Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
Lancet Infect Dis. 2019 Feb;19(2):156-164. doi: 10.1016/S1473-3099(18)30568-1. Epub 2019 Jan 8.
Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval.
We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40-60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 μg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov, number NCT02385513.
Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI -9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [-2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [-7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference -4·92% [-9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference -3·39% [95% CI -13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference -10·23% [-21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference -10·41% [-20·65 to -0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference -4·91% [-15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference -15·31% [-25·78 to -4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference -2·01% [-12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 μg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6 + 14 group.
The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection.
Gavi, the Vaccine Alliance.
尼泊尔婴儿因计划原因，在接受基础免疫接种时，需在第 1 个月和第 3 个月之间间隔 1 个月接种 10 价肺炎球菌结合疫苗（PCV10）。我们旨在研究如果将第 2 次 PCV10 基础免疫接种的间隔时间从 2 个月缩短至 1 个月，那么针对 PCV10 血清型的免疫反应是否仍然具有非劣效性。
我们在尼泊尔加德满都的帕坦医院进行了一项开放性、随机、平行分组试验，纳入年龄为 40-60 天的健康尼泊尔婴儿。符合纳入条件的婴儿需要满足以下标准：健康、胎龄大于或等于 37 周、居住在加德满都，且除卡介苗和口服脊髓灰质炎疫苗外，没有接受过任何其他疫苗接种。参与者按照 1:1 的比例随机分配（通过一个经过验证的网络界面访问的随机排列、大小可变的随机区组分配），分别在 6 周龄和 10 周龄（6+10 组）或 6 周龄和 14 周龄（6+14 组）时接受 PCV10 接种，两组均在 9 月龄时进行加强免疫。实验室工作人员对血清样本进行血清型特异性 IgG 抗体的酶联免疫吸附试验（ELISA）分析，分析结果设为盲态。主要结局是在 9 个月龄时，比较两组血清型特异性 IgG 抗体滴度大于或等于 0.35 μg/mL 的婴儿比例，判断 6+10 方案是否不劣于 6+14 方案。采用 10%的边际，确定非劣效性，主要终点在仅成功采集血样的改良意向治疗人群中进行测量。本试验在 ClinicalTrials.gov 注册，编号为 NCT02385513。
2015 年 8 月 21 日至 2016 年 4 月 4 日，304 名尼泊尔儿童被随机分配至 6+10 组（n=152）或 6+14 组（n=152）。在 9 个月龄时，6+10 方案对血清型 5（79[55.2%]例 143 例，78[53.4%]例 146 例，差值 1.82%[-9.6 至 13.25]，p=0.021）、血清型 9V（66[46.1%]例 143 例，55[37.6%]例 146 例，差值 8.48%[-2.8 至 19.8]，p=0.001）、血清型 14（110[77.4%]例 142 例，110[74.8%]例 147 例，差值 2.63%[-7.2 至 12.54]，p=0.006）和血清型 19F（135[95%]例 142 例，146[100%]例 146 例，差值-4.92%[-9.8 至 0]，p=0.022）的非劣效性得到证实。同时，在同一时间点，6+10 方案对血清型 1（36[25.1%]例 143 例，42[28.5%]例 147 例，差值 3.39%[-13.5 至 6.77]，p=0.102）、血清型 4（70[48.9%]例 143 例，87[59.1%]例 147 例，差值-10.23%[-21.6 至 1.18]，p=0.516）、血清型 6B（96[67.1%]例 143 例，114[77.5%]例 147 例，差值-10.41%[-20.6 至-0.18]，p=0.532）、血清型 7F（99[69.2%]例 143 例，109[74.1%]例 147 例，差值-4.91%[-15.2 至 5.42]，p=0.168）、血清型 18C（89[62.2%]例 143 例，114[77.5%]例 147 例，差值-15.31%[-25.7 至-4.83]，p=0.840）和血清型 23F（37[25.8%]例 143 例，41[27.8%]例 147 例，差值-2.01%[-12.1 至 8.16]，p=0.062）的非劣效性未得到证实。在加强免疫接种后，在 10 个月龄时，当比较两种方案时，对于这 10 种血清型中的任何一种，免疫原性（抗体滴度大于或等于 0.35 μg/mL 的儿童比例）均无显著差异。32 名参与者发生了严重不良事件，其中 6+10 组 11 例（7%），6+14 组 21 例（14%）。
如果可能的话，应实施 6 周、14 周和 9 个月的方案。然而，在两种方案中，增强后的反应（被认为是驱动群体免疫的反应）相似。因此，当从后勤角度考虑时，6 周、10 周和 9 个月的方案是一个替代方案，预计可以提供群体保护。
全球疫苗免疫联盟（Gavi）。
