Pneumococcal conjugate vaccines in infants and children under 5 years of age: WHO position paper – February 20195岁以下婴幼儿接种肺炎球菌结合疫苗：世卫组织立场文件 - 2019年2月 

 Introduction 导言

 In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale vaccination programmes. They summarize essential background information on diseases and vaccines and conclude with the current WHO position on the use of vaccines worldwide.世卫组织的任务是就卫生政策问题向会员国提供指导，根据这一任务，世卫组织发布了一系列定期更新的立场文件，内容涉及针对具有国际公共卫生影响的疾病的疫苗和疫苗组合。这些文件主要涉及疫苗在大规模疫苗接种计划中的使用。它们总结了有关疾病和疫苗的基本背景信息，最后提出了世卫组织目前在全球范围内使用疫苗的立场。

 The papers are reviewed by external experts and WHO staff and endorsed by the WHO Strategic Advisory Group of Experts (SAGE) on Immunization (http:// www.who.int/immunization/sage/en). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method is used to assess the quality of the available evidence systematically. The SAGE decision-making process is reflected in “evidence-to-recommendation” tables. The processes followed for the preparation of vaccine position papers are described at: http://www.who.int/immunization/position_papers/position_paper_ process.pdf. The position papers are intended for use mainly by national public health officials and managers of immunization programmes. They may also be of interest to international funding agencies, vaccine advisory groups, vaccine manufacturers, health professionals, researchers, the scientific media and the general public. A 23-valent polysaccharide vaccine has been available since the early 1980s, and pneumococcal conjugate vaccines (PCV) have been available since 2009. The focus of this position paper is use of PCV in infants and children <5 years of age; a separate position paper on vaccination of older age groups with conjugate and polysaccharide vaccines will be developed after consideration by SAGE. The present position paper includes data on the effects of the 10- and 13-valent PCVs (PCV10 and PCV13) published up to June 2017 and specifically addresses the dosing schedule, product choice and the value of catch-up vaccination in children under 5 years of age.这些论文由外部专家和世卫组织工作人员审查，并由世卫组织免疫战略专家咨询小组（SAGE）批准（http:// www.who.int/immunization/sage/en）。建议评估、发展和评价分级法（GRADE）用于系统评估现有证据的质量。SAGE 的决策过程反映在 "证据到建议 "表格中。疫苗立场文件的编写过程见 http://www.who.int/immunization/position_papers/position_paper_ process.pdf。立场文件主要供国家公共卫生官员和免疫计划管理人员使用。国际资助机构、疫苗咨询小组、疫苗生产商、卫生专业人员、研究人员、科学媒体和公众也可能对这些文件感兴趣。23 价多糖疫苗自 20 世纪 80 年代初开始供应，肺炎球菌结合疫苗 (PCV) 自 2009 年开始供应。本立场文件的重点是肺炎球菌结合疫苗在婴儿和 5 岁以下儿童中的应用；经耆老学会审议后，将另行制定一份关于较大年龄组接种结合疫苗和多糖疫苗的立场文件。本立场文件包括截至 2017 年 6 月发布的有关 10 价和 13 价 PCV（PCV10 和 PCV13）效果的数据，特别涉及剂量表、产品选择和 5 岁以下儿童补种疫苗的价值。

 Recommendations on the use of PCVs were discussed by SAGE in October 2017. Evidence presented at the meeting can be accessed at: http://www.who.int/immunization/sage/meetings/2017/october/presentations_ background_docs/en/2017年10月，SAGE讨论了关于使用PCV的建议。会上提出的证据可在以下网址查阅：http://www.who.int/immunization/sage/meetings/2017/october/presentations_ background_docs/en/

Background 背景介绍

 Epidemiology 流行病学

 Pneumococcal infections can lead to serious invasive diseases such as meningitis, septicaemia and pneumonia, as well as milder but more common illnesses such as sinusitis and otitis media. The causative agent, Streptococcus pneumoniae, frequently colonizes the human肺炎球菌感染可导致脑膜炎、败血症和肺炎等严重的侵袭性疾病，以及鼻窦炎和中耳炎等较轻但更常见的疾病。致病菌肺炎链球菌经常在人体内定植。

nasopharynx and is transmitted mainly through respiratory droplets. Infants and young children are the main reservoir of this organism, in whom the cross-sectional point prevalence of nasopharyngeal (NP) carriage ranges from 27% to 85%, with higher carriage rates among children in low- and middle-income countries (LMICs) and in some indigenous populations in highincome countries. There are >90 known serotypes of S. pneumoniae. The distribution of serotypes that cause disease varies over time and by age, disease syndrome, disease severity, geographical region and the presence of antimicrobialresistant genes. Before the introduction of PCVs in the different WHO regions, 6–11 serotypes accounted for ≥70% of all invasive pneumococcal disease (IPD), defined as morbidity associated with isolation of pneumococci from a normally sterile body site, in children <5 years. Most illnesses occur sporadically. Outbreaks of pneumococcal disease, although uncommon, may occur in closed institutions, such as in nursing homes and childcare centres; however, large outbreaks of meningitis caused by serotype 1 have been reported from the African “meningitis belt”.主要通过呼吸道飞沫传播。婴幼儿是这种病菌的主要贮存地，鼻咽部（NP）携带的横断面点流行率从27%到85%不等，在中低收入国家（LMICs）和高收入国家的一些土著居民中，婴幼儿的携带率更高。已知的肺炎双球菌血清型超过 90 种。致病血清型的分布随时间、年龄、疾病综合征、疾病严重程度、地理区域和抗菌基因的存在而变化。在世界卫生组织的不同地区引入肺炎球菌疫苗之前，6-11 种血清型的肺炎球菌占所有侵袭性肺炎球菌疾病（IPD）的≥70%，IPD 的定义是与从正常无菌的身体部位分离出肺炎球菌有关的发病率，发病年龄小于 5 岁。大多数疾病都是偶发的。肺炎球菌疾病的爆发虽然并不常见，但可能发生在封闭的机构中，如疗养院和托儿所；不过，据报道，非洲 "脑膜炎带 "曾爆发过由血清 1 型引起的大规模脑膜炎。

Of the estimated 5.83 million deaths among children <5 years of age globally in 2015, 294 000 (uncertainty range [UR], 192 000–366 000) were estimated to be caused by pneumococcal infections. An additional 23 300 deaths (UR 15 300–40 700) were estimated to have occurred in children co-infected with HIV. Disease and mortality rates are higher in developing than in industrialized settings, with most deaths occurring in Africa and Asia.据估计，在 2015 年全球约 583 万例 5 岁以下儿童死亡病例中，有 294 000 例（不确定范围 [UR]，192 000-366 000）是由肺炎球菌感染造成的。据估计，另有 23 300 例死亡（不确定范围 [UR]，15 300-40 700）发生在合并感染艾滋病毒的儿童身上。发展中国家的发病率和死亡率均高于工业化国家，大多数死亡病例发生在非洲和亚洲。

 Before widespread introduction of PCVs into national immunization programmes since 2006, the reported mean annual incidence of IPD in children aged <2 years was 44.4/100 000 per year in Europe and 167/100 000 per year in the United States of America. In comparison, the annual incidence of IPD in children <2 years in Africa ranged from 60/100 000 in South Africa to 797/100 000 in Mozambique. Although differences in the reported incidence can be explained partly by differences in the sensitivity of case ascertainment and surveillance (e.g., limited to hospitalized children in some studies but including outpatients with febrile illness in others), the incidence in Africa appeared to be generally higher than that in Europe or North America. The reported incidence rates in Asia and Latin America range between these extremes.在自 2006 年起将 PCVs 广泛引入国家免疫计划之前，欧洲报告的小于 2 岁儿童 IPD 年平均发病率为 44.4/100000，美国为 167/100000。相比之下，非洲小于2岁儿童的IPD年发病率从南非的60/100 000到莫桑比克的797/100 000不等。虽然报告发病率的差异可部分归因于病例确定和监测的敏感性不同（例如，一些研究仅限于住院儿童，而另一些研究则包括发热门诊患者），但非洲的发病率似乎普遍高于欧洲或北美。亚洲和拉丁美洲报告的发病率介于这两个极端之间。

