Background

The meningococcal serogroup B-factor H binding protein vaccine (MenB-FHbp) is licensed for use in children aged 10 years or older for protection against invasive serogroup B meningococcal disease. Because young children are at increased risk of invasive meningococcal disease, MenB-FHbp clinical data in this population are needed.

Methods

We conducted two phase 2 randomised, controlled, observer-blinded studies including healthy toddlers (age 12−23 months) across 26 Australian, Czech, Finnish, and Polish centres, and older children (age 2−9 years) across 14 Finnish and Polish centres. Exclusion criteria included previous vaccinations against serogroup B meningococcus or hepatitis A virus (HAV), and chronic antibiotic use. Toddlers were randomly allocated (2:1) via an interactive response technology system to receive either 60 μg or 120 μg MenB-FHbp or HAV vaccine and saline (control). Older children were randomly allocated (3:1) to receive 120 μg MenB-FHbp or control, with stratification by age group (2–3 years and 4–9 years). All vaccinations were administered as three doses (0, 2, and 6 months, with only saline given at 2 months in the control group). Toddlers who received 120 μg MenB-FHbp could receive a 120 μg booster dose 24 months after the end of the primary series. The percentages of participants with serum bactericidal activity using human complement (hSBA) titres at or above the lower limit of quantification (LLOQ; all greater than the 1:4 correlate of protection) against four test strains of serogroup B meningococcus 1 month after the third dose (primary immunogenicity endpoint) were measured in the evaluable immunogenicity populations (participants who received the vaccine as randomised, had available and determinate hSBA results, and had no major protocol violations). Not all participants were tested against all strains because of serum sample volume constraints. The frequencies of reactogenicity and adverse events after each dose were recorded in the safety population (all participants who received at least one dose and had safety data available). These studies are registered with ClinicalTrials.gov (NCT02534935 and NCT02531698) and are completed.

Findings

Between Aug 31, 2015, and Aug 22, 2016, for the toddler study and between Aug 27, 2015, and March 7, 2016, for the older children study, we enrolled and randomly allocated 396 toddlers (60 μg MenB-FHbp group n=44; 120 μg MenB-FHbp group n=220; control group n=132) and 400 older children (120 μg MenB-FHbp group n=294; control group n=106). 1 month after the third dose, the proportions of participants with hSBA titres at or above the LLOQ ranged across test strains from 85·0% (95% CI 62·1−96·8; 17 of 20 participants) to 100·0% (82·4−100·0; 19 of 19) in toddlers receiving 60 μg MenB-FHbp, and from 71·6% (61·4−80·4; 68 of 95) to 100·0% (96·2−100·0; 95 of 95) in toddlers receiving 120 μg MenB-FHbp, and from 79·1% (71·2−85·6; 106 of 134) to 100·0% (97·4−100·0; 139 of 139) in children aged 2–9 years receiving 120 μg MenB-FHbp. hSBA titres peaked at 1 month after the third primary dose of MenB-FHbp and then declined over time. 24 months after the third dose in the toddler study, the proportions with hSBA titres at or above the LLOQ ranged from 0·0% (0·0−17·6; 0 of 19 participants) to 41·2% (18·4−67·1; seven of 17) in those who received 60 μg MenB-FHbp and from 3·7% (0·8−10·4; three of 81) to 22·8% (14·1−33·6; 18 of 79) in those who received 120 μg MenB-FHbp. 1 month after the booster dose in toddlers, the proportions with hSBA titres at or above the LLOQ were higher than at 1 month after the primary series. MenB-FHbp reactogenicity was mostly transient and of mild to moderate severity. Adverse event frequency was similar between the MenB-FHbp and control groups and less frequent following MenB-FHbp booster than following primary doses. Two participants from the toddler study (both from the 120 μg MenB-FHbp group) and four from the older children study (three from the 120 μg MenB-FHbp group and one from the control group) were withdrawn from the study because of adverse events.

Interpretation

MenB-FHbp was well tolerated and induced protective immune responses in a high proportion of participants. These findings support a favourable MenB-FHbp immunogenicity and reactogenicity profile in young children, a population at increased risk of adverse invasive meningococcal disease outcomes.

Funding

Pfizer.

