果。984名健康婴儿纳入总接种队列（TVC）,962名完成了研究。455名婴儿（1:1:1）按照协议(ATP)进行的免疫原性研究：A组在2-3-4月龄接种五联疫苗，B组在3-4-5月龄时接种五联疫苗，151名婴儿同时接种DTaP/Hib和IPV疫苗（对照组）。825名婴儿在18-24月龄时接种DTaP/Hib或IPV的加强针。结果显示，A组在三剂基础免疫的效果优于对照组。除了抗聚核糖核糖醇磷酸酯和抗脊髓灰质炎病毒 1-3 型的抗体浓度在 DTPa-IPV/Hib 接种者中较高外，其他各组的抗体浓度相似。 针对所有疫苗抗原的保护性抗体水平在加强免疫前一直很高24。
另有一项使用中国国家免疫接种后不良事件监测系统（CNAEFIS）进行回顾性研究的研究显示，2011至2017年间，广州共有接种了51.6万剂次DTaP-IPV-Hib疫苗，共有376例不良反应被报告，大多数报告的 DTaP-IPV/Hib 疫苗接种后 AEFI 并不严重。 仅有8例为严重不良反应25。
1998年至1999年间，在意大利进行的一项多中心试验入组了360名儿童，受试者被随机分为两组，一组接种DTaP-Hib-HepB五联疫苗，另一组接种DTaP-HepB四联疫苗与Hib单价疫苗的组合，研究者在两组受试者的血清中都检测到了相似的抗体浓度。在接受DTaP-Hib-HepB五联疫苗和DTaP-HepB四联疫苗与Hib单价疫苗组合的组别中，分别有97.0%和99.4%的受试者产生浓度[大于或等于]1.0μg/mL的Hib抗PRP抗体。试验证明，在四联DTaP-HepB疫苗中加入Hib抗原成分并不会提高局部或全身反应的发生率26。
与四联、五联疫苗类似，多数现有证据支持儿童用六联疫苗与分开接种低联及单价疫苗组合具有相似的免疫原性和安全性27,28,29,30,31。
一项在斯洛伐克进行的六联苗的研究显示，接种 DTaP-HBV-IPV/Hib 疫苗10-11年后，48.4% 的人抗-HBs 维持在≥10 mIU/ml，单独接种五联疫苗(DTaP-IPV/Hib)和单价乙肝疫苗(HBV)的受试者，58.4%的人抗-HBs维持在≥10 mIU/ml。DTaP-HBV-IPV/Hib 诱导的免疫记忆与单价 HBV 诱导的受试者相似，DTPa-HBV-IPV/Hib 和单价 HBV 的保护持续时间可能相似28。
西班牙的一项开放标签、随机、多中心试验结果揭示，儿童接种DTaP-IPV-Hib-HepB六联疫苗后的发热概率高于分别接种DTaP-IPV/Hib五联疫苗及HBV单价疫苗组合（21% vs.12%），接种六联疫苗引发的局部疼痛概率略高于分开接种组(2.5% vs. 1.2%) 。值得关注的是，接种六联疫苗组对百日咳抗原产生的免疫应答率超过97%，这一数据高出分开接种组90%的免疫应答率32。
另一项在美国进行的开放标签、随机、多中心研究评估了接种DTaP-HBV-IPV-Hib六联疫苗与同时注射DTaP-HBV-IPV五联疫苗和Hib单价疫苗组合或者DTaP-IPV-Hib五联和HepB单价疫苗组合的免疫原性和安全性，这项研究共入组585名受试者。研究证明，接种DTaP-HBV-IPV-Hib六联疫苗、接种DTaP-HBV-IPV五联疫苗和Hib单价疫苗组合或者DTaP-IPV-Hib五联和HepB单价疫苗组合三种方式对所有疫苗抗原成分的血清保护/阳性率都很高，分别为94.8%、98.1%、97.8%，研究者在三组受试者中均观察到接种疫苗后产生的强大免疫反应以及相似的反应原性33。
审核校对：陈姝，潘张旸，邓添艺
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参考文献
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