It is difficult to determine the proportion of pneumonia that is due to S. pneumoniae. In a compilation of data from studies of lung aspirates from various regions, S. pneumoniae was found to be the cause of 78% of 284 lobar pneumonia cases and 13% of 515 bronchopneumonia cases proven to be of bacterial etiology by transthoracic needle aspiration. A systematic Cochrane review of studies on PCVs in children <2 years of age showed a pooled vaccine efficacy of 27% (95% confidence interval [CI], 15%, 36%) against radiologically confirmed pneumonia as defined by WHO, suggesting that at least 27% of radiologically confirmed pneumonia could be caused by S. pneumoniae. An analysis of the efficacy of PCV against radiologically confirmed pneumonia in children under 5 years of age indicated that the proportion of pneumonia caused by S. pneumoniae is 34% [UR 26-36%]; such proportions are considered to be more precise than estimates based on data from studies of laboratory-confirmed cases. On average, about 75% of cases of IPD, and 83% of cases of pneumococcal meningitis, occur in children aged <2 years, but the incidence and age distribution of cases may vary by country, study method and socio-economic status within countries. Seasonal and climatic trends in both IPD and community-acquired pneumonia have been reported that coincide with the seasonal circulation of influenza and respiratory syncytial viruses, suggesting that these viruses predispose to pneumococcal infection.很难确定肺炎双球菌在肺炎中所占的比例。在对不同地区肺部抽吸物研究数据的汇编中发现，在 284 例大叶性肺炎病例和 515 例支气管肺炎病例中，肺炎双球菌分别占 78% 和 13%。Cochrane 对有关 2 岁以下儿童 PCV 的研究进行了系统性回顾，结果显示，对世卫组织定义的经放射学确诊的肺炎，疫苗的总有效率为 27%（95% 置信区间 [CI]，15%，36%），这表明至少 27% 经放射学确诊的肺炎可能是由肺炎双球菌引起的。一项关于 PCV 对 5 岁以下儿童经放射学确诊肺炎疗效的分析表明，由肺炎双球菌引起的肺炎比例为 34% [UR 26-36%]。平均而言，约 75% 的 IPD 病例和 83% 的肺炎球菌脑膜炎病例发生在 2 岁以下的儿童身上，但病例的发生率和年龄分布可能因国家、研究方法和国家内部的社会经济状况而异。有报道称，IPD 和社区获得性肺炎的季节和气候趋势与流感病毒和呼吸道合胞病毒的季节性流行相吻合，这表明这些病毒易导致肺炎球菌感染。

 Pathogen 病原体

 S. pneumoniae is a Gram-positive, encapsulated diplococcus. The polysaccharide capsule of this bacterium is an essential virulence factor, and pneumococcal serotypes are defined on the basis of differences in its composition. Antibody to the capsular polysaccharide protects against disease. In general, immunity from natural infection or vaccination is serotype-specific, but cross-protection among related serotypes can occur (namely between serotypes 6A/6B, 6A/6C and 19A/19F).肺炎双球菌是一种革兰氏阳性的包裹双球菌。这种细菌的多糖胶囊是一个重要的致病因子，肺炎球菌血清型是根据其组成成分的不同而确定的。囊多糖抗体可预防疾病。一般来说，自然感染或接种疫苗产生的免疫力具有血清型特异性，但相关血清型之间也会出现交叉保护（即血清型 6A/6B、6A/6C 和 19A/19F 之间）。

While a wide variety of serotypes cause non-invasive diseases such as otitis media and sinusitis, fewer cause invasive disease. Serotypes 1, 5, 6A, 6B, 14, 19F and 23F are common causes of IPD globally in children <5 years of age. Before widespread use of PCV, serotypes 1, 5 and 14 together accounted for 28–43% of cases of IPD in children under 5 years worldwide and for about 30% of IPD in 20 of the world’s poorest countries; serotypes 19F and 23F were responsible for 9–18% of cases globally. Serotype 18C was common in regions with larger proportions of high-income countries (Europe, North America and Oceania). Some serotypes, such as 6B, 9V, 14, 19A, 19F and 23F, are more likely than others to be resistant to antimicrobials.虽然有多种血清型可引起中耳炎和鼻窦炎等非侵袭性疾病，但引起侵袭性疾病的血清型较少。血清型 1、5、6A、6B、14、19F 和 23F 是全球 5 岁以下儿童 IPD 的常见病因。在广泛使用 PCV 之前，血清型 1、5 和 14 共占全球 5 岁以下儿童 IPD 病例的 28-43%，占全球 20 个最贫穷国家 IPD 病例的 30%左右；血清型 19F 和 23F 占全球病例的 9-18%。血清型 18C 常见于高收入国家比例较高的地区（欧洲、北美和大洋洲）。某些血清型，如 6B、9V、14、19A、19F 和 23F 型，比其他血清型更容易对抗菌药产生耐药性。

 Disease 疾病

 Pneumococcal infection and disease can affect various organ systems. Bloodstream invasion results in bacteraemia that occasionally causes infection at secondary sites, such as the meninges, joints and peritoneum. In other instances, contiguous spread from the nasopharynx can cause diseases such as otitis media or sinusitis. Pneumonia is often caused by aspiration of pneumococci from the nasopharynx and may also be caused by blood-borne spread. When associated with bacteraemia, pneumonia is classified as IPD. As IPD can be diagnosed unambiguously by microbiology, its incidence is frequently used as a measure of the incidence of severe pneumococcal disease in general.肺炎球菌感染和疾病可影响多个器官系统。血流入侵会导致菌血症，偶尔会引起继发感染，如脑膜、关节和腹膜。在其他情况下，从鼻咽部连续传播可引起中耳炎或鼻窦炎等疾病。肺炎通常由鼻咽部吸入肺炎球菌引起，也可能由血液传播引起。如果肺炎伴有菌血症，则被归类为 IPD。由于 IPD 可通过微生物学明确诊断，因此其发病率经常被用来衡量严重肺炎球菌疾病的总体发病率。

Case fatality rates from IPD in children can be high, ranging up to 20% for septicaemia and 50% for meningitis in LMICs. Long-term neurological sequelae such as hearing loss, mental retardation, motor abnormalities and seizures have been observed in 24.7% (interquartile range, 16.2–35.3%) of survivors of childhood pneumococcal meningitis; the risk of sequelae was 3 times higher among survivors in Africa and Asia than among those in Europe. Pneumococcal middle-ear infection and sinusitis are less severe clinical manifestations, but they are considerably more common health problems worldwide and represent a high economic burden, particularly in countries where out-of-pocket expenditure constitutes a large proportion of health expenditure. They also result in significant consumption of antimicrobials.儿童 IPD 的病死率很高，在低收入国家，败血症的病死率高达 20%，脑膜炎的病死率高达 50%。在儿童肺炎球菌脑膜炎幸存者中，有 24.7%（四分位距为 16.2-35.3%）的人出现听力损失、智力迟钝、运动异常和癫痫发作等长期神经系统后遗症；非洲和亚洲幸存者出现后遗症的风险是欧洲幸存者的 3 倍。肺炎球菌中耳炎和鼻窦炎的临床表现并不严重，但它们是全球范围内更为常见的健康问题，造成了沉重的经济负担，尤其是在自费支出占医疗支出很大比例的国家。这些疾病还导致抗菌药物的大量消耗。

 Lack of exclusive breastfeeding, nutritional deficiency and indoor air pollution are risk factors for pneumonia, including pneumococcal pneumonia, in infants and young children. In addition to the high incidence of pneumococcal disease in children <2 years of age, the risk is also increased in individuals with chronic medical conditions such as heart disease, lung disease, diabetes, sickle-cell anaemia, asplenia or other conditions that suppress the immune system, such as advanced HIV infection. Development of pneumococcal resistance to commonly used antimicrobials such as penicillins, macrolides, cephalosporins and co-trimoxazole is a serious problem in some parts of the world. Since large-scale introduction of pneumococcal vaccination, however, a reduction in the circulation of antimicrobial-resistant strains has been observed; among children under 2 years of age, disease caused by strains that are not susceptible to penicillins decreased from 70.3 to 13.1 cases per 100 000 (a decrease of 81%).缺乏纯母乳喂养、营养缺乏和室内空气污染是婴幼儿患肺炎（包括肺炎球菌肺炎）的危险因素。除了两岁以下儿童肺炎球菌疾病发病率高之外，患有慢性疾病（如心脏病、肺病、糖尿病、镰状细胞性贫血、脾功能减退症或其他抑制免疫系统的疾病，如晚期艾滋病病毒感染）的人患肺炎球菌疾病的风险也会增加。肺炎球菌对青霉素类、大环内酯类、头孢菌素类和共三唑类等常用抗菌药产生抗药性，在世界一些地区是一个严重问题。不过，自从大规模引入肺炎球菌疫苗接种以来，抗菌菌株的流通量有所减少；在 2 岁以下儿童中，对青霉素类药物不敏感的菌株引起的疾病从每 10 万例中的 70.3 例减少到 13.1 例（减少了 81%）。

