Pneumococcal conjugate vaccines (PCV) were first licensed in 2000 and have been introduced into national immunisation programme in more than 145 countries. They have had a profound effect on reducing invasive pneumococcal disease (IPD) caused by serotypes in the vaccine. These reductions have been seen both in infants immunised directly with PCV and in the general population protected indirectly by reduced transmission of pneumococci from immunised infants in whom the vaccine prevented nasopharyngeal carriage. PCV7 (Prevenar7, Pfizer, New York, NY, USA) was first introduced in the UK in 2006 followed by PCV13 (Prevenar13, Pfizer, New York, NY, USA) in 2010. Both vaccines have had a striking impact on vaccine serotype IPD although a trend, seen first following PCV7, for an increase in IPD caused by serotypes not included in the vaccine(s) has been reported. Surveillance of the impact of PCVs is focused on IPD, defined as isolation of pneumococcus from an otherwise sterile site, and has been the bedrock of monitoring the serotypespecific impact of vaccination at a population level for many years. It is however, well understood that from a numerical point of view, IPD is only the tip of the iceberg, with pneumonia and otitis media caused by Streptococcus pneumoniae responsible for a much larger burden of disease. In this edition of the journal, Pick and colleagues describe the outcome of their prospective populationbased study of adult community acquired pneumonia (CAP) in two teaching hospitals in Nottingham, England. They focus on trends in pneumococcal serotype contribution to the burden of adult CAP over 5 years (2013–2018), a period associated with sustained high coverage of PCV13 in the infant schedule. Attributing an episode of pneumonia to the pneumococcus is complicated as blood cultures are only positive in approximately 10% of clinical episodes of pneumonia and the isolation of the pneumococcus from nonsterile sites such as sputum, lacks specificity for the underlying aetiology of a clinical episode of pneumonia. The ability to detect pneumococcal capsular antigen in the urine of patients with pneumococcal disease has provided a sensitive and specific way of assessing, at the level of serotype, the contribution of the pneumococcus to CAP in adults. Using a recently modified multiplex immunoassay to detect pneumococcal derived carbohydrate antigen in urine and an assay that detects a common pneumococcal cell wall carbohydrate (Cpolysaccharide) the authors were able to evaluate temporal changes in the incidence rate of hospitalised pneumococcal CAP in adults (those over 15 years of age) and the specific contributions of the 24 serotypes measured in their assay. The authors describe an increase in incidence of CAP overall and pneumococcal CAP over this period, with the latter driven by the increase in nonvaccine pneumococcal CAP and serotype 3 (ST3). Using incident rate ratios (IRRs) the authors reported a statistically significant average annual increase of 19% over this 5year period in CAP due to serotypes that are not represented in any currently