Background

A multicomponent meningococcal serogroups ABCWY vaccine (MenABCWY) could provide broad protection against disease-causing meningococcal strains and simplify the immunisation schedule. The aim of this trial was to confirm the effect of the licensed meningococcal serogroup B (MenB) vaccine, 4CMenB, against diverse MenB strains, and to assess the breadth of immune response against a panel of 110 MenB strains for MenABCWY containing the antigenic components of 4CMenB and licensed serogroups ACWY vaccine, MenACWY-CRM, the non-inferiority of the immune response with MenABCWY versus 4CMenB and MenACWY-CRM, safety, and MenABCWY lot-to-lot consistency.

Methods

We conducted a phase 3 randomised, controlled, observer-blinded trial of healthy adolescents and young adults (age 10–25 years) across 114 centres in Australia, Canada, Czechia, Estonia, Finland, Türkiye, and the USA. Exclusion criteria included previous vaccination with a MenB vaccine or (within the last 4 years) MenACWY vaccine. Participants were randomly allocated (5:5:3:3:3:1 ratio) via a central randomisation system using a minimisation procedure to receive 4CMenB at months 0, 2, and 6 (referred to as 4CMenB 0–2–6 hereafter); or 4CMenB at months 0 and 6 (referred to as 4CMenB 0–6 hereafter); or MenABCWY (three groups, each receiving one production lot of the MenACWY-CRM component) at months 0 and 6; or MenACWY-CRM at month 0. Demonstration in the per-protocol set of the consistency of three MenACWY-CRM component lots of the MenABCWY vaccine was a primary objective (demonstrated with two-sided 95% CIs for the ratio of human serum bactericidal antibody [hSBA] geometric mean titres against each serogroup within predefined criteria [0·5–2·0]). The primary endpoints (breadth of immune response) for the MenB component of MenABCWY and 4CMenB were measured using the endogenous complement hSBA (enc-hSBA) assay against a panel of 110 diverse MenB invasive disease strains. For each serum sample, 35 strains from the 110 MenB strain panel were randomly selected for testing. The 4CMenB breadth of immune response data have been published separately. For MenABCWY, breadth of immune response was assessed in two analyses: a test-based analysis of the percentage of samples (tests) without bactericidal serum activity against MenB strains 1 month after two MenABCWY doses versus the percentage after one MenACWY-CRM dose in the per-protocol set, and a responder-based analysis of the percentage of participants (responders) whose sera killed 70% or more strains at 1 month after two MenABCWY doses in the full analysis set. A lower limit of two-sided 95% CI above 65% would demonstrate breadth of immune response. Other primary outcomes included non-inferiority (5% margin) of two MenABCWY doses versus two 4CMenB doses by enc-hSBA assay in the per-protocol set, non-inferiority (10% margin) of two MenABCWY doses versus one MenACWY-CRM dose in MenACWY vaccine-naive participants by traditional hSBA assay in the per-protocol set, and safety in all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT04502693, and is complete.

Findings

Between Aug 14, 2020, and Sept 3, 2021, 3651 participants were enrolled and randomly allocated (900 in the 4CMenB 0–2–6 group and 908 in the 4CMenB 0–6 group, 1666 in the three MenABCWY groups combined, and 177 in the MenACWY-CRM group). All primary objectives for MenABCWY were met. Consistency of immune responses against the three production lots of the MenACWY component of MenABCWY was demonstrated since two-sided 95% CIs for the ratios of hSBA geometric mean titres against serogroups A, C, W, and Y for each pair of lots were within the predefined equivalence criteria. The lot data were pooled for the remainder of MenABCWY endpoints. By enc-hSBA assay, breadth of immune response against the MenB strain panel was 77·9% (95% CI 76·6 to 79·2) in the test-based analysis and 84·1% (81·4 to 86·5; 687 of 817 participants) in the responder-based analysis. Non-inferiority of MenABCWY to 4CMenB was demonstrated by enc-hSBA assay: the difference in percentage of samples with bactericidal serum activity between the MenABCWY group (82·5% [95% CI 82·1 to 83·0]; 21 222 of 25 715) and 4CMenB 0–2 group (83·1% [82·7 to 83·6]; 22 921 of 27 569) was –0·61% (–1·25 to 0·03). Non-inferiority of two-dose MenABCWY to one-dose MenACWY-CRM was demonstrated by traditional hSBA assay, with differences between the MenABCWY group and MenACWY group in percentages of participants with a four-fold rise in hSBA titres of 11·3% (5·9 to 19·0) for serogroup A, 47·2% (38·1 to 56·3) for serogroup C, 35·3% (26·9 to 44·5) for serogroup W, and 27·0% (19·4 to 35·8) for serogroup Y. MenABCWY reactogenicity was mostly of mild or moderate severity and transient, with similar frequencies of adverse events in the MenABCWY and 4CMenB groups and no safety concerns were identified.

Interpretation

This study demonstrates breadth of immune response against a panel of 110 MenB strains for the MenB component of the investigational MenABCWY vaccine, when administered as a 0–6 months schedule to the target population of adolescents and young adults, with predefined criteria for success met for both breadth of immune response endpoints and for non-inferiority versus 4CMenB. This investigational vaccine could provide broad meningococcal serogroup coverage in a simplified immunisation schedule, thus aiding the public health attempt in preventing invasive meningococcal disease due to five Neisseria meningitidis serogroups in adolescents and young adults.

Funding

GSK.