Diagnosis 诊断

 While clinical diagnosis of pneumonia or meningitis is based on symptoms, signs and radiological tests, diagnosis of pneumococcal disease requires laboratory confirmation. A definitive diagnosis of pneumococcal infection is made by isolating the bacterium from blood or other normally sterile body sites, such as cerebrospinal fluid; however, etiological diagnosis is usually not possible in cases of non-bacteraemic pneumococcal disease, such as pneumonia and otitis media, as biological specimens are usually not available for testing. Rapid diagnostic tests, such as for antigens, and polymerase chain reaction assays are increasingly used, especially for the diagnosis of pneumococcal meningitis; these tests are more sensitive than bacterial culture, especially in patients pretreated with antimicrobials.肺炎或脑膜炎的临床诊断基于症状、体征和放射学检查，而肺炎球菌疾病的诊断则需要实验室确诊。从血液或其他正常无菌的身体部位（如脑脊液）分离出细菌，就能明确诊断肺炎球菌感染；但是，在肺炎和中耳炎等非细菌性肺炎球菌疾病的病例中，通常无法进行病原学诊断，因为通常无法获得生物标本进行检测。抗原等快速诊断检测和聚合酶链反应检测的使用越来越多，尤其是在肺炎球菌脑膜炎的诊断中；这些检测比细菌培养更敏感，尤其是在使用抗菌药预处理的患者中。

 Treatment 治疗

 Pneumococcal disease can be treated with antimicrobials. The choice of antimicrobial and the duration of treatment depend on the site of infection and the pattern of susceptibility to antimicrobials; the outcome depends on age, disease syndrome, severity, duration of illness before initiation of treatment and susceptibility to the antimicrobials used. 肺炎球菌疾病可以用抗菌药物治疗。抗菌药的选择和治疗时间取决于感染部位和对抗菌药的敏感性模式；疗效取决于年龄、疾病综合征、严重程度、开始治疗前的病程以及对所用抗菌药的敏感性。

Naturally acquired immunity自然获得的免疫力

 The risk of pneumococcal disease decreases after early childhood and increases again in old age, suggesting acquisition of natural immunity and loss of immunity in older adults due to immunosenescence and increased susceptibility due to other diseases. The mechanisms of natural immunity are not fully understood, although antibodies to capsular polysaccharide, protein antigens and cell-mediated immune responses are thought to contribute.婴幼儿时期之后，患肺炎球菌疾病的风险会降低，到老年时又会升高，这表明老年人获得了天然免疫，但由于免疫衰老和其他疾病导致的易感性增加，老年人的免疫力会丧失。虽然人们认为荚膜多糖抗体、蛋白质抗原和细胞介导的免疫反应对自然免疫的机制有影响，但目前还不完全清楚。

Pneumococcal conjugate vaccines肺炎球菌结合疫苗

 Two polysaccharide-protein conjugate vaccines have been on the market since 2009: the 10-valent (PCV10) and the 13-valent (PCV13) vaccines. Previously, a 7-valent pneumococcal conjugate vaccine (PCV7) was available, and at least 9 other pneumococcal conjugate vaccines containing 10–20 serotypes are undergoing trials in humans. WHO has developed a set of principles to ensure the quality, safety and efficacy of these vaccines.32 This position paper pertains to the currently licensed PCV10 and PCV13 used in children <5 years of age. The recommendations in this paper do not necessarily apply to products that become available in the future. Data on other PCV formulations, including the previously licensed PCV7 and the 9- and 11-valent conjugate vaccines that were evaluated in phase-3 clinical trials in Africa and Asia but were not licensed, are referred to where relevant to the use of PCV10 and PCV13.自 2009 年以来，有两种多糖-蛋白结合疫苗上市：10 价（PCV10）和 13 价（PCV13）疫苗。在此之前，已有 7 价肺炎球菌结合疫苗（PCV7）上市，另外至少有 9 种含有 10-20 个血清型的肺炎球菌结合疫苗正在人体试验中。世卫组织已制定了一套原则，以确保这些疫苗的质量、安全性和有效性。32 本立场文件涉及目前获准用于 5 岁以下儿童的 PCV10 和 PCV13。本文中的建议不一定适用于将来上市的产品。在与 PCV10 和 PCV13 的使用相关的地方，参考了其他 PCV 制剂的数据，包括之前获得许可的 PCV7 以及在非洲和亚洲的第 3 阶段临床试验中进行了评估但未获得许可的 9 价和 11 价结合疫苗。

Vaccine characteristics, content, dosage,  administration and storage PCV10 is composed of capsular polysaccharides purif ied from 10 serotypes: 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Each capsular polysaccharide is conjugated to a carrier protein, either protein D (an outer membrane protein from non-typable Haemophilus influenzae), tetanus toxoid or diphtheria toxoid. Protein D is used as the carrier protein for 8 of the 10 serotypes (1, 4, 5, 6B, 7F, 9V, 14 and 23F); 19F is conjugated to diphtheria toxoid and serotype 18C to tetanus toxoid.疫苗特性、含量、剂量、用法和储存 PCV10 由从 10 个血清型中纯化的荚膜多糖组成：1、4、5、6B、7F、9V、14、18C、19F 和 23F。每种胶囊多糖都与载体蛋白连接，载体蛋白可以是蛋白 D（一种来自非特异性流感嗜血杆菌的外膜蛋白）、破伤风类毒素或白喉类毒素。在 10 个血清型（1、4、5、6B、7F、9V、14 和 23F）中，有 8 个使用蛋白 D 作为载体蛋白；19F 与类白喉毒素共轭，血清型 18C 与类破伤风毒素共轭。

 PCV10 contains the adjuvant aluminium phosphate and is presented in a single-dose syringe, a single-dose vial without preservative or a 4-dose vial that contains 2-phenoxyethanol as the preservative. The volume per dose is 0.5 mL. Each vaccine dose contains 1 µg each of the polysaccharide of serotypes 1, 5, 6B, 7F, 9V, 14 and 23F and 3 µg each of the serotype-specific polysaccharide of serotypes 4, 18C and 19F.PCV10 含有佐剂磷酸铝，采用单剂量注射器、不含防腐剂的单剂量小瓶或含 2-苯氧基乙醇防腐剂的 4 剂量小瓶包装。每剂疫苗的容量为 0.5 毫升。每剂疫苗含有 1、5、6B、7F、9V、14 和 23F 血清型多糖各 1 µg，以及 4、18C 和 19F 血清型特异性多糖各 3 µg。

PCV13 contains the capsular polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, individually conjugated to a nontoxic diphtheria crossreactive material (CRM197) carrier protein. A 0.5-mL PCV13 dose contains approximately 2.2 µg of polysaccharide from each of 12 serotypes and approximately 4.4 µg of polysaccharide from serotype 6B. The vaccine contains aluminium phosphate as an adjuvant. PCV13 is available as a single-dose pre-filled syringe, in a single-dose vial without preservative or in a 4-dose vial that contains 2-phenoxyethanol as the preservative.PCV13 含有血清型 1、3、4、5、6A、6B、7F、9V、14、18C、19A、19F 和 23F 的荚膜多糖，分别与无毒的白喉交叉反应物 (CRM197) 载体蛋白共轭。每剂 0.5 毫升 PCV13 疫苗含有 12 个血清型中每个血清型约 2.2 微克的多糖和约 4.4 微克的 6B 血清型多糖。疫苗含有磷酸铝作为佐剂。PCV13 以单剂预灌封注射器、不含防腐剂的单剂小瓶或含 2-苯氧基乙醇防腐剂的四剂小瓶形式供应。

 The storage temperature for both PCV10 and PCV13 recommended by the manufacturers is 2–8 °C, and the vaccines must not be frozen. The 1- and 4-dose vials of both vaccines come with a Vaccine Vial Monitor 30. A systematic review and meta-analysis of data on IPD serotypes from children <5 years during the period 1980–2007 (i.e. before national introduction of PCV in the country of the study) showed that the serotypes in PCV10 and PCV13 cover ≥70% of IPD in each geographical region (range, 70–84% for PCV10 and 74–88% for PCV13).生产商建议 PCV10 和 PCV13 的储存温度为 2-8 °C，疫苗不得冷冻。两种疫苗的 1 剂和 4 剂小瓶均配有疫苗瓶监测器 30。对1980-2007年期间（即研究国家在全国范围内引入PCV之前）小于5岁儿童的IPD血清型数据进行的系统回顾和荟萃分析表明，PCV10和PCV13中的血清型覆盖了每个地理区域≥70%的IPD（PCV10为70-84%，PCV13为74-88%）。