licensed pneumococcal vaccine, including the 23 valent plain polysaccharide vaccine (PPV23). The only other pneumococcal CAP subgroup that showed a significant increase in IRR over the 5 years was the group of serotypes included in PCV13 and not PCV7 (PCV13non7). This category is however dominated by infection caused by serotype 3 (ST3) which in 2016/2017 and 2017/2018 ST3 represented twothirds of all PCV13non7 pneumococcal CAP cases. This dominance of ST3 among the vaccine associated serotypes complicates other associations explored by the authors. For example, the authors attempted to identify potential risk factors in those whose pneumonia is due to serotypes contained in PCV13 compared with other serotypes, which might be informative for a risk based selective PCV13 strategy in adults. A number of risk factors were identified associated with an increased susceptibility to PCV13 serotype disease including increasing age, chronic kidney disease and other risk factors while living in residential care was associated with lower risk. However, none of these associations were significant when ST3 was excluded from the analysis. The preponderance of ST3 among VT pneumococcal CAP cases in the UK study is consistent with a recent study of CAP in the US and with the serotype distribution of IPD cases in both the UK and the USA 5 and is a consequence of infant PCV13 immunisation having little impact on ST3 carriage. Since the overall CAP incidence itself irrespective of any vaccine effect may be influenced each year by external factors such as influenza or other respiratory viruses it is informative to look at the percentage of all adult CAP that is caused by vaccine serotypes. PCV7 attributable pneumonia was approximately 2% of total CAP during this period of study compared with 12.3% in 2008/9, soon after PCV7 introduction. PCV13non7 attributable CAP (after exclusion of ST3) accounted for less than 5% of the total CAP in the last 3 years compared with 10.7% in 2008/2009. This illustrates the beneficial impact of infant immunisation with PCV on adult VT CAP, at least in settings such as the UK which has achieved high PCV overage over many years. In such settings any additional benefit achieved by immunisation of adults with PCVs containing the same serotypes as those used in infants would be small, although some direct protection in adults against ST3 CAP might be achieved. Onethird of pneumococcal CAP in 2017/18 (34%) was due to serotypes in the 23 valent vaccine but not in PCV13 (PPV23non13); of these ST8 and ST12F were most prominent, serotypes also shown to be contributing to the increase in IPD in the UK. A lack of consistent evidence showing the effectiveness of PPV23 against CAP has led to PPV23non13 serotypes included in new extended multivalent pneumococcal conjugate vaccine being evaluated. Following licensure, the use of extended valency vaccines will be influenced by a number of factors including their licensed indication (IPD or both IPD and pneumonia), the age group for which they are licensed (adults only or adults and children), their serotype composition