Oxford Vaccine Group, Department of Paediatrics, University of Oxford, UK.
Statistics, Modelling and Economics Department, Public Health England, London, UK.
Lancet Infect Dis. 2021 May;21(5):688-696. doi: 10.1016/S1473-3099(20)30600-9. Epub 2021 Jan 8.
The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate.
In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete.
Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5-98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2-97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0-92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5-94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions.
These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important.
Bill & Melinda Gates Foundation and the National Institute for Health Research.
在英国，2 月龄、4 月龄和 12 月龄时接种多组份脑膜炎球菌疫苗 4CMenB 已被证明可有效预防 B 群侵袭性脑膜炎球菌病，预防效果为 59.1%。在此，我们报告该简化接种程序的免疫原性的首批数据，以帮助解读该有效性估计值。
在这项多中心、平行组、开放标签、随机临床试验中，通过牛津郡儿童健康数据库邮件和格洛斯特郡及赫特福德郡的普通外科手术，招募了即将接受基础免疫的最多 13 周龄婴儿。通过区组随机化（1∶1）将婴儿随机分配至接受 2+1（2、4 和 12 月龄；组 1）或 1+1（3 和 12 月龄；组 2）的 13 价肺炎球菌结合疫苗（PCV13）接种程序。所有婴儿还会在 2、4 和 12 月龄时接种 4CMenB，并且在 5 月龄和 13 月龄时采集血样。参与者和临床试验工作人员不设盲法。用人类补体血清杀菌抗体（hSBA）滴度至少为 4 的比例来确定 B 群脑膜炎球菌（MenB）参考株 5/99（黏附素 A [NadA]）、NZ98/254（孔蛋白 A）和 44/76-SL（因子 H 结合蛋白 [fHbp]）的血清杀菌抗体。还计算了几何均数滴度（GMT）及其 95%可信区间，并比较了各组间伴随疫苗的反应（C 群脑膜炎球菌[MenC]、流感嗜血杆菌 b [Hib]、破伤风、白喉和百日咳）。主要结局为 PCV13 的免疫原性，次要结局为 4CMenB 的免疫原性和反应原性。所有通过随机分组有实验室结果的个体均纳入分析。本研究在 EudraCT 临床试验数据库中注册，注册号为 2015-000817-32，在 ClinicalTrials.gov 注册，注册号为 NCT02482636，现已完成。
2015 年 9 月 22 日至 2017 年 11 月 1 日，对 376 名筛查者进行筛查，其中 213 名入组（组 1 106 名，组 2 107 名）。204 份基础免疫后样本和 180 份加强免疫后样本可供分析。两组的 hSBA 滴度比例相似。对于菌株 5/99，两组所有参与者的 hSBA 滴度在两个时间点均超过 4。对于菌株 44/76-SL，该比例在基础免疫后分别为 95·3%（95%CI 88·5-98·7）或以上（组 1 86 名参与者中的 82 名）和加强免疫后为 92·4%（84·2-97·2）或以上（组 1 79 名参与者中的 73 名）。对于菌株 NZ98/254，该比例在基础免疫后分别为 86·5%（78·0-92·6）或以上（组 2 96 名参与者中的 83 名）和加强免疫后为 88·6%（79·5-94·7）或以上（组 1 79 名参与者中的 70 名）。组 1 的 MenC 兔补体血清杀菌抗体（rSBA）滴度显著高于组 2（888·3 比 540·4；p=0·025）。两组的白喉、破伤风、Hib 和百日咳加强免疫后几何平均浓度无显著差异。少数儿童对 44/76-SL 和 NZ98/254 没有产生保护反应。两组间除了 3 月龄时一组额外接种了一剂 PCV13 并记录了更多的全身反应外，局部和全身反应相似。
这些数据支持最近对欧洲批准的 4CMenB 接种程序进行修改，即在常规的英国疫苗接种计划中添加一个 2+1 接种程序，该程序在英国常规免疫程序中的有效性为 59.1%。与历史数据相比，我们的数据并没有表明 3+1 接种程序的效果会更高，但针对疫苗抗原 fHbp 的杀菌抗体的加强免疫反应不佳，表明需要对由于 fHbp 匹配菌株引起的疫苗突破进行持续监测。英国从 2+1 改为 1+1 的 PCV13 接种程序不太可能影响对白喉、破伤风和 Hib 的保护，但新方案中观察到针对 MenC 的杀菌抗体的意外降低，表明需要对重新出现的 MenC 疾病进行持续监测。
比尔及梅琳达·盖茨基金会和英国国家卫生研究院。
