University of Tampere Medical School, Tampere, Finland.
Lancet. 2013 Mar 9;381(9869):825-35. doi: 10.1016/S0140-6736(12)61961-8.
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.
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.
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.
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.
Novartis Vaccines and Diagnostics.
脑膜炎奈瑟菌 B 群疾病在很大程度上影响婴儿。我们评估了 LOT 一致性、安全性和免疫原性，以及在该人群中，同时接种常规疫苗对研究性多组分疫苗（4CMenB）的影响。
我们于 2008 年 3 月 31 日至 2010 年 8 月 16 日在欧洲的 70 个地点进行了主要和加强阶段的 3 期研究。我们使用两系列赞助商提供的、计算机生成的随机化信封，将健康的 2 个月大的婴儿随机分配，接受常规疫苗（白喉-破伤风-无细胞百日咳、灭活脊髓灰质炎病毒、乙型肝炎和 H 型流感嗜血杆菌，以及 7 价肺炎球菌疫苗），在 2、4 和 6 个月大时单独接种，或与 4CMenB 或 C 群脑膜炎球菌结合疫苗（MenC）同时接种：1）3 个 4CMenB LOT 的开放性、LOT 免疫原性和安全性亚研究与常规疫苗单独比较（1:1:1:1，块大小 8）；或 2）3 个 4CMenB LOT 的观察者盲法、LOT 安全性亚研究与 MenC 比较（1:1:1:3，块大小 6）。在 12 个月时，来自任何一个亚研究的 4CMenB 初免的儿童被随机（1:1，块大小 2）接受 4CMenB 加强剂，无论是否同时接种麻疹-腮腺炎-风疹-水痘（MMRV）疫苗。免疫原性通过人补体（hSBA）对血清杀菌试验检测针对 B 群测试株的血清抗体，以及在常规疫苗的随机样本子集上进行检测；实验室人员对分配情况进行了盲法。第一个主要次要终点是 LOT 一致性（所有 LOT 的 hSBA 几何平均比在 0.5 和 2.0 之间），第二个是三种菌株中的每一种的免疫反应（hSBA 滴度≥5）。加强研究的主要终点是加强剂量的免疫反应。4CMenB 的免疫原性数据适用于改良的意向治疗人群，包括开放性亚研究中提供血清样本的所有婴儿。安全性人群包括至少接受一剂研究疫苗后提供安全性数据的所有参与者。这些试验在 ClinicalTrials.gov 上注册，编号分别为 NCT00657709 和 NCT00847145。
我们在开放性阶段招募了 2627 名婴儿，在观察者盲法阶段招募了 1003 名，在加强研究中招募了 1555 名。三种 4CMenB LOT 均显示出 LOT 一致性，最低的 95%置信下限为 0.74，最高的上限为 1.33。在接受三种 4CMenB 剂量（所有 LOT 混合）1 个月后，1181-1184 名婴儿中的 1181-1184 名（95%CI 99-100）的 hSBA 滴度为 5 或更高，对因子 H 结合蛋白和 Neisserial 黏附素 A 具有选择性，84%（82-86）对新西兰外膜囊泡。在一个亚组（n=100）中，84%（75-91）的婴儿对肝素结合抗原的 hSBA 滴度为 5 或更高。在 12 个月大时，第四剂加强剂可增强衰减的滴度，使得所有抗原的 hSBA 滴度为 5 或更高，无论是否同时接种 MMRV。与同时接种常规疫苗相比，同时接种 4CMenB 对常规疫苗的免疫反应影响不大，但同时接种会增加不良反应。在任何 4CMenB 剂量后，77%（1912 名/2478 名）的婴儿有 38.5°C 或更高的发热，而单独接种常规疫苗的发热率为 45%（295 名/659 名），接种 MenC 的发热率为 47%（228 名/490 名），但只有两例热性惊厥被认为可能与 4CMenB 有关。
4CMenB 在 12 个月大的婴儿和幼儿中具有免疫原性，与常规疫苗无临床相关干扰，但与常规疫苗同时接种时会增加不良反应。这种突破性疫苗为婴儿和幼儿细菌性脑膜炎的主要剩余病因提供了创新性的解决方案。
诺华疫苗和诊断公司。