 Although the details of labelling may differ by country, both PCV10 and PCV13 are prequalified by WHO and licensed for active vaccination for the prevention of IPD, pneumonia and acute otitis media caused by the respective vaccine serotypes of S. pneumoniae in infants and children aged from 6 weeks to 5 years.36, 37 The vaccines are given by injection into the anterolateral aspect of the thigh of infants and into the deltoid from the second year of life onwards. For PCV10 and PCV13, the manufacturers recommend 3 primary doses at an interval of at least 4 weeks, plus a booster dose at least 6 months after the third dose (3p+1 schedule). The first dose can be given as early as 6 weeks of age; the booster dose is given preferably between 9 and 15 months of age. An alternative schedule consists of 2 primary doses given 2 months apart, starting at 2 months of age (6 weeks for PCV10), followed by a booster dose at least 6 months after the second dose (2p+1 schedule) for PCV10 and at 11–15 months of age for PCV13.尽管各国的标签细节可能有所不同，但 PCV10 和 PCV13 均通过了世界卫生组织的资格预审，并获准用于主动接种，预防 6 周至 5 岁婴幼儿因肺炎双球菌血清型引起的 IPD、肺炎和急性中耳炎。对于 PCV10 和 PCV13，生产商建议至少间隔 4 周接种 3 次，并在接种第 3 次后至少 6 个月接种 1 次加强剂（3p+1 计划）。第一剂最早可在 6 周大时注射；加强剂最好在 9 至 15 个月大时注射。另一种方案是，从 2 个月大（PCV10 为 6 周）开始，间隔 2 个月注射 2 次初免剂量，然后在 PCV10 第二次注射后至少 6 个月注射加强剂量（2p+1 方案），PCV13 则在 11-15 个月大时注射加强剂量。

The manufacturers further recommend that previously unvaccinated infants aged 7–11 months should receive 2 doses, the second dose at least 4 weeks after the first, followed by a third dose in the second year of life at an interval of at least 2 months after the last primary dose. For PCV10, it is recommended that unvaccinated children aged 12 months to 5 years receive 2 doses, with an interval of at least 2 months between the first and second dose. For PCV13, unvaccinated children aged 12–23 months should receive 2 doses at an interval of at least 2 months, and children aged 2–5 years should receive a single dose.生产商还建议，以前未接种过疫苗的 7-11 个月大婴儿应接种 2 剂，第 2 剂应在第 1 剂后至少 4 周接种，然后在出生后第二年接种第 3 剂，间隔时间与上一次初次接种间隔至少 2 个月。对于 PCV10，建议 12 个月至 5 岁未接种儿童接种 2 剂，第一剂和第二剂之间至少间隔 2 个月。对于 PCV13，12-23 个月大的未接种儿童应接种 2 剂，间隔至少 2 个月，2-5 岁的儿童应接种 1 剂。

Serological criteria for evaluation of immunological responses to pneumococcal conjugate vaccines评估肺炎球菌结合疫苗免疫反应的血清学标准

WHO has defined serological criteria for non-inferiority that should be used in the primary analysis of studies of immunological responses to PCV. The criteria are: (i) the percentage of PCV recipients with serotypespecific immunoglobulin G ≥0.35 µg/mL (hereafter referred to as “percentage of responders”) in a WHO reference assay (or an alternative, well-justified threshold based on a specific in-house assay) and (ii) the serotype-specific immunoglobulin G geometric mean concentration (GMC) measured 4 weeks after completion of the primary infant vaccination series. In view of the efficacy of PCV7 and the experimental PCV9 against IPD, it is reasonable to use the proportion of infants with an antibody concentration ≥0.35 µg/mL as a marker of efficacy. It is unknown whether a lower serotype-specific GMC of antibody indicates less efficacy for those serotypes. The threshold is meant to be used to establish non-inferiority against the reference PCV in aggregate, and no serotype-specific thresholds have been defined.世卫组织确定了非劣效性血清学标准，应在 PCV 免疫反应研究的初步分析中使用。这些标准是(i) PCV 接种者中血清型特异性免疫球蛋白 G ≥ 0.35 µg/mL（以下简称 "应答者百分比"）的百分比，该百分比是根据世卫组织参考测定法（或基于特定内部测定法的合理替代阈值）得出的；(ii) 血清型特异性免疫球蛋白 G 几何平均浓度 (GMC) 是在初级婴儿疫苗接种系列完成 4 周后测量的。鉴于 PCV7 和试验性 PCV9 对 IPD 的疗效，使用抗体浓度≥0.35 µg/mL 的婴儿比例作为疗效指标是合理的。目前尚不清楚血清型特异性抗体 GMC 值越低是否表明对这些血清型的疗效越差。该阈值旨在用于确定与参考 PCV 相比的总体非劣效性，尚未确定特定血清型的阈值。

 Immunogenicity, efficacy and effectiveness免疫原性、功效和作用

 The recommendations in this position paper are based on a systematic review of primary evidence from the literature on the immunogenicity and effectiveness against clinical disease (IPD and pneumonia) and NP carriage (which provides an indication of potential indirect effects of vaccination) of the 2 available PCV products used either as 3 primary doses with no booster (3p+0) or a 2p+1 schedule; studies that included schedules of 2 primary doses with no booster (2p+0) and 3p+1 were included when technically relevant.本立场文件中的建议是基于对文献中关于 2 种现有 PCV 产品的免疫原性和对临床疾病（IPD 和肺炎）和 NP 带菌（可显示疫苗接种的潜在间接效果）的有效性的主要证据进行的系统性回顾；在技术相关的情况下，包括 2 剂无加强剂（2p+0）和 3p+1 的研究也包括在内。

 Both PCV10 and PCV13 have been shown to be safe and effective and to have both direct (in vaccinated individuals) and indirect (in unvaccinated individuals living in communities with vaccinated children) effects against pneumococcal disease caused by vaccine serotypes when used in a 3-dose schedule (either 2p+1 or 3p+0) or in a 4-dose schedule (3p+1). There is substantial evidence of the impact of each schedule on disease in various routine use settings. There are “head-to-head” studies39 of effects on immunogenicity and NP carriage but not on the effects of products or schedules on disease outcomes.PCV10 和 PCV13 均已被证明是安全有效的，在按 3 剂程序（2p+1 或 3p+0）或 4 剂程序（3p+1）使用时，对疫苗血清型引起的肺炎球菌疾病有直接（接种疫苗的个人）和间接（生活在有接种疫苗儿童的社区中未接种疫苗的个人）的影响。有大量证据表明，在不同的常规使用环境中，每种接种程序对疾病都有影响。有 "头对头 "研究39 证明了对免疫原性和 NP 携带的影响，但没有证明产品或方案对疾病结果的影响。

The results of the analysis of choice of schedules and of products are briefly summarized here.在此简要概述对时间表和产品选择的分析结果。

Choice of schedule  时间表的选择

In head-to-head studies on immunogenicity, after the primary series, the 2p+1 schedule resulted in lower evidence from ecological and case–control studies indicates that both schedules reduce the burden of IPD due to vaccine serotypes in both vaccinated (direct effects) and unvaccinated (indirect effects) members of the population. Evaluation of which schedule is better is, however, confounded by factors such as previous population exposure to PCV7 and differences in baseline IPD incidence. Data on the impact on IPD of the 2p+1 schedule are available mainly from high-income countries in which PCV13 is used, PCV7 was used previously, and there is a low baseline incidence of IPD, whereas data on the impact of the 3p+0 schedule are mainly from LMICs in which PCV10 is used, PCV7 was not used previously and there is a high baseline IPD incidence. Because of the booster dose in the 2p+1 schedule and the older age at which it is given, this schedule may provide longer protection and have greater indirect effects than the 3p+0 schedule.在关于免疫原性的头对头研究中，2p+1 接种方案在初级系列接种后的免疫原性较低，生态学和病例对照研究的证据表明，两种接种方案都能减少已接种（直接影响）和未接种（间接影响）人群中因疫苗血清型引起的 IPD 负担。然而，对哪种接种方案更好的评估会受到一些因素的影响，如人群以前接种 PCV7 的情况以及 IPD 基线发病率的差异。关于 2p+1 接种方案对 IPD 影响的数据主要来自高收入国家，这些国家使用 PCV13，以前使用过 PCV7，而且 IPD 的基线发病率较低；而关于 3p+0 接种方案影响的数据主要来自低收入和中等收入国家，这些国家使用 PCV10，以前未使用过 PCV7，而且 IPD 的基线发病率较高。由于 2p+1 接种方案中的加强剂量和接种年龄较大，该方案可能比 3p+0 接种方案提供更长的保护时间和更大的间接影响。

 The evidence for an impact on pneumonia of each schedule depends on the pneumonia outcome studied (radiologically confirmed pneumonia, empyema or pneumococcal pneumonia), and more data were available for the 2p+1 than for the 3p+0 schedule. The evidence does not indicate an advantage of one schedule over the other in preventing pneumonia.每种方案对肺炎影响的证据取决于所研究的肺炎结果（经放射证实的肺炎、肺水肿或肺炎球菌肺炎），而 2p+1 方案比 3p+0 方案有更多的数据。有证据表明，两种方案在预防肺炎方面并无优劣之分。

 Few data were available on the association between different schedules and mortality, and no conclusions could be drawn.关于不同时间表与死亡率之间关系的数据很少，因此无法得出结论。

