Background

Meningococcal disease remains an important public health problem globally. We assessed the non-inferiority and the lot-to-lot consistency of a pentavalent meningococcal ACYWX conjugate vaccine (NmCV-5; Serum Institute of India, Pune, India) versus a quadrivalent meningococcal ACWY conjugate vaccine (MenACWY-D) in healthy adults.

Methods

In this observer-blind, randomised, active-controlled, phase 2/3 study, healthy adults aged 18–85 years were recruited from nine hospitals across seven cities in India. Participants were grouped by age (age 18–29, 30–60, and 61–85 years), and within each age group they were randomly assigned (3:1) to receive either NmCV-5 or MenACWY-D (Sanofi Pasteur). In the age 18–29 years group, participants were additionally randomly assigned (1:1:1:1) to either lot A, lot B, or lot C of NmCV-5 or MenACWY-D. Block randomisation was used (block sizes of 4, 8, and 12). Study participants and study personnel were masked to treatment assignment. Participants received either a 0·5 mL dose of NmCV-5, containing 5 μg each of conjugated A, C, W, Y, and X polysaccharides, or 0·5 mL MenACWY-D, containing 4 μg of each of conjugated A, C, W, and Y polysaccharides. Vaccinations were administered intramuscularly in the deltoid muscle. The primary outcomes were seroresponse (non-inferiority margin of –10%) and geometric mean titres (GMTs; non-inferiority margin of 0·5) in all participants, and lot-to-lot consistency of NmCV-5 (in participants aged 18–29 years; consistency was shown if the geometric mean ratio [GMR] 95% CIs were within the limit interval of 0·5 to 2). For non-inferiority, serogroup X immune response in the NmCV-5 group was compared with the lowest immune response among serogroups A, C, W, and Y in the MenACWY-D group. Immunogenicity was assessed with a serum bactericidal activity assay that used baby rabbit serum as the complement (rSBA) on days 1 and 29 in the modified per-protocol population (including all participants who were randomly assigned, received vaccine, had a post-vaccination rSBA measurement up to 121 days after vaccination, and no major protocol violations). Solicited events were collected for 7 days and serious adverse events were collected for 180 days, and assessed in the safety population (all participants who received vaccination). This study is registered with ClinicalTrials.gov, NCT04358731, and CTRI, CTRI/2019/12/022436, and is now complete.

Findings

Between Dec 27, 2019, and Sept 19, 2020, 1712 individuals were screened, of whom 1640 were randomly assigned and received NmCV-5 (n=1233) or MenACWY-D (n=407; mean age 26·4 years [SD 12·2], 551 [33·6%] of 1640 were female, and 1089 [66·4%] were male). 1441 participants were aged 18–29 years (362 received lot A, 360 received lot B, and 361 received lot C of NmCV-5 and 357 received MenACWY-D, with one participant mis-randomised by age group and excluded from lot-to-lot consistency analysis). Non-inferiority of NmCV-5 against MenACWY-D was met in terms of seroresponse rates and GMT ratios for all five serogroups. The seroresponse rates were 84·3% (97·5% CI 81·7 to 86·7; serogroup A) or higher in the NmCV-5 group and 54·5% (48·5 to 60·3; serogroup A) or higher in the MenACWY-D group, with the difference in the seroresponse rate between vaccine groups ranging from 0·2 (97·5% CI –2·2 to 2·6) for serogroup W to 29·8 (24·4 to 35·2) for serogroup A. GMTs on day 29 were 7016·9 (97·5% CI 6475·7 to 7603·4; serogroup Y) or higher in the NmCV-5 group and 3646·8 (3188·2 to 4171·5; serogroup Y) or higher in the MenACWY-D group, with GMT ratios between vaccine groups for serogroups A, C, Y, and W ranging from 1·9 (97·5% CI 1·5–2·3) for serogroup W to 2·5 (2·2–2·8) for serogroup A. NmCV-5 induced robust immune responses against serogroup X. Lot-to-lot consistency of NmCV-5 was found for all five serogroups, with 95% CIs for the GMT ratio for each pair of lots being between 0·5 and 2: the lowest lower bound and the highest upper bound of the 95% CI for the GMR between NmCV-5 lot A and lot B were 0·6 and 1·4, between lot A and lot C were 0·7 and 1·6, and between lot B and lot C were 0·8 and 1·6, respectively, for any of the five serogroups. At least one solicited adverse event was reported by 527 (42·7%) of 1233 participants in the NmCV-5 group and 142 (34·9%) of 407 in the MenACWY-D group. No serious adverse events occurred that were determined to be causally related to vaccination.

Interpretation

NmCV-5 was non-inferior to MenACWY-D in terms of seroresponse and GMTs, was safe, and demonstrated lot-to-lot consistency. NmCV-5 is prequalified by WHO and was rolled out in the African meningitis belt in April, 2024.

Funding

Serum Institute of India.

