Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
Health Technol Assess. 2024 Jul;28(34):1-109. doi: 10.3310/YWHA3079.
Vaccination of infants with pneumococcal conjugate vaccines is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines.
The primary objective was to compare the immunogenicity of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. The main secondary objective was to compare the seroefficacy of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13.
We searched the Cochrane Library, EMBASE, Global Health, MEDLINE, ClinicalTrials.gov and trialsearch.who.int up to July 2022. Studies were eligible if they directly compared either pneumococcal conjugate vaccine-7, pneumococcal conjugate vaccine-10 or pneumococcal conjugate vaccine-13 in randomised trials of children under 2 years of age, and provided immunogenicity data for at least one time point. Individual participant data were requested and aggregate data used otherwise. Outcomes included the geometric mean ratio of serotype-specific immunoglobulin G and the relative risk of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Each trial was analysed to obtain the log of the ratio of geometric means and its standard error. The relative risk of seroinfection ('seroefficacy') was estimated by comparing the proportion of participants with seroinfection between vaccine groups. The log-geometric mean ratios, log-relative risks and their standard errors constituted the input data for evidence synthesis. For serotypes contained in all three vaccines, evidence could be synthesised using a network meta-analysis. For other serotypes, meta-analysis was used. Results from seroefficacy analyses were incorporated into a mathematical model of pneumococcal transmission dynamics to compare the differential impact of pneumococcal conjugate vaccine-10 and pneumococcal conjugate vaccine-13 introduction on invasive pneumococcal disease cases. The model estimated the impact of vaccine introduction over a 25-year time period and an economic evaluation was conducted.
In total, 47 studies were eligible from 38 countries. Twenty-eight and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. Geometric mean ratios comparing pneumococcal conjugate vaccine-13 versus pneumococcal conjugate vaccine-10 favoured pneumococcal conjugate vaccine-13 for serotypes 4, 9V and 23F at 1 month after primary vaccination series, with 1.14- to 1.54-fold significantly higher immunoglobulin G responses with pneumococcal conjugate vaccine-13. Risk of seroinfection prior to the time of booster dose was lower for pneumococcal conjugate vaccine-13 for serotype 4, 6B, 9V, 18C and 23F than for pneumococcal conjugate vaccine-10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Twofold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (relative risk 0.46, 95% confidence interval 0.23 to 0.96). In modelled scenarios, pneumococcal conjugate vaccine-13 or pneumococcal conjugate vaccine-10 introduction in 2006 resulted in a reduction in cases that was less rapid for pneumococcal conjugate vaccine-10 than for pneumococcal conjugate vaccine-13. The pneumococcal conjugate vaccine-13 programme was predicted to avoid an additional 2808 (95% confidence interval 2690 to 2925) cases of invasive pneumococcal disease compared with pneumococcal conjugate vaccine-10 introduction between 2006 and 2030.
Analyses used data from infant vaccine studies with blood samples taken prior to a booster dose. The impact of extrapolating pre-booster efficacy to post-booster time points is unknown. Network meta-analysis models contained significant heterogeneity which may lead to bias.
Serotype-specific differences were found in immunogenicity and seroefficacy between pneumococcal conjugate vaccine-13 and pneumococcal conjugate vaccine-10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These methods can be used to compare the pneumococcal conjugate vaccines and optimise vaccination strategies. For future work, seroefficacy estimates can be determined for other pneumococcal vaccines, which could contribute to licensing or policy decisions for new pneumococcal vaccines.
This study is registered as PROSPERO CRD42019124580.
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/03) and is published in full in ; Vol. 28, No. 34. See the NIHR Funding and Awards website for further award information.
世界卫生组织建议为婴儿接种肺炎球菌结合疫苗。不同的肺炎球菌疫苗在免疫原性和功效方面的差异证据不一。
主要目的是比较肺炎球菌结合疫苗-10 与肺炎球菌结合疫苗-13 的免疫原性。主要次要目标是比较肺炎球菌结合疫苗-10 与肺炎球菌结合疫苗-13 的血清效力。
我们在 Cochrane 图书馆、EMBASE、全球卫生、MEDLINE、ClinicalTrials.gov 和 trialsearch.who.int 上搜索至 2022 年 7 月的文献。如果研究直接比较了年龄在 2 岁以下的儿童使用的肺炎球菌结合疫苗-7、肺炎球菌结合疫苗-10 或肺炎球菌结合疫苗-13，并提供了至少一个时间点的免疫原性数据，则将其纳入研究。如果无法获得个体参与者数据，则使用汇总数据。结果包括血清型特异性免疫球蛋白 G 的几何均数比和血清感染的相对风险。将血清感染定义为每个个体在初次接种系列后时间点和加强剂量之间的抗体升高，即假定的亚临床感染的证据。对每个试验进行分析，以获得比值几何均数的对数及其标准误差。血清感染的相对风险（血清效力）通过比较疫苗组之间血清感染的参与者比例来估计。血清效力分析的结果被纳入肺炎球菌传播动力学的数学模型中，以比较肺炎球菌结合疫苗-10 和肺炎球菌结合疫苗-13 引入对侵袭性肺炎球菌病病例的差异影响。该模型估计了在 25 年的时间内疫苗引入的影响，并进行了经济评估。
共有来自 38 个国家的 47 项研究符合纳入标准。28 项和 12 项有数据可用的研究分别纳入了免疫原性和血清效力分析。比较肺炎球菌结合疫苗-13 与肺炎球菌结合疫苗-10 ，在初次接种系列后 1 个月时，血清型 4、9V 和 23F 的几何均数比有利于肺炎球菌结合疫苗-13，肺炎球菌结合疫苗-13 的免疫球蛋白 G 反应高出 1.14 至 1.54 倍。与肺炎球菌结合疫苗-10 相比，肺炎球菌结合疫苗-13 血清型 4、6B、9V、18C 和 23F 的血清感染风险在加强剂量前的时间较低。两种疫苗接种后抗体增加两倍与血清感染风险降低 54%相关（相对风险 0.46，95%置信区间 0.23 至 0.96）。在模型情景中，2006 年引入肺炎球菌结合疫苗-13 或肺炎球菌结合疫苗-10 导致肺炎球菌结合疫苗-10 的病例减少速度比肺炎球菌结合疫苗-13 慢。与 2006 年至 2030 年引入肺炎球菌结合疫苗-10 相比，预测肺炎球菌结合疫苗-13 计划将避免 2808 例（95%置信区间 2690 至 2925）侵袭性肺炎球菌病病例。
分析使用了在加强剂量前采集血样的婴儿疫苗研究的数据。将预加强效力外推至加强后时间点的影响尚不清楚。网络荟萃分析模型存在显著的异质性，这可能导致偏倚。
在肺炎球菌结合疫苗-13 和肺炎球菌结合疫苗-10 之间发现了血清型特异性免疫原性和血清效力的差异。接种后抗体水平较高与随后感染的风险较低相关。这些方法可用于比较肺炎球菌结合疫苗并优化疫苗接种策略。未来的工作可以确定其他肺炎球菌疫苗的血清效力估计值，这可能有助于新肺炎球菌疫苗的许可或政策决策。
本研究已在 PROSPERO CRD42019124580 注册。
该奖项由英国国家卫生与保健优化研究所（NIHR）健康技术评估计划（NIHR 奖励编号：17/148/03）资助，并全文发表在；第 28 卷，第 34 期。有关该奖项的更多信息，请访问 NIHR 资助和奖项网站。