and their likely cost effectiveness, bearing in mind that they will be licensed on immunogenicity alone, and at the time of licensure there will be no direct evidence for the ability of the vaccines to prevent CAP caused by the novel serotypes contained therein. The limitation of evaluating urine with an assay that can only recognise 24 antigens is apparent from the large increase in serotypes referred to by the authors as untyped. These episodes of pneumonia were associated with a positive Cpolysaccharide urinary antigen detection test but no confirmatory 24 valent bioplex results. Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, UK Infectious Disease Epidemiology, LSHTM, London, UK

中文翻译：

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肺炎球菌肺炎

肺炎球菌结合疫苗 (PCV) 于 2000 年首次获得许可，并已被引入超过 145 个国家的国家免疫计划。它们对减少由疫苗中的血清型引起的侵袭性肺炎球菌病 (IPD) 产生了深远的影响。这些减少在直接接种 PCV 的婴儿和通过减少肺炎球菌从接种疫苗防止鼻咽部携带的免疫婴儿传播而受到间接保护的普通人群中都可见到。PCV7 (Prevenar7, Pfizer, New York, NY, USA) 于 2006 年首次在英国推出，随后于 2010 年推出 PCV13 (Prevenar13, Pfizer, New York, NY, USA)。这两种疫苗对 IPD 疫苗血清型产生了显着影响虽然是在 PCV7 之后首先出现的趋势，据报道，由于未包含在疫苗中的血清型导致 IPD 增加。PCV 影响的监测集中在 IPD，定义为从其他无菌部位分离肺炎球菌，并且多年来一直是在人群水平监测疫苗接种的血清型特异性影响的基石。然而，众所周知，从数字的角度来看，IPD只是冰山一角，由肺炎链球菌引起的肺炎和中耳炎要承担更大的疾病负担。在本期杂志中，Pick 及其同事描述了他们在英格兰诺丁汉的两家教学医院进行的基于人群的成人社区获得性肺炎 (CAP) 前瞻性研究的结果。他们关注 5 年（2013-2018 年）期间肺炎球菌血清型对成人 CAP 负担的影响趋势，这一时期与婴儿期 PCV13 的持续高覆盖率相关。将肺炎发作归因于肺炎球菌很复杂，因为血培养仅在大约 10% 的临床肺炎发作中呈阳性，并且从非无菌部位（如痰）中分离出肺炎球菌，对临床肺炎发作的潜在病因缺乏特异性. 在肺炎球菌疾病患者的尿液中检测肺炎球菌荚膜抗原的能力为在血清型水平上评估肺炎球菌对成人 CAP 的贡献提供了一种敏感和特异的方法。使用最近改进的多重免疫测定法检测尿液中肺炎球菌衍生的碳水化合物抗原和检测常见肺炎球菌细胞壁碳水化合物 (C多糖) 的测定法，作者能够评估成人（15 岁以上的人）住院肺炎球菌 CAP 发生率的时间变化岁）以及在其测定中测量的 24 种血清型的具体贡献。作者描述了在此期间 CAP 总体和肺炎球菌 CAP 发生率的增加，后者是由非疫苗肺炎球菌 CAP 和血清型 3 (ST3) 的增加驱动的。作者使用事件率比率 (IRR) 报告了 CAP 在这 5 年期间平均每年增加 19% 的显着统计显着性，这是由于任何当前获得许可的肺炎球菌疫苗中都没有出现的血清型，包括23价普通多糖疫苗（PPV23）。在过去 5 年中显示 IRR 显着增加的唯一其他肺炎球菌 CAP 亚组是 PCV13 而不是 PCV7 (PCV13non7) 中包含的血清型组。然而，这一类别主要是由血清型 3 (ST3) 引起的感染，在 2016/2017 和 2017/2018 年 ST3 占所有 PCV13non7 肺炎球菌 CAP 病例的三分之二。ST3 在疫苗相关血清型中的这种优势使作者探索的其他关联复杂化。例如，与其他血清型相比，作者试图确定因 PCV13 中所含血清型引起肺炎的患者的潜在危险因素，这可能为成人中基于风险的选择性 PCV13 策略提供信息。确定了许多与 PCV13 血清型疾病易感性增加相关的风险因素，包括年龄增加、慢性肾病和其他风险因素，而居住在住宅护理中与较低的风险相关。然而，当 ST3 被排除在分析之外时，这些关联都不显着。英国研究中 VT 肺炎球菌 CAP 病例中 ST3 的优势与美国最近对 CAP 的研究以及英国和美国 IPD 病例的血清型分布一致 5，这是婴儿 PCV13 免疫接种很少的结果对 ST3 支架的影响。由于总体 CAP 发病率本身（无论疫苗效果如何）每年都可能受到流感或其他呼吸道病毒等外部因素的影响，因此查看由疫苗血清型引起的所有成人 CAP 的百分比是有益的。在此研究期间，PCV7 归因性肺炎约占 CAP 总数的 2%，而在 PCV7 引入后不久，2008/9 年这一比例为 12.3%。PCV13non7 归因于 CAP（排除 ST3 后）在过去 3 年中占总 CAP 的比例不到 5%，而 2008/2009 年为 10.7%。这说明了婴儿接种 PCV 对成人 VT CAP 的有益影响，至少在英国这样的环境中，PCV 已达到多年高超龄。在这种情况下，用含有与婴儿相同血清型的 PCV 对成人进行免疫接种所获得的任何额外益处都是很小的，尽管可能会在成人中获得一些针对 ST3 CAP 的直接保护。2017/18 年度肺炎球菌 CAP 的三分之一 (34%) 是由 23 价疫苗中的血清型引起的，而不是 PCV13 (PPV23non13) 中的血清型；在这些 ST8 和 ST12F 中最为突出，血清型也被证明有助于英国 IPD 的增加。由于缺乏一致的证据表明 PPV23 对 CAP 的有效性，因此正在评估新的扩展多价肺炎球菌结合疫苗中包含的 PPV23non13 血清型。获得许可后，延长效价疫苗的使用将受到许多因素的影响，包括其许可适应症（IPD 或 IPD 和肺炎），他们获得许可的年龄组（仅限成人或成人和儿童）、他们的血清型组成及其可能的成本效益，记住他们将仅凭免疫原性获得许可，并且在获得许可时将没有直接证据用于疫苗预防由其中包含的新型血清型引起的 CAP 的能力。用只能识别 24 种抗原的测定法评估尿液的局限性从作者称为未分型的血清型的大量增加中可见一斑。这些肺炎发作与阳性 C 多糖尿抗原检测试验有关，但没有确证的 24 价生物复合物结果。大奥蒙德街儿童健康生物医学研究中心，伦敦大学学院，伦敦，英国传染病流行病学，LSHTM，伦敦，