中文翻译：

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印度成人五价脑膜炎球菌结合疫苗与四价脑膜炎球菌结合疫苗的安全性和免疫原性：一项观察者盲法、随机、主动对照的 2/3 期研究

 背景

脑膜炎球菌病仍然是全球重要的公共卫生问题。我们评估了五价脑膜炎球菌 ACYWX 结合疫苗 （NmCV-5;印度血清研究所，印度浦那）与健康成人的四价脑膜炎球菌 ACWY 结合疫苗 （MenACWY-D）。

 方法

在这项观察员盲法、随机、主动对照的 2/3 期研究中，从印度 7 个城市的 9 家医院招募了 18-85 岁的健康成年人。参与者按年龄（18-29 岁、30-60 岁和 61-85 岁）分组，在每个年龄组中，他们被随机分配 （3：1） 接受 NmCV-5 或 MenACWY-D（赛诺菲巴斯德）。在 18-29 岁组中，参与者还被随机分配 （1：1：1：1） 到 NmCV-5 或 MenACWY-D 的 A 批次、B 批次或 C 批次。使用随机分组 （块大小为 4 、 8 和 12）。研究参与者和研究人员对治疗分配不知情。参与者接受 0·5 mL 剂量的 NmCV-5，每种含有 5 μg 共轭 A、C、W、Y 和 X 多糖，或 0·5 mL MenACWY-D，含有 4 μg 共轭 A、C、W 和 Y 多糖。在三角肌肌肉注射疫苗接种。主要结局是所有参与者的血清反应（非劣效性边际为 -10%）和几何平均滴度 （GMT;非劣效性边际为 0·5），以及 NmCV-5 的批次间一致性（在 18-29 岁的参与者中;如果几何平均比 [GMR] 95% CI 在 0·5 至 2 的极限区间内，则显示一致性）。在非劣效性方面，将 NmCV-5 组的血清型 X 免疫应答与 MenACWY-D 组血清型 A 、 C 、 W 和 Y 中最低的免疫应答进行了比较。在修改后的按方案人群（包括所有被随机分配、接受疫苗接种、接种疫苗后 121 天内进行疫苗接种后 rSBA 测量且无重大协议违规）第 1 天和第 29 天使用婴儿兔血清作为补体 （rSBA） 的血清杀菌活性测定评估免疫原性。 收集 7 天的请求事件，收集 180 天的严重不良事件，并在安全人群（所有接受疫苗接种的参与者）中进行评估。本研究已在 ClinicalTrials.gov、NCT04358731 和 CTRI 注册，CTRI/2019/12/022436，现已完成。

 发现

在 2019 年 12 月 27 日至 2020 年 9 月 19 日期间，筛选了 1712 例个体，其中 1640 例被随机分配并接受了 NmCV-5 （n=1233） 或 MenACWY-D （n=407;平均年龄 26·4 岁 [SD 12·2]，1640 例中有 551 例 [33·6%] 为女性，1089 例 [66·4%] 为男性）。1441 名参与者年龄在 18-29 岁之间（362 名接受批次 A，360 名接受批次 B，361 名接受 NmCV-5 批次 C，357 名接受 MenACWY-D，其中一名参与者按年龄组错误随机分配，并被排除在批次间一致性分析之外）。在所有 5 个血清群的血清反应率和 GMT 比率方面，NmCV-5 优于 MenACWY-D 的非劣效性。NmCV-5 组的血清反应率为 84·3%（97·5% CI 81·7 至 86·7;血清型 A）或更高，MenACWY-D 组为 54·5%（48·5 至 60·3;血清型 A）或更高，疫苗组间血清反应率的差异范围从血清型 W 的 0·2（97·5% CI -2·2 至 2·6）到血清型 A 的 29·8（24·4 至 35·2）不等。第 29 天，NmCV-5 组为 7016·9（97·5% CI 6475·7 至 7603·4;血清型 Y）或更高，MenACWY-D 组为 3646·8（3188·2 至 4171·5;血清型 Y）或更高，血清型 A、C、Y 和 W 疫苗组之间的 GMT 比值范围为 W 血清型 1·9（97·5% CI 1·5-2·3）至血清型 A 的 2·5（2·2-2·8）。NmCV-5 诱导了针对血清型 X 的强烈免疫反应。在所有五个血清型中发现了 NmCV-5 的批次间一致性，每对批次的 GMT 比率的 95% CI 在 0·5 和 2 之间：NmCV-5 批次 A 和批次 B 之间 GMR 的 95% CI 的最低下限和最高上限为 0·6 和 1·4， 对于五个血清型中的任何一个，批次 A 和批次 C 之间的分别为 0·7 和 1·6，批次 B 和批次 C 之间的分别为 0·8 和 1·6。 NmCV-5 组的 1233 名参与者中有 527 名 （42·7%） 和 MenACWY-D 组的 407 名参与者中有 142 名 （34·9%） 报告了至少一次引发的不良事件。未发生被确定与疫苗接种有因果关系的严重不良事件。

 解释

NmCV-5 在血清反应和 GMT 方面不劣于 MenACWY-D，安全性高，并表现出批次间一致性。NmCV-5 已通过 WHO 的资格预审，并于 2024 年 4 月在非洲脑膜炎地带推出。

 资金

印度血清研究所。