Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
Lancet Infect Dis. 2018 Oct;18(10):1088-1096. doi: 10.1016/S1473-3099(18)30400-6. Epub 2018 Aug 14.
Invasive meningococcal disease is an important public health problem, especially in sub-Saharan Africa. After introduction of MenAfriVac in 2010, Neisseria meningitidis serogroup A disease has been almost eliminated from the region. However, serogroups C, W, Y, and X continue to cause disease outbreaks. We assessed the NmCV-5 pentavalent meningococcal conjugate vaccine targeting A, C, Y, W, and X serogroups in a first-in-man, phase 1 study.
We did a single-centre, double-blind, randomised controlled trial at a research clinic in Baltimore (MD, USA). Participants were healthy adults aged 18-45 years with no history of meningococcal vaccination or previous meningococcal infection. We randomly assigned participants (1:1:1) by an SAS-generated random schedule to a single, 0·5 mL, intramuscular injection of aluminium-phosphate adjuvanted NmCV-5, non-adjuvanted NmCV-5, or control (the quadrivalent meningococcal conjugate vaccine Menactra). The randomisation sequence used a permuted block design with randomly chosen block sizes of three and six. The vaccines were prepared, labelled, and administered with procedures to ensure participants and study personnel remained masked to treatment. After vaccination, participants were observed in the clinic for 60 min for adverse reactions. Participants recorded daily temperature and injection site or systemic reactions at home and returned to the clinic for follow-up visits on days 7, 28, and 84 for safety assessments; blood samples were also collected on day 7 for safety laboratory assessment. A phone call contact was made 6 months after vaccination. Serum was collected before vaccination and 28 days after vaccination for immunological assessment with a rabbit complement-dependent serum bactericidal antibody (rSBA) assay. The primary objective was an intention-to-treat assessment of safety, measuring local and systemic reactogenicity over 7 days, unsolicited adverse events through 28 days, and serious adverse events over 6 months. The secondary objective for the assessment of immunogenicity, was a per-protocol analysis of rSBA before and 28 days after vaccination. This trial is registered with ClinicalTrials.gov, number NCT02810340.
Between Aug 17, 2016, and Feb 16, 2017, we assigned 20 participants to each vaccine. All vaccines were well-tolerated. Pain was the most common local reaction, occurring in 12 (60%), ten (50%), and seven (35%) participants in the adjuvanted NmCV-5, non-adjuvanted NmCV-5, and control groups, respectively. Headache was the most common systemic reaction, occurring in five (25%), three (15%), and three (15%), respectively. Most solicited reactogenicity adverse reactions were mild (60 [74%] of 81) and all were self-limiting. None of the differences in proportions of individuals with each solicited reaction was significant (p>0·300 for all comparisons) between the three vaccination groups. There were no serious adverse events and 19 unsolicited non-serious adverse events in 14 (23%) participants. Both adjuvanted and non-adjuvanted NmCV-5 elicited high rSBA titres against all five meningococcal serogroups. The pre-vaccination geometric mean titres (GMTs) ranged from 3·36 to 53·80 for the control, from 6·28 to 187·00 for the adjuvanted vaccine, and from 4·29 to 350·00 for the non-adjuvanted vaccine, and the post-vaccination GMT ranged from 3·14 to 3214 for the control, from 1351 to 8192 for the adjuvanted vaccine, and from 1607 to 11 191 for the non-adjuvanted vaccine. Predicted seroprotective responses (ie, an increase in rSBA titres of eight times or more) for the adjuvanted and non-adjuvanted NmCV-5 were similar to control responses for all five serogroups.
The adjuvanted and non-adjuvanted NmCV-5 vaccines were well tolerated and did not produce concerning adverse effects and resulted in immune responses that are predicted to confer protection against all five targeted serogroups of invasive meningococcal disease. Further clinical testing of NmCV-5 is ongoing, and additional clinical trials are necessary to confirm the safety and immunogenicity of NmCV-5 in target populations.
UK Department for International Development.
侵袭性脑膜炎球菌病是一个重要的公共卫生问题，尤其是在撒哈拉以南非洲地区。2010 年引入 MenAfriVac 后，A 群脑膜炎奈瑟菌疾病几乎从该地区消除。然而，C、W、Y 和 X 群继续引起疾病爆发。我们评估了针对 A、C、Y、W 和 X 群的 NmCV-5 五价结合脑膜炎球菌疫苗在首例人体、1 期研究中的效果。
我们在巴尔的摩（马里兰州，美国）的一个研究诊所进行了一项单中心、双盲、随机对照试验。参与者为年龄在 18-45 岁之间的健康成年人，没有脑膜炎球菌疫苗接种或既往脑膜炎球菌感染史。我们通过一个由 SAS 生成的随机时间表，将参与者（1:1:1）随机分配到单次、0.5 mL、肌肉内注射铝磷酸佐剂 NmCV-5、非佐剂 NmCV-5 或对照（四价脑膜炎球菌结合疫苗 Menactra）。随机序列使用随机选择的 3 个和 6 个块大小的置换块设计。疫苗是用确保参与者和研究人员对治疗保持盲法的程序制备、标记和给药的。接种疫苗后，参与者在诊所观察 60 分钟，以观察不良反应。参与者在家中每天记录体温和注射部位或全身反应，并在第 7、28 和 84 天返回诊所进行安全性评估；第 7 天还采集血样进行安全性实验室评估。接种疫苗后 6 个月进行一次电话随访。接种前和接种后 28 天采集血清，用兔补体依赖性血清杀菌抗体（rSBA）检测进行免疫评估。主要目的是通过对 7 天内的局部和全身反应、28 天内的不良事件和 6 个月内的严重不良事件进行意向治疗评估，评估安全性。免疫原性的次要目的是在接种前和接种后 28 天对 rSBA 进行方案分析。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02810340。
2016 年 8 月 17 日至 2017 年 2 月 16 日期间，我们将 20 名参与者分配到每种疫苗组。所有疫苗均耐受良好。疼痛是最常见的局部反应，分别有 12 名（60%）、10 名（50%）和 7 名（35%）参与者在接受佐剂 NmCV-5、非佐剂 NmCV-5 和对照疫苗后出现疼痛。头痛是最常见的全身反应，分别有 5 名（25%）、3 名（15%）和 3 名（15%）参与者出现。大多数自述的不良反应均为轻度（81 例中有 60 例[74%]），且均为自限性的。在三组接种疫苗者中，没有任何一种不良反应的发生率存在显著差异（p>0.300 均为）。14 名（23%）参与者中有 19 例（19 名）为非严重不良事件。两种佐剂和非佐剂 NmCV-5 对所有 5 种脑膜炎奈瑟菌血清群均产生了高 rSBA 滴度。对照组的预接种几何平均滴度（GMT）范围为 3.36-53.80，佐剂组为 6.28-187.00，非佐剂组为 4.29-350.00，对照组的接种后 GMT 范围为 3.14-3214，佐剂组为 1351-8192，非佐剂组为 1607-11191。佐剂和非佐剂 NmCV-5 的预测血清保护反应（即 rSBA 滴度增加 8 倍或以上）与对照组针对所有 5 个血清群的反应相似。
佐剂和非佐剂 NmCV-5 疫苗均耐受良好，未产生令人担忧的不良反应，并产生了预计能针对所有 5 种侵袭性脑膜炎球菌疾病目标血清群提供保护的免疫反应。目前正在对 NmCV-5 进行进一步的临床测试，需要开展更多的临床试验来确认 NmCV-5 在目标人群中的安全性和免疫原性。
英国国际发展部。