中文翻译：

---

五价脑膜炎球菌 ABCWY 疫苗在健康青少年和年轻人中的免疫反应、免疫原性、反应原性和安全性的广度：3 期、随机、对照观察者盲法试验的结果

 背景

多组分脑膜炎球菌血清型 ABCWY 疫苗 （MenABCWY） 可以针对致病的脑膜炎球菌菌株提供广泛的保护，并简化免疫接种计划。该试验的目的是确认获得许可的脑膜炎球菌血清型 B （MenB） 疫苗 4CMenB 对不同 MenB 菌株的影响，并评估针对一组 110 种 MenB 菌株的免疫反应广度 MenABCWY，其中包含 4CMenB 和获得许可的血清型 ACWY 疫苗 MenACWY-CRM，MenABCWY 与 4CMenB 和 MenACWY-CRM 的免疫反应的非劣效性， 安全性和 MenABCWY 批次间一致性。

 方法

我们在澳大利亚、加拿大、捷克、爱沙尼亚、芬兰、土耳其和美国的 114 个中心对健康的青少年和年轻人（10-25 岁）进行了一项 3 期随机、对照、观察者盲法试验。排除标准包括既往接种过 MenB 疫苗或（在过去 4 年内）MenACWY 疫苗。参与者通过中央随机化系统使用最小化程序随机分配（5：5：3：3：3：1 比例），在第 0 、 2 和 6 个月接受 4CMenB（以下简称 4CMenB 0-2-6）;或第 0 个月和第 6 个月的 4CMenB（以下称为 4CMenB 0-6）;或 MenABCWY（三组，每组接受一个生产批次的 MenACWY-CRM 组件）在第 0 个月和第 6 个月;或第 0 个月的 MenACWY-CRM。在每方案集中证明 MenABCWY 疫苗的三个 MenACWY-CRM 组分批次的一致性是一个主要目标（在预定标准 [0·5–2·0] 内，用人血清杀菌抗体 [hSBA] 几何平均滴度与每个血清群的比率的双侧 95% CI 证明]）。使用内源性补体 hSBA （enc-hSBA） 测定法针对一组 110 种不同的 MenB 侵袭性疾病菌株测量 MenABCWY 和 4CMenB 的 MenB 成分的主要终点 （免疫反应的广度）。对于每个血清样品，从 110 个 MenB 菌株组中随机选择 35 个菌株进行测试。4CMenB 免疫应答数据的广度已单独发布。 对于 MenABCWY，在两项分析中评估了免疫反应的广度：基于测试的分析，即在两次 MenABCWY 给药后 1 个月对 MenB 菌株没有杀菌血清活性的样本（测试）百分比与每个方案集中一次 MenACWY-CRM 给药后的百分比，以及基于反应者的分析，在完整分析集中，两次 MenABCWY 给药后 1 个月血清杀死 70% 或更多菌株的参与者（反应者）的百分比。高于 65% 的双侧 95% CI 的下限将表明免疫反应的广度。其他主要结局包括在每个方案集中通过 enc-hSBA 测定两剂 MenABCWY 与两剂 4CMenB 的非劣效性（5% 边际），在每方案集中通过传统 hSBA 测定在 MenACWY 疫苗初治参与者中两剂 MenABCWY 与一剂 MenACWY-CRM 剂量的非劣效性（10% 边际），以及所有接种疫苗的参与者的安全性。此试用版已在 ClinicalTrials.gov， NCT04502693 注册，并且已完成。

 发现

在 2020 年 8 月 14 日至 2021 年 9 月 3 日期间，招募并随机分配了 3651 名参与者（4CMenB 0-2-6 组 900 名，4CMenB 0-6 组 908 名，三个 MenABCWY 组共 1666 名，MenACWY-CRM 组 177 名）。MenABCWY 的所有主要目标均已实现。证明了针对 MenABCWY 的 MenACWY 成分的三个生产批次的免疫反应的一致性，因为每对批次的 hSBA 对血清型 A、C、W 和 Y 的几何平均滴度比率的双侧 95% CI 在预定义的等效标准内。其余 MenABCWY 终点的批次数据被汇集在一起。通过 enc-hSBA 测定，在基于测试的分析中，针对 MenB 菌株组的免疫反应广度为 77·9%（95% CI 76·6 至 79·2），在基于反应者的分析中为 84·1%（81·4 至 86·5;817 名参与者中的 687 名）。enc-hSBA 测定证明了 MenABCWY 不劣于 4CMenB：MenABCWY 组（82·5% [95% CI 82·1 至 83·0];25 715 中的 21 222）和 4CMenB 0-2 组（83·1% [82·7 至 83·6];27 569 中的 22 921）之间具有杀菌血清活性的样品百分比差异为 -0·61%（-1·25 至 0·03）。传统的 hSBA 测定证明了两剂 MenABCWY 与一剂 MenACWY-CRM 的非劣效性，MenABCWY 组和 MenACWY 组在参与者百分比方面存在差异，其中 h SBA 滴度增加四倍（血清型 A）为 11·3%（5·9 至 19·0），血清型 C 为 47·2%（38·1 至 56·3），血清型 W 为 35·3%（26·9 至 44·5）。 血清型 Y 为 27·0% （19·4 至 35·8）。MenABCWY 反应原性大多为轻度或中度严重程度和短暂性，MenABCWY 和 4CMenB 组的不良事件频率相似，未发现安全问题。

 解释

本研究展示了研究性 MenABCWY 疫苗的 MenB 成分对一组 110 种 MenB 毒株的免疫反应广度，当作为 0-6 个月的时间表对青少年和年轻人的目标人群进行给药时，免疫反应终点的广度和非劣效性都满足预定义的成功标准与 4CMenB 相比。这种研究性疫苗可以在简化的免疫接种计划中提供广泛的脑膜炎球菌血清型覆盖，从而有助于公共卫生尝试预防青少年和年轻人中由五个脑膜炎奈瑟菌血清型引起的侵袭性脑膜炎球菌病。

 资金

 葛兰素史克。