Vaccine effectiveness of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial
Vaccine effectiveness of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial
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DOI：
10.1016/s2213-2600(14)70139-0
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发表时间：
2014-09-01
影响因子：
76.2
通讯作者：
Kilpi, T. M.
中科院分区：
文献类型：
--
作者：
Palmu, A. A.;Jokinen, J.;Kilpi, T. M.
背景 肺炎球菌结合疫苗针对培养证实的侵袭性肺炎球菌疾病的疫苗有效性已得到充分证明。在芬兰侵袭性肺炎球菌病 (FinIP) 试验中，我们报告了针对实验室确诊的侵袭性肺炎球菌病的疫苗有效性和绝对率降低（通过培养或抗原或 DNA 检测确认，无论血清型如何）。在这里，我们通过使用医院出院登记册中编码的诊断来评估 PHiD-CV10 疫苗对临床疑似侵袭性肺炎球菌疾病的儿童的有效性。方法对于 2009 年 2 月 18 日至 2011 年 12 月 31 日期间在市卫生保健中心和坦佩雷大学疫苗研究中心（芬兰）进行的这项 3/4 阶段随机、双盲试验，我们随机分配(2:2:1:1) 将 78 个簇分为 PHiD-CV10 三加一、PHiD-CV10 二加一、对照三加一、对照二加一组（26:26:13:13 分散者），以三加一或二加一时间表（如果在 7 个月大之前入组；婴儿时间表）、二加一（如果在 7 个月到 11 个月之间入组；赶超时间表）给予 PHiD-CV10，以及两剂疫苗间隔至少 6 个月（如果在 12 至 18 个月之间入组；补课时间表）。如果儿童未接种且预计不会接种任何研究疫苗并且没有一般疫苗接种禁忌症，则符合资格。我们从国家医院出院登记处收集了符合国际疾病分类 (ICD) 10 种与侵袭性肺炎球菌疾病或未明确脓毒症诊断相符的住院和门诊出院通知，并与患者档案核实了数据。我们排除了通过正常无菌体液中培养或 DNA/RNA 检测呈阳性证实的侵袭性肺炎球菌疾病病例。主要目的是评估疫苗对入组时 7 个月以下婴儿的所有基于登记的非实验室确诊的侵袭性肺炎球菌疾病或未明确的败血症以及患者档案验证的非实验室确诊的侵袭性肺炎球菌疾病的有效性。不公开随访从第一次疫苗接种之日起一直持续到 2011 年 12 月 31 日。针对所有事件计算疫苗有效性。该试验已在 ClinicalTrials.gov 注册，编号为 NCT00861380 和 NCT00839254。结果 我们招募了 47 366 名儿童。根据 ICD-10 诊断，我们记录了 264 例基于登记的非实验室确诊的侵袭性肺炎球菌疾病或未明确的败血症，其中 102 例是经患者档案验证的非实验室确诊的侵袭性肺炎球菌疾病。在 30 527 名采用三加一和二加一方案的婴儿中，疫苗有效性为 50%（95% CI 32-63），绝对发病率降低为每 10 万人年 207 次（95% CI 127-286）。在婴儿三加一和二加一方案中，针对经患者档案验证的非实验室确认的侵袭性肺炎球菌疾病的疫苗有效性为 71% (95% CI 52-83)。在婴儿队列中，绝对发生率降低为每 10 万人年 142 次 (95% CI 91-191)。 解释 该疫苗探针分析是第一份显示肺炎球菌结合疫苗对临床疑似侵袭性肺炎球菌疾病的影响的报告。与实验室确诊的侵袭性肺炎球菌疾病相比，绝对下降率明显更高，这意味着基于实验室的病例定义的敏感性较低，因此肺炎球菌结合疫苗针对侵袭性肺炎球菌疾病的公共卫生效果比之前估计的要高。
Background Vaccine effectiveness of pneumococcal conjugate vaccines against culture-confirmed invasive pneumococcal disease has been well documented. In the Finnish Invasive Pneumococcal disease (FinIP) trial, we reported vaccine effectiveness and absolute rate reduction against laboratory-confirmed invasive pneumococcal disease (confirmation by culture or antigen or DNA detection irrespective of serotype). Here, we assessed vaccine effectiveness of PHiD-CV10 against clinically suspected invasive pneumococcal disease in children by use of diagnoses coded in hospital discharge registers.Methods For this phase 3/4 duster-randomised, double-blind trial, undertaken between Feb 18, 2009, and Dec 31, 2011, in municipal health-care centres and the Tampere University Vaccine Research Centre (Finland), we randomly assigned (2:2:1:1) 78 clusters into PHiD-CV10 three plus one, PHiD-CV10 two plus one, control three plus one, control two plus one groups (26:26:13:13 dusters) to give PHiD-CV10 in either three plus one or two plus one schedule (if enrolled before 7 months of age; infant schedules), two plus one (if enrolled between 7 and 11 months; catch-up schedules), and two doses at least 6 months apart (if enrolled between 12 and 18 months; catch-up schedules). Children were eligible if they had not received and were not anticipated to receive any of the study vaccines and had no general contraindications to vaccinations. We collected all inpatient and outpatient discharge notifications from the national hospital discharge register with International Classification of Diseases (ICD) 10 diagnoses compatible with invasive pneumococcal disease or unspecified sepsis, and verified data with patient files. We excluded invasive pneumococcal disease cases confirmed by positive culture or DNA/RNA detection from normally sterile body fluid. The primary objective was to estimate vaccine effectiveness against all register-based non-laboratory-confirmed invasive pneumococcal disease or unspecified sepsis and patient-file verified non-laboratory-confirmed invasive pneumococcal disease in infants younger than 7 months at enrolment. Masked follow-up lasted from the date of the first vaccination to Dec 31, 2011. Vaccine effectiveness was calculated against all episodes. This trial is registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254.Findings We enrolled 47 366 children. On the basis of ICD-10 diagnoses, we recorded 264 episodes of register-based non-laboratory-confirmed invasive pneumococcal disease or unspecified sepsis, of which 102 were patient-file verified non-laboratory-confirmed invasive pneumococcal disease. The vaccine effectiveness was 50% (95% CI 32-63) in the 30 527 infants with three plus one and two plus one schedules combined and the absolute incidence rate reduction was 207 episodes per 100 000 person-years (95% CI 127-286). The vaccine effectiveness against the patient-file verified non-laboratory-confirmed invasive pneumococcal disease was 71% (95% CI 52-83) in infant three plus one and two plus one schedules combined. The absolute rate reduction was 142 episodes per 100 000 person-years (95% CI 91-191) in infant cohorts.Interpretation This vaccine-probe analysis is the first report showing the effect of pneumococcal conjugate vaccines on clinically suspected invasive pneumococcal disease. The absolute rate reduction was markedly higher compared with laboratory-confirmed invasive pneumococcal disease, which implies low sensitivity of the laboratory-based case definitions and subsequently higher public health effect of pneumococcal conjugate vaccines against invasive pneumococcal disease than previously estimated.