 Evidence for the impact of different schedules on NP carriage in different settings was inconclusive, as it is confounded by factors including use of PCV7 before the introduction of PCV10/13, the PCV product used and differences in the baseline prevalence of carriage. Nevertheless, 2 studies in which PCV10 was used in the 2p+1 or 3p+0 schedules showed that both were effective in reducing vaccine-type NP carriage, with no significant difference; both studies were small and conducted in low-carriage settings.在不同环境下，不同接种方案对NP携带的影响尚无定论，因为这受到多种因素的影响，包括在引入PCV10/13之前使用PCV7、所使用的PCV产品以及携带基线流行率的差异。尽管如此，在 2p+1 或 3p+0 方案中使用 PCV10 的两项研究表明，这两种方案都能有效减少疫苗型 NP 带菌率，且无显著差异；这两项研究规模较小，均在低带菌率环境中进行。

Product choice  产品选择

Both PCV10 and PCV13 induce antibodies against the serotypes common to both vaccines (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). Although the mean antibody response to the common serotypes differed with the 2 products, in general, they induced comparable immunogenicity, as assessed by the proportion of children with protective antibody levels; however, no head-tohead studies of protective levels were available. The clinical implications, if any, of the relatively small differences in immunogenicity against the common serotypes have not been established.PCV10 和 PCV13 都能诱导出针对两种疫苗常见血清型（1、4、5、6B、7F、9V、14、18C、19F 和 23F）的抗体。虽然这两种产品对常见血清型的平均抗体反应不同，但总体而言，它们诱导的免疫原性相当，这可以通过具有保护性抗体水平的儿童比例来评估；不过，目前还没有关于保护性抗体水平的头对头研究。针对常见血清型的免疫原性差异相对较小，其临床影响尚未确定。

PCV13 has 3 additional serotypes, 3, 6A and 19A. PCV13 induces an immune response to serotype 3; PCV10 contains neither serotype 3 nor any cross-reactive serotype, and immunogenicity against serotype 3 is not measured in studies of this vaccine. Both PCV10 and PCV13 induce an antibody response to serotype 6A, which is included in PCV13 but not in PCV10; in PCV10, this is thought to be due to cross-reactivity with serotype 6B. Evidence indicates that PCV13 induces higher serotype 6A GMCs and a higher percentage of responders than PCV10. Both PCV10 and PCV13 induce an antibody response against serotype 19A, although PCV13 induces higher serotype 19A GMCs and a higher percentage of responders than PCV10; for PCV10, the antibody response against serotype 19A is thought to be due to cross-reactivity with serotype 19F.PCV13 还有 3 个血清型，即 3、6A 和 19A。PCV13 可诱导对血清型 3 的免疫应答；PCV10 既不包含血清型 3，也不包含任何交叉反应血清型，因此在对该疫苗的研究中没有测量针对血清型 3 的免疫原性。PCV10 和 PCV13 都能诱导对血清 6A 型的抗体反应，PCV13 中含有血清 6A 型，而 PCV10 中却没有；在 PCV10 中，这被认为是由于与血清 6B 型的交叉反应所致。有证据表明，与 PCV10 相比，PCV13 能诱导更多的血清 6A 型 GMC 和更高比例的应答者。PCV10 和 PCV13 都会诱导针对血清 19A 型的抗体反应，但 PCV13 比 PCV10 诱导更多的血清 19A 型 GMC 和更高比例的应答者；对于 PCV10，针对血清 19A 型的抗体反应被认为是由于与血清 19F 型的交叉反应所致。

 Although no head-to-head studies of the impact or effectiveness of the 2 products on IPD outcomes have been reported, the available evidence indicates that both products are effective in reducing overall vaccine-type IPD in both vaccinated and unvaccinated individuals. Although PCV13 contains 3 additional serotypes, there is currently insufficient evidence to determine whether they change the impact on overall IPD burden (vaccinetype and non-vaccine-type disease combined).虽然目前还没有关于这两种产品对 IPD 结果的影响或有效性的正面研究报告，但现有证据表明，这两种产品都能有效减少接种疫苗和未接种疫苗者的疫苗型 IPD 总量。尽管 PCV13 包含 3 种额外的血清型，但目前还没有足够的证据来确定它们是否会改变对 IPD 总体负担（疫苗型和非疫苗型疾病的总和）的影响。

 PCV10 use did not reduce IPD due to serotype 3 in either vaccine-eligible or non-eligible age groups, as it does not contain serotype 3. Despite immunogenicity data, evidence for a direct or indirect reduction in IPD due to serotype 3 after administration of PCV13 was inconclusive, although most studies showed no effect. Few data are available on the impact of PCV10 on IPD due to serotype 6A, but they generally indicate a direct effect. Most assessments of the effects of PCV13 on IPD due to serotype 6A were conducted in settings in which there had been prior use of PCV7, with a residual low burden of serotype 6A IPD remaining after use of PCV7 in both vaccine-eligible and non-eligible cohorts. In the only reported case-control study, effectiveness against serotype 6A was observed.PCV10 不含血清 3 型，因此在符合接种条件或不符合接种条件的年龄组中使用 PCV10 都不会减少血清 3 型引起的 IPD。尽管有免疫原性数据，但关于接种 PCV13 后血清 3 型导致的 IPD 直接或间接减少的证据并不确定，尽管大多数研究显示没有影响。关于 PCV10 对血清 6A 型 IPD 影响的数据很少，但这些数据一般都表明有直接影响。PCV13 对血清 6A 型 IPD 影响的大多数评估都是在曾使用过 PCV7 的情况下进行的，在使用 PCV7 后，符合接种条件和不符合接种条件的人群中血清 6A 型 IPD 的残留量都很低。在唯一一项报告的病例对照研究中，观察到了对血清 6A 型的有效性。

 Four case–control studies and an indirect cohort study of the effectiveness of PCV10 indicate a protective effect against serotype 19A IPD in vaccinated children, although not all the results reached statistical signifcance; 2 population-based incidence studies were less关于 PCV10 效果的四项病例对照研究和一项间接队列研究表明，接种 PCV10 的儿童对血清型 19A IPD 具有保护作用，但并非所有结果都具有统计学意义；两项基于人群的发病率研究结果表明，接种 PCV10 的儿童对血清型 19A IPD 的保护作用较弱。

conclusive, neither demonstrating an impact. Among cohorts not eligible for the vaccine, those living in communities where PCV10 was used showed increases or no change in serotype 19A IPD rates; therefore, there is no evidence that PCV10 induces indirect protection against serotype 19A. PCV13 was effective against serotype 19A IPD, with both direct and indirect effects. Very few data are available on the impact of PCV10 against serotype 6C IPD. Some studies showed a significant impact of PCV13 on serotype 6C IPD.结论，两者均未显示出影响。在不符合疫苗接种条件的人群中，那些生活在使用 PCV10 的社区中的人的血清 19A 型 IPD 感染率有所上升或没有变化；因此，没有证据表明 PCV10 能诱导对血清 19A 型的间接保护。PCV13 对血清 19A 型 IPD 有效，既有直接作用，也有间接作用。关于 PCV10 对血清 6C 型 IPD 影响的数据很少。一些研究表明 PCV13 对血清 6C 型 IPD 有明显影响。

 Both PCV10 and PCV13 had direct and indirect effects against pneumonia; however, as there are no comparative studies, there is no evidence of a difference in impact. No conclusions could be drawn about a differential impact on mortality by product.PCV10 和 PCV13 对肺炎都有直接和间接的影响；但是，由于没有进行比较研究，因此没有证据表明两者的影响存在差异。对于不同产品对死亡率的不同影响，无法得出结论。

Limited evidence was available from head-to-head studies on the differential impact or effectiveness of PCV10 and PCV13 on NP carriage. Both products reduced carriage of the serotypes common to both vaccines, but studies of individual products could not be compared quantitatively because of substantial confounding by schedule, local epidemiology and prior PCV7 use in the community.关于 PCV10 和 PCV13 对 NP 带菌率的不同影响或效果，正面对比研究提供的证据有限。这两种产品都能减少两种疫苗常见血清型的携带，但由于疫苗接种时间、当地流行病学和之前在社区使用 PCV7 的情况会产生大量混杂因素，因此无法对单个产品的研究进行定量比较。

With respect to the 3 additional serotypes in PCV13, no significant direct or indirect effects were found for PCV10 on serotype 3 carriage, and evidence for an effect of PCV13 on serotype 3 NP carriage was mixed. Direct effects of both products on serotype 6A carriage were observed, but there was insufficient evidence to conclude whether the magnitude of the impact differed. Possible indirect effects against serotype 6A carriage were found for PCV10 in studies in communities with no prior use of PCV7. No evidence is available on indirect effects of PCV13 because serotype 6A carriage had already been substantially reduced by PCV7 use where this was studied. PCV10 use was associated with statistically significant increases in serotype 19A carriage in some studies and nonsignificant increases or reductions in other studies with low pre-study carriage; in settings with high baseline carriage, statistically significant reductions in carriage were observed. Studies of PCV13 demonstrated consistent reductions in serotype 19A carriage in children age-eligible for routine vaccination. No analyses of indirect effects of PCV13 on serotype 19A carriage are available.至于 PCV13 中新增的 3 个血清型，PCV10 对血清 3 型携带未发现显著的直接或间接影响，而 PCV13 对血清 3 NP 型携带的影响证据不一。两种产品对血清 6A 型携带均有直接影响，但没有足够证据断定影响程度是否不同。在未使用过 PCV7 的社区进行的研究发现，PCV10 对血清 6A 型携带可能有间接影响。没有证据表明 PCV13 有间接影响，因为在研究 PCV13 的地方，使用 PCV7 已经大大减少了血清 6A 型携带。在一些研究中，PCV10 的使用与血清型 19A 带菌量在统计学上的显著增加有关，而在研究前带菌量较低的其他研究中，PCV10 的使用与血清型 19A 带菌量在统计学上的显著增加或减少无关；在基线带菌量较高的环境中，可以观察到带菌量在统计学上的显著减少。PCV13 的研究表明，在符合常规接种年龄的儿童中，血清 19A 型携带率持续下降。目前还没有 PCV13 对血清 19A 型携带的间接影响分析。