中文翻译：

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脑膜炎球菌血清群 B 因子结合蛋白疫苗 (MenB-FHbp) 初级系列和加强剂量在 1-9 岁健康儿童中的安全性和免疫原性：两项 2 期随机、对照、观察员盲法研究

背景

脑膜炎球菌血清群 B 因子 H 结合蛋白疫苗 (MenB-FHbp) 获准用于 10 岁或以上的儿童，以预防侵袭性血清群 B 脑膜炎球菌疾病。由于幼儿患侵袭性脑膜炎球菌病的风险增加，因此需要该人群的 MenB-FHbp 临床数据。

方法

我们进行了两项 2 期随机、对照、观察者盲法研究，包括 26 个澳大利亚、捷克、芬兰和波兰中心的健康幼儿（12-23 个月），以及 14 个芬兰和波兰中心的年龄较大的儿童（2-9 岁）中心。排除标准包括既往接种过 B 群脑膜炎球菌或甲型肝炎病毒 (HAV) 疫苗，以及长期使用抗生素。通过交互式响应技术系统将幼儿随机分配 (2:1) 以接受 60 μg 或 120 μg MenB-FHbp 或 HAV 疫苗和盐水（对照）。年龄较大的儿童被随机分配 (3:1) 接受 120 μg MenB-FHbp 或对照组，并按年龄组（2-3 岁和 4-9 岁）分层。所有疫苗接种分三剂进行（0、2 和 6 个月，对照组仅在 2 个月时注射生理盐水）。接受 120 μg MenB-FHbp 的幼儿可以在初级系列结束后 24 个月接受 120 μg 加强剂量。使用人类补体 (hSBA) 滴度达到或高于定量下限（LLOQ；均大于 1:4 的保护相关性）的参与者在第三次 B 型脑膜炎球菌的四种测试菌株的血清杀菌活性的百分比剂量（主要免疫原性终点）是在可评估的免疫原性人群（随机接种疫苗的参与者，具有可用和确定的 hSBA 结果，并且没有严重违反方案）中测量的。由于血清样本量的限制，并非所有参与者都针对所有菌株进行了测试。在安全人群（接受至少一剂并有安全数据的所有参与者）中记录每次剂量后反应原性和不良事件的频率。这些研究已在 ClinicalTrials.gov（NCT02534935 和 NCT02531698）注册并完成。

发现

在 2015 年 8 月 31 日至 2016 年 8 月 22 日期间，对于幼儿研究以及在 2015 年 8 月 27 日和 2016 年 3 月 7 日之间，对于年龄较大的儿童研究，我们招募并随机分配了 396 名幼儿（60 μg MenB-FHbp 组 n =44；120 μg MenB-FHbp 组 n=220；对照组 n=132）和 400 名年龄较大的儿童（120 μg MenB-FHbp 组 n=294；对照组 n=106）。第三次给药后 1 个月，hSBA 滴度等于或高于 LLOQ 的参与者比例跨测试菌株从 85·0%（95% CI 62·1-96·8；20 名参与者中的 17 名）到 100·0% （82·4-100·0；19 人中的 19 人）接受 60 微克 MenB-FHbp 的幼儿，从 71·6%（61·4-80·4；95 人中的 68 人）到 100·0%（96·2 −100·0；95 人中的 95 人）接受 120 μg MenB-FHbp，从 79·1%（71·2−85·6；134 人中的 106 人）到 100·0%（97·4−100·0 ; 139 名中的 139 名）接受 120 μg MenB-FHbp 的 2-9 岁儿童。hSBA 滴度在第三次主要剂量 MenB-FHbp 后 1 个月达到峰值，然后随时间下降。在幼儿研究中第三次给药后 24 个月，hSBA 滴度等于或高于 LLOQ 的比例范围为 0·0%（0·0-17·6；19 名参与者中有 0 人）至 41·2%（18·4 −67·1；17 人中有 7 人）接受 60 μg MenB-FHbp 的患者中，从 3·7%（0·8−10·4；81 人中有 3 人）到 22·8%（14·1−33·6 ；79 人中的 18 人）接受 120 μg MenB-FHbp 的患者。幼儿接受加强剂量后 1 个月，hSBA 滴度等于或高于 LLOQ 的比例高于初级系列后 1 个月。MenB-FHbp 的反应原性主要是短暂的并且具有轻度到中度的严重程度。MenB-FHbp 组和对照组之间的不良事件频率相似，并且 MenB-FHbp 加强剂后的不良事件频率低于初次剂量后的频率。

解释

MenB-FHbp 耐受性良好，并在很大一部分参与者中诱导了保护性免疫反应。这些发现支持在幼儿中具有良好的 MenB-FHbp 免疫原性和反应原性特征，该人群患侵袭性脑膜炎球菌疾病不良后果的风险增加。

资金

辉瑞。