婴儿细菌性脑膜炎的终结？

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关于新型重组血清群 B 群疫苗的试验
背景
血清群 B 群脑膜炎球菌病会对婴儿造成严重影响。 我们在这一人群中，评估了一种研究性多组分疫苗 (4CMenB) 的批次一致性、安全性和免疫原性，以及同时接种对常规疫苗接种反应的效应。
方法
我们在 2008 年 3 月 31 日至 2010 年 8 月 16 日之间，在欧洲的 70 个地点进行了初次免疫和强化免疫 3 期研究。 借助由赞助商提供、计算机生成的两个系列的随机信封，我们对 2 个月大的健康婴儿进行了分配，使其在 2 个月、4 个月和 6 个月大时分别仅接受常规疫苗（白喉-破伤风-无细胞型百日咳、灭活脊髓灰质炎病毒乙肝加 b 型流感嗜血杆菌以及七价肺炎球菌疫苗），或同时接种 4CMenB 或血清群 C 群结合疫苗 (MenC)，并进行：1) 开放标签、批次免疫原性和安全性子研究，对三个批次的 4CMenB 与单纯常规疫苗接种进行比较（1:1:1:1，区组大小为八）；或 2) 观察员单盲、批次安全性子研究，对三个批次的 4CMenB 与 MenC 进行比较（1:1:1:3，区组大小为六）。 在 12 个月时，子研究中接受 4CMenB 初次免疫的儿童随机（1:1，区组大小为二）接受了 4CMenB 强化免疫，附加或不附加麻疹-腮腺炎-风疹-水痘 (MMRV) 疫苗。 我们使用人补体 (hSBA) 血清杀菌测试评估了抗血清群 B 群测试菌株的免疫原性，并根据随机选择的血清样本亚组评估了常规疫苗的免疫原性；实验室工作人员并不知道分组情况。 第一共同主要预后为批次间的一致性（所有批次的 hSBA 的几何平均比值在 0.5 至 2·0 之间），第二共同主要预后为对三个菌株分别产生免疫反应（hSBA 滴度 ≥ 5）。 强化免疫研究的主要预后为对强化免疫剂量产生免疫反应。 4CMenB 免疫原性数据基于改良意向性治疗人群，包括开放标签子研究中提供血清样本的所有婴儿。 安全性研究人群包括在至少一剂研究疫苗接种后提供了安全性数据的所有参与者。 这些研究已在 ClinicalTrials.gov 登记，编号为 NCT00657709 及 NCT00847145。
结果
我们在开放标签阶段招募了 2627 名婴儿，在观察员单盲阶段招募了 1003 人，在强化免疫研究中招募了 1555 人。 研究显示，在三批 4CMenB 间存在批次一致性，最低 95% 置信下限为 0·74，最高上限为 1·33。 在接种三剂 4CMenB 1 个月后，1181—1184 名婴儿接受了测试（汇总所有批次），其中有 100% (95% CI 99—100) 抗选定菌株（根据 H 因子结合蛋白和淋病奈瑟菌粘附素 A 选择）的 hSBA 滴度不低于 5，有 84% (82—86) 对根据新西兰外膜囊泡选择的菌株产生上述反应。 在一个亚组 (n=100) 中，有 84% (75—91) 的婴儿的抗淋病奈瑟菌结合抗原 hSBA 滴度不低于 5。 在 12 个月大时，第四剂疫苗强化了日益减弱的滴度，从而有 95—100% 的儿童（无论是否同时接种 MMRV）对所有抗原的 hSBA 滴度均不低于 5。 无论是否同时接种 4CMenB，常规疫苗的免疫反应基本相同，但同时接种会增加反应原性。 77% (1912/2478) 的婴儿在任何一剂 4CMenB 接种后发热至不低于 38.5°C，相比之下，在仅接受常规疫苗后该比例为 45% (295/659)，在接种 MenC 后为 47% (228/490)，但我们认为，仅有两例热性惊厥可能与 4CMenB 相关。
结果解读
在不存在常规疫苗的临床相关干扰时，4CMenB 在婴儿和 12 个月大的儿童中具有免疫原性，但当其与常规疫苗同时接种时，会增加反应原性。 这一突破性疫苗为婴幼儿细菌性脑膜炎的主要剩余原因提供了一种新型解决方案。

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作者 ： Timo Vesikari ,Susanna Esposito ,Roman Prymula ,Ellen Ypma ,Igor Kohl ,Daniela Toneatto

期刊名称：柳叶刀杂志(Lancet)

发表时间：2013-01-11

索引：Lancet.2013 Jan 11;

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Lancet. 2013 Jan 11. pii: S0140-6736(12)61961-8. doi: 10.1016/S0140-6736(12)61961-8. [Epub ahead of print]
Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.
Vesikari T, Esposito S, Prymula R, Ypma E, Kohl I, Toneatto D, Dull P, Kimura A; for the EU Meningococcal B Infant Vaccine Study group.
SourceUniversity of Tampere Medical School, Tampere, Finland. Electronic address: timo.vesikari@uta.fi.

Abstract
BACKGROUND: Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population.

METHODS: We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145.

FINDINGS: We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181-1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99-100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82-86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75-91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95-100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB.

INTERPRETATION: 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers.

FUNDING: Novartis Vaccines and Diagnostics.