 Results of the impact of vaccination on serotype 6C carriage were limited for both products, and the studies were generally underpowered. The 2 studies of PCV10 showed increased serotype 6C carriage, and the results of 1 study were statistically significant. Conversely, all 4 studies of PCV13 showed decreased serotype 6C carriage, and the 1 with sufficient power showed a statistically significant reduction in carriage.关于接种疫苗对血清 6C 型携带的影响，两种产品的研究结果都很有限，而且研究结果普遍不充分。PCV10 的 2 项研究显示血清 6C 型携带率增加，其中 1 项研究的结果具有统计学意义。相反，对 PCV13 进行的所有 4 项研究均显示血清 6C 型携带率有所下降，其中 1 项研究具有足够的研究力量，其结果显示血清 6C 型携带率的下降具有统计学意义。

In summary, PCV10 and PCV13 have comparable immunogenicity and impact on IPD, pneumonia and NP carriage due to shared vaccine serotypes. While differences were found in their immunogenicity and impact on the 3 serotypes included in PCV13 and not PCV10 and on serotype 6C, there is currently insufficient evidence that the 2 vaccines differ in their impact on overall pneumococcal disease burden.总之，PCV10 和 PCV13 由于共享疫苗血清型，因此其免疫原性以及对 IPD、肺炎和 NP 携带的影响具有可比性。虽然在免疫原性和对 PCV13 所含而非 PCV10 所含的 3 种血清型的影响以及对血清型 6C 的影响方面存在差异，但目前还没有足够的证据表明这两种疫苗在对肺炎球菌疾病总体负担的影响方面存在差异。

 Catch-up vaccination  补种疫苗

Empirical evidence of the impact of catch-up PCV vaccination at the time of its introduction among children in older birth cohorts is limited. Results from modelling studies of catch-up vaccination with PCV on disease impact in Kenya40 and Viet Nam41 were reviewed, which suggest that catch-up vaccination of children <5 years in older birth cohorts at the time of national PCV introduction accelerated both direct and indirect protection and thereby hastened the impact of PCV. Modelling of NP carriage and IPD data from a study in Kenya indicated that, at the time of PCV introduction, a catch-up campaign for children <5 years of age had a greater benefit per dose administered than catch-up campaigns for more narrow age strata or routine infant vaccination alone.40 Limited evidence is available to determine whether a single dose is sufficient or whether 2 doses are required for catch-up vaccination after infancy. For children aged 12–23 months of age, some programmes have used 2 PCV doses separated by at least 8 weeks, while others have used a single dose. The benefits of a catch-up campaign are mitigated if the resources used divert resources from wider PCV coverage in the birth cohort, delay introduction or if those in the catch-up age cohort have only moderate vaccine serotype carriage and disease.在大出生组群儿童中引入 PCV 补种疫苗时，有关其影响的经验证据十分有限。对肯尼亚40 和越南41 PCV 补种对疾病影响的建模研究结果进行了回顾，结果表明，在全国 PCV 引入时，对大出生队列中小于 5 岁的儿童进行补种可加速直接和间接保护，从而加快 PCV 的影响。肯尼亚一项研究对 NP 携带和 IPD 数据进行的建模表明，在 PCV 引入时，对小于 5 岁的儿童进行补种比对较窄年龄层进行补种或仅进行常规婴儿疫苗接种的单位剂量效益更大40。对于 12-23 个月大的儿童，一些计划使用 2 剂 PCV 疫苗，间隔至少 8 周，而另一些则使用单剂。如果所使用的资源占用了出生队列中更广泛的 PCV 覆盖范围，推迟了引入时间，或者如果补种年龄队列中的儿童仅有中等程度的疫苗血清型携带和疾病，那么补种活动的益处就会降低。

Vaccination in pneumococcal disease outbreaks肺炎球菌疾病爆发时的疫苗接种

 Limited evidence exists on the effectiveness of PCV as a response to pneumococcal disease outbreaks. Serotype 1 has been associated with disease outbreaks.Recent data from an outbreak of serotype 1 disease in Ghana, where PCV is used in the routine infant immunization programme in a 3p+0 schedule, showed lower rates of disease in the vaccinated cohort of children <5 years than in serotype 1 outbreaks before introduction of vaccination.4 This suggests direct protection against serotype 1 disease in vaccinated children but no indirect effects.关于 PCV 应对肺炎球菌疾病爆发的效果，目前证据有限。加纳在常规婴儿免疫接种计划中采用 PCV 3p+0 接种程序，最近在加纳爆发的血清 1 型疾病的数据显示，接种疫苗的 5 岁以下儿童发病率低于接种疫苗前血清 1 型疾病爆发时的发病率。

Serotype replacement following PCV use使用 PCV 后的血清型替换

 An increase in the incidence of non-vaccine-type disease after use of PCV, a phenomenon referred to as “serotype replacement”, has been described with PCV7 in many settings. A review of data from 21 eligible surveillance datasets showed that the overall IPD incidence in children had decreased by year 1 after vaccine introduction (relative risk [RR] 0.55, 95% CI 0.46–0.65) and remained stable through year 7 (RR 0.49, 95% CI 0.35–0.68), as compared with the pre-vaccine era. The incidence of vaccine-type IPD decreased annually through year 7 (RR 0.03; 95% CI, 0.01–0-10); the incidence of non-vaccinetype IPD increased by year 7 (RR 2.81; 95% CI, 2.123.71), and a single serotype, 19A, was responsible for most of the replacement.42 Limited data were available from LMICs in the above analysis, and no data on PCV10 or PCV13 were available for inclusion at the time of the analysis. A systematic review is being conducted of data on serotype replacement that includes data after use of PCV10 and PCV13 and from LMICs.使用 PCV 后，非疫苗型疾病的发病率有所上升，这种现象被称为 "血清型替代"，在许多情况下，PCV7 都出现过这种情况。对 21 个符合条件的监测数据集的数据回顾显示，与接种疫苗前相比，儿童 IPD 的总体发病率在接种疫苗后第 1 年有所下降（相对风险 [RR] 0.55，95% CI 0.46-0.65），并在第 7 年保持稳定（RR 0.49，95% CI 0.35-0.68）。到第 7 年，疫苗型 IPD 的发病率逐年下降（RR 为 0.03；95% CI 为 0.01-0-10）；到第 7 年，非疫苗型 IPD 的发病率上升（RR 为 2.81；95% CI 为 2.123.71），且大部分更换由单一血清型 19A 引起。目前正在对有关血清型替代的数据进行系统回顾，其中包括 PCV10 和 PCV13 使用后的数据以及来自低收入国家的数据。

Non-vaccine factors may influence the recorded rates of serotype-specific disease and thereby confound interpretation of the relation between introduction of PCV and changes in serotype distribution. Such factors include variation in the proportion of isolates serotyped before and after vaccine introduction, changes in blood culture practice, secular trends and outbreaks of pneumococcal disease. These factors should be considered in interpreting surveillance data on pneumococcal disease.非疫苗因素可能会影响记录的血清型特异性疾病发病率，从而混淆对引入 PCV 与血清型分布变化之间关系的解释。这些因素包括引入疫苗前后血清型分离比例的变化、血液培养方法的改变、世俗趋势和肺炎球菌疾病的爆发。在解释肺炎球菌疾病的监测数据时应考虑这些因素。

