University of Western Australia School of Paediatrics and Child Health, Vaccine Trials Group, Telethon Institute for Child Health Research, Princess Margaret Hospital for Children, Subiaco, WA, Australia.
Lancet Infect Dis. 2012 Aug;12(8):597-607. doi: 10.1016/S1473-3099(12)70087-7. Epub 2012 May 7.
Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine.
This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028.
539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg).
The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease.
Wyeth, Pfizer.
脑膜炎奈瑟菌 B 群是侵袭性脑膜炎球菌病的主要病因，但目前尚无广泛保护作用的疫苗获得许可。一种双价重组因子 H 结合蛋白疫苗（重组脂蛋白 2086）已被开发出来，以提供针对多种侵袭性脑膜炎球菌 B 群菌株的广泛保护。我们旨在检验这种疫苗的免疫反应。
这项随机、安慰剂对照试验纳入了来自澳大利亚、波兰和西班牙的 25 个研究地点的健康青少年。排除标准为既往侵袭性脑膜炎球菌病或 B 群疫苗接种、既往对疫苗或其成分有不良反应或已知过敏、任何重大合并症，以及过去 6 个月内接受过免疫抑制治疗或血制品。参与者按照计算机化的区组随机化方案，接受递增剂量的疫苗（60、120 或 200μg）或安慰剂，分别在 0、2 和 6 个月时接种。主要研究者、参与者及其监护人以及实验室人员对分组情况设盲；配药人员除外。采用人补体（hSBA）血清杀菌试验来测量免疫原性，针对 8 种不同的脑膜炎球菌 B 群菌株。主要的终点是根据 Clopper-Pearson 方法分析的两个指示菌株（PMB1745 和 PMB17）的血清转化率。记录局部和全身反应以及不良事件。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00808028。
539 名参与者被纳入，其中 511 名接受了全部 3 次研究接种——116 名在安慰剂组，21 名在 60μg 组，191 名在 120μg 组，183 名在 200μg 组。两种最大剂量组的 hSBA 滴度等于或大于 hSBA 检测下限（取决于测试菌株，滴度为 7 至 18 的倒数）的参与者比例相似，120μg 剂量组的比例为 75.6%至 100.0%，200μg 剂量组的比例为 67.9%至 99.0%。PMB1745 参考株血清转化率为 60μg 剂量组 19 名（89.5%）参与者，120μg 剂量组 111 名（92.8%）参与者，200μg 剂量组 100 名（94.0%）参与者，安慰剂组 73 名（5.5%）参与者。PMB17 参考株血清转化率为 60μg 剂量组 21 名（81.0%）参与者，120μg 剂量组 112 名（86.6%）参与者，200μg 剂量组 105 名（84.8%）参与者，安慰剂组 79 名（1.3%）参与者。hSBA 反应很强烈，在 hSBA 滴度高达 16 的情况下，有很高比例的应答者。轻度至中度注射部位疼痛是最常见的局部反应（60μg 剂量组发生 50 次，120μg 剂量组发生 437 次，200μg 剂量组发生 464 次，安慰剂组发生 54 次）。包括疲劳和头痛在内的全身事件通常为轻度至中度。总的来说，18 名（81.8%）参与者报告了 60μg 剂量组、77 名（38.9%）参与者报告了 120μg 剂量组、92 名（47.2%）参与者报告了 200μg 剂量组、54 名（44.6%）参与者报告了安慰剂组发生了不良事件。发热罕见且通常为轻度（60μg 组 1 例，120μg 组 24 例，200μg 组 35 例，安慰剂组 5 例；范围为每次接种后 0-6.3%）。各组内随着后续疫苗剂量的增加，发热的发生率和严重程度并未增加。第三剂（200μg）后发生了 1 例与疫苗相关的严重不良事件，无后遗症。
双价重组脂蛋白 2086 疫苗具有免疫原性，能诱导针对多种侵袭性脑膜炎球菌 B 群疾病株的强烈 hSBA 活性，且具有良好的耐受性。重组脂蛋白 2086 疫苗是预防侵袭性脑膜炎球菌 B 群疾病的一种有前途的候选疫苗。
惠氏、辉瑞。
