BACKGROUND A resurgence of pertussis has increased the demand for low-cost vaccines. The aim of this study was to test the immunogenicity of a booster acellular monovalent pertussis vaccine containing reduced-dose (2 μg) recombinant pertussis toxin (PT) and 5 μg filamentous haemagglutinin (FHA; apgen) against a version of apgen containing tetanus and reduced-dose diphtheria toxoids (Tdapgen) and a licensed vaccine containing chemically detoxified PT and FHA combined with tetanus toxoid and reduced-dose diphtheria toxoid (Tdapchem). METHODS This phase 2/3, observer-blinded, randomised, controlled, non-inferiority trial was