 Safety of PCVs  PCV 的安全性

The safety profiles of PCV10 and PCV13 are as favourable as that of PCV7 when they are administered to infants and young children.43–46 The most common adverse reactions observed after administration of PCV10 to infants were redness at the injection site and irritability, which occurred after approximately 41% and 55% of all doses, respectively. These adverse reactions were more common after booster vaccination. Fever was reported in 30–40% of infants with solicited adverse events, although grade 3 fever (>40 °C) occurred after no more than 3.9% of primary doses, 2.9% of booster doses and 2.2% of catch-up doses.33 Similarly, redness (24–42%) and swelling (20–32%) were the most common local adverse events observed after PCV13, with higher rates of local reactions after the booster dose. Irritability, observed in up to 85.6% of infants, was the most common systemic adverse event. Fever was reported in 24–36% of recipients of PCV13, although severe fever was reported in only 0.1–0.3%.婴幼儿接种 PCV10 和 PCV13 与 PCV7 一样具有良好的安全性。43-46 婴儿接种 PCV10 后最常见的不良反应是注射部位发红和烦躁，分别发生在约 41% 和 55% 的剂量之后。这些不良反应在加强免疫后更为常见。有 30-40% 的婴儿在接种 PCV13 后出现发热，但在 3.9% 的初次接种、2.9% 的加强接种和 2.2% 的补种后出现 3 级发热（>40°C）。33 同样，发红（24-42%）和肿胀（20-32%）是 PCV13 接种后最常见的局部不良反应，加强接种后的局部不良反应发生率更高。多达 85.6% 的婴儿出现烦躁，这是最常见的全身性不良反应。据报告，24%-36%的 PCV13 接种者出现发热，但严重发热的比例仅为 0.1%-0.3%。

There was a trend towards more Kawasaki disease 0–28 days after vaccination with PCV13 as compared with PCV7 (RR, 1.94; 95% CI, 0.79–4.86). Kawasaki disease was also observed more commonly in PCV10vaccinated groups than in controls, although it was rare (<1/10 000 children), and the incidence was below or within the expected population background range.与 PCV7 相比，接种 PCV13 后 0-28 天的川崎病有增多趋势（RR，1.94；95% CI，0.79-4.86）。与对照组相比，接种 PCV10 疫苗的人群中也更常出现川崎病，尽管这种病很少见（<1/10 000 名儿童），而且发病率低于或在预期的人群背景范围内。

 Concurrent administration with diphtheria, tetanus and pertussis vaccine resulted in rates of fever among recipients of PCV13 of 15–34%, with higher rates after the second dose. Administration of trivalent inactivated influenza vaccines on the same day as PCV13 was associated with a higher risk of febrile seizures than when they were given on a separate day (incidence rate ratio, 3.5; 95% CI, 1.13–10.85); however, the absolute risk of post-vaccination febrile seizures was small.同时接种白喉、破伤风和百日咳疫苗会导致 PCV13 接种者的发热率达到 15-34%，第二剂后的发热率更高。与 PCV13 在同一天接种三价灭活流感疫苗相比，在不同天接种三价灭活流感疫苗的发热风险更高（发病率比，3.5；95% CI，1.13-10.85）；但接种后发热的绝对风险很小。

 Vaccination of special risk groups, contraindications and precautions特殊风险群体的疫苗接种、禁忌症和预防措施

 Children with impaired immune responsiveness may have a reduced antibody response to vaccination with PCV. The available data suggest that the safety profiles of the 2 vaccines are similar in these risk groups and in healthy children.免疫反应能力受损的儿童对 PCV 疫苗的抗体反应可能会降低。现有数据表明，这两种疫苗对这些风险群体和健康儿童的安全性相似。

 Vaccine co-administration联合接种疫苗

 The immunogenicity and reactogenicity of PCVs are not significantly altered when they are given concomitantly with monovalent or combination vaccines against diphtheria, tetanus, pertussis (acellular and whole-cell vaccines), hepatitis B, polio (inactivated and live oral vaccines), H. influenzae type b, measles, mumps, rubella, varicella, meningococcus serogroup C (conjugate vaccine) or rotavirus.33, 34 Co-administration with yellow fever vaccine has not been studied.PCV 与白喉、破伤风、百日咳（无细胞和全细胞疫苗）、乙型肝炎、脊髓灰质炎（灭活和口服活疫苗）、 乙型流感嗜血杆菌、麻疹、流行性腮腺炎、风疹、水痘、C 型脑膜炎球菌血清群（结合疫苗）或轮状病毒的单价或联合疫苗同时接种时，其免疫原性和反应原性不会发生明显改变、34尚未对与黄热病疫苗同时接种进行过研究。

 Cost–effectiveness 成本效益

 The cost–effectiveness of PCV use depends on many factors, including the burden of disease, vaccine effectiveness, indirect effects, vaccination coverage, vaccine price, delivery costs and schedule.使用 PCV 的成本效益取决于许多因素，包括疾病负担、疫苗效果、间接影响、疫苗接种覆盖率、疫苗价格、接种成本和接种时间。

 An analysis of data from 22 studies in LMICs showed that vaccination with PCV10 and PCV13 is cost-effective from the perspective of both health care providers andsociety. The cost-effectiveness according to product choice will depend on country characteristics, including local serotype prevalence and coverage rates achieved with different schedules.对低收入和中等收入国家的 22 项研究数据进行的分析表明，从医疗服务提供者和社会的角度来看，接种 PCV10 和 PCV13 都具有成本效益。产品选择的成本效益取决于国家的特点，包括当地血清型流行率和不同接种程序的覆盖率。

 WHO position 世卫组织立场

 Currently available PCVs are safe and effective, and the increase in the number of serotypes in these vaccines as compared with the first licensed PCV7 represents significant progress in the fight against pneumococcal disease-related morbidity and mortality, particularly for developing countries.目前可用的 PCV 安全有效，与第一批获得许可的 PCV7 相比，这些疫苗的血清型数量有所增加，这表明在抗击肺炎球菌疾病相关的发病率和死亡率方面取得了重大进展，尤其是对发展中国家而言。

 WHO recommends the inclusion of PCVs in childhood immunization programmes worldwide.世卫组织建议将 PCV 纳入全球儿童免疫计划。

 Use of pneumococcal vaccine should be complementary to other disease prevention and control measures, such as appropriate case management, promotion of exclusive breastfeeding for the first 6 months of life and reducing known risk factors such as indoor air pollution and tobacco smoke.肺炎球菌疫苗的使用应与其他疾病预防和控制措施相辅相成，如适当的病例管理、提倡出生后 6 个月内纯母乳喂养以及减少已知的风险因素（如室内空气污染和烟草烟雾）。

 Schedule 时间安排

 For administration of PCV to infants, WHO recommends a 3-dose schedule administered either as 2p+1 or as 3p+0, starting as early as 6 weeks of age. In choosing between the 2p+1 and 3p+0 schedules, countries should consider programmatic factors, including timeliness of vaccination and expected coverage. The 2p+1 schedule has potential benefits over the 3p+0 schedule, when programmatically feasible, as higher antibody levels are induced in the second year of life, which may be important in maintaining herd immunity, although no high-quality evidence is available.对于婴儿 PCV 的接种，世卫组织建议采用 2p+1 或 3p+0 的三剂接种方案，最早从 6 周龄开始接种。在选择 2p+1 和 3p+0 两种方案时，各国应考虑项目因素，包括接种的及时性和预期覆盖率。在计划可行的情况下，2p+1 接种程序比 3p+0 接种程序有潜在的优势，因为 2p+1 接种程序可在婴儿出生后第二年诱导出更高的抗体水平，这可能对维持群体免疫力非常重要，但目前尚无高质量的证据。

 If the 2p+1 schedule is selected, an interval of ≥8 weeks is recommended between the 2 primary doses, but the interval may be shortened if there is a compelling reason to do so, such as timeliness of receipt of the second dose and/or achieving higher coverage when a 4-week interval is used. For the 2p+1 schedule, the booster dose should be given at 9–18 months of age, according to programmatic considerations; there is no defined minimum or maximum interval between the primary series and the booster dose. If the 3p+0 schedule is used, a minimum interval of 4 weeks should be maintained between doses.如果选择 2p+1 接种程序，建议两次初次接种的间隔时间≥8 周，但如果有充分的理由，如及时接种第二剂和/或在使用 4 周间隔时间时达到更高的覆盖率，间隔时间可以缩短。对于 2p+1 接种程序，根据计划的考虑，加强剂应在 9-18 个月大时接种；初次接种与加强剂之间没有规定最短或最长的间隔时间。如果采用 3p+0 接种程序，两次接种之间至少应间隔 4 周。

Previously unvaccinated or incompletely vaccinated children who recover from IPD should be vaccinated according to the recommended age-appropriate regimens. Interrupted schedules should be resumed without repeating the previous dose.之前未接种疫苗或未完全接种疫苗的 IPD 恢复期儿童应按照建议的适龄方案接种疫苗。应恢复中断的接种计划，而无需重复之前的剂量。

Product choice 产品选择

 Both PCV10 and PCV13 have substantial impacts against pneumonia, vaccine-type IPD and NP carriage. There is at present insufficient evidence of a difference in the net impact of the 2 products on overall disease burden.PCV13 may have an additional benefit in settings where disease attributable to serotype 19A or serotype 6C is significant. The choice of product to be used in a country should be based on programmatic characteristics, vaccine supply, vaccine price, the local and regional prevalence of vaccine serotypes and antimicrobial resistance patterns.PCV10 和 PCV13 对肺炎、疫苗型 IPD 和 NP 携带都有很大的影响。PCV13 在血清 19A 型或血清 6C 型引起的疾病严重的情况下可能会带来额外的益处。一个国家在选择使用哪种产品时应考虑项目特点、疫苗供应、疫苗价格、疫苗血清型在当地和区域的流行情况以及抗菌药耐药性模式。

Interchangeability 互换性

 Once a PCV vaccination programme has been initiated, product switching is not recommended unless there are substantial changes in the epidemiological or programmatic factors that determined the original choice of product, e.g. an increasing burden of serotype 19A. If a series cannot be completed with the same type of vaccine, the available PCV product should be used. Restarting a series is not recommended, even for the primary series.PCV 疫苗接种计划一旦启动，就不建议更换产品，除非决定最初选择产品的流行病学或计划因素发生了重大变化，例如血清型 19A 的接种量增加。如果无法使用同类型疫苗完成一个系列，则应使用现有的 PCV 产品。不建议重新开始一个系列，即使是初级系列。

 Catch-up vaccination  补种疫苗

Wherever possible, catch-up vaccination at the time of introduction of PCV should be used to accelerate its impact on disease in children aged 1–5 years, particularly in settings with a high disease burden and mortality. If there is limited availability of vaccine or of financial resources for catch-up vaccination, the youngest children (e.g. <2 years of age) should be prioritized to receive catch-up doses of PCV because of their higher risk for pneumococcal disease.只要有可能，就应在引入 PCV 时进行补种，以加快 PCV 对 1-5 岁儿童疾病的影响，尤其是在疾病负担和死亡率较高的环境中。如果疫苗供应或用于补种的财政资源有限，则应优先为年龄最小的儿童（如小于 2 岁）接种 PCV 补种剂，因为他们患肺炎球菌疾病的风险较高。

Catch-up vaccination can be done with a single dose of vaccine for children ≥24 months. Current data are insufficient for a firm recommendation on the optimal number of doses (1 or 2) required in 12–23-month-olds as part of catch-up vaccination, so countries choosing to use 1 dose might wish to monitor for impact and vaccine failures.≥24个月的儿童可接种单剂疫苗进行补种。目前的数据不足以就 12-23 月龄儿童作为补种疫苗的一部分所需的最佳剂量（1 剂或 2 剂）提出明确建议，因此选择使用 1 剂疫苗的国家可能希望对影响和疫苗失效情况进行监测。

 Unvaccinated children aged 1–5 years who are at high risk for pneumococcal infection because of underlying medical conditions, such as HIV infection or sickle-cell disease, should receive at least 2 doses separated by at least 8 weeks.未接种疫苗的 1-5 岁儿童如果因潜在疾病（如艾滋病毒感染或镰状细胞病）而成为肺炎球菌感染的高危人群，应至少接种 2 次，每次间隔至少 8 周。

 In humanitarian or other emergency situations, ageappropriate schedules of PCV vaccination should be used for children <1 year of age and considered for children ≤5 years of age, as indicated by the situation.在人道主义或其他紧急情况下，应根据实际情况为小于 1 岁的儿童接种 PCV 疫苗，并考虑为小于 5 岁的儿童接种 PCV 疫苗。

Catch-up vaccination may also be an important means to prevent outbreaks. Vaccine campaigns in response to outbreaks of confirmed vaccine-type pneumococcal disease are under consideration, but experience is currently lacking.补种疫苗也可能是预防疾病爆发的重要手段。目前正在考虑针对确诊疫苗型肺炎球菌疾病的爆发开展疫苗接种活动，但目前还缺乏经验。

 Vaccination of special populations特殊人群的疫苗接种

 PCVs should not be given to individuals with a history of anaphylactic reactions or severe allergic reactions to any component of the vaccine. HIV-positive infants and pre-term neonates who have received their 3 primary vaccine doses before 12 months of age may benefit from a booster dose in the second year of life.有过敏反应史或对疫苗中任何成分有严重过敏反应的人不应接种 PCV。艾滋病毒呈阳性的婴儿和早产新生儿如果在 12 个月前接种过 3 剂初级疫苗，可能会在出生后的第二年接种一剂加强剂。

Vaccination of travelling children为旅行儿童接种疫苗

 Travelling children are generally not at special risk of pneumococcal disease, unless they travel to an outbreak setting. They should follow the vaccine recommendations for the general population and ensure they are up to date with their vaccinations before travelling. Co-administration除非旅行到疫情爆发的地方，否则旅行儿童一般没有患肺炎球菌疾病的特殊风险。他们应遵循普通人群的疫苗接种建议，并确保在旅行前完成最新的疫苗接种。联合接种

 Despite the lack of comprehensive data on the immunogenicity, effectiveness and safety of all possible combinations of PCV and other routine vaccines, co-administration for programmatic reasons appears to be acceptable.尽管缺乏有关 PCV 和其他常规疫苗所有可能组合的免疫原性、有效性和安全性的全面数据，但出于计划原因联合接种似乎是可以接受的。

Surveillance 监视

 While a comprehensive surveillance system for pneumococcal disease is recommended, countries without such a system in place should not wait to introduce PCV vaccines. WHO recommends that the epidemiological impact of PCV be carefully monitored in sustained, high-quality sentinel and population-based surveillance for pneumococcal disease and in periodic NP carriage surveys. Such surveillance and surveys should be conducted to monitor changes in disease and the circulation of pneumococcal serotypes in the community after use of different PCV products at different dosing schedules and in different geographical and epidemiological settings with different pneumococcal disease burdens and transmission. Ideally, surveillance should be started at least 1–2 years before introduction of PCV and be continued indefinitely but at least for 5 years after introduction. While population-based surveillance is required to document impact on disease incidence and serotype replacement, IPD surveillance at sentinel sites in hospitals without a defined catchment population provides useful information on the distribution of serotypes in routine use of PCV. A qualitative estimate of its impact can be made by comparing the proportions of disease due to different pneumococcal serotypes over time. Periodic cross-sectional studies of NP carriage could offer insight into the roles of cases and carriers in continuing circulation of vaccine serotypes. In countries with no surveillance in place, data from neighbouring countries with similar disease burden, socioeconomic and demographic patterns can be used, but WHO encourages countries to conduct high-quality surveillance to monitor their immunization programmes, with the goal of strengthening overall disease surveillance and laboratory capacity.虽然建议建立全面的肺炎球菌疾病监测系统，但没有建立此类系统的国家不应等待引入肺炎球菌疫苗。世卫组织建议，在对肺炎球菌疾病进行持续、高质量的哨点和人群监测时，以及在定期进行的 NP 携带情况调查中，应仔细监测 PCV 对流行病学的影响。应开展此类监测和调查，以监测在使用不同剂量的 PCV 产品后，以及在肺炎球菌疾病负担和传播情况不同的地理和流行病环境中，疾病的变化和肺炎球菌血清型在社区中的流行情况。理想情况下，监测应在引入 PCV 前至少 1-2 年开始，并在引入 PCV 后无限期地持续进行，但至少持续 5 年。要记录对疾病发病率和血清型替代的影响，需要进行基于人群的监测，而在没有明确覆盖人群的医院中的哨点进行 IPD 监测，可提供有关 PCV 常规使用中血清型分布的有用信息。通过比较不同肺炎球菌血清型在不同时期的发病比例，可以对肺炎球菌疫苗的影响做出定性估计。对肺炎球菌携带情况进行定期横断面研究，可以深入了解病例和携带者在疫苗血清型持续传播中的作用。在没有开展监测的国家，可以使用疾病负担、社会经济和人口模式相似的邻国的数据，但世卫组织鼓励各国开展高质量的监测，以监测其免疫接种计划，目标是加强总体疾病监测和实验室能力。

 Research priorities 研究重点

 Additional research should be conducted on: (1) further assessment of vaccine impact, duration of protection and indirect effects of different dosing schedules; (2) serotype replacement; (3) further establishment of serotype-specific immune correlates of protection against IPD in different transmission settings; (4) the epidemiology of pneumococcal outbreaks, particularly epidemics of serotype 1 disease, including use of PCV to prevent or respond to outbreaks; (5) the impact of PCV on antimicrobial use and resistance; and (6) comparison of a 1-dose versus a 2-dose catch-up schedule for children >12 months of age. 应在以下方面开展更多研究(1) 进一步评估疫苗的影响、保护持续时间和不同给药方案的间接影响；(2) 血清型替换；(3) 进一步确定不同传播环境中血清型特异性的 IPD 保护免疫相关性；(4) 肺炎球菌疾病爆发的流行病学，特别是血清 1 型疾病的流行，包括使用 PCV 预防或应对疾病爆发；(5) PCV 对抗菌药物使用和耐药性的影响；以及 (6) 12 个月以上儿童接种 1 剂与 2 剂补种计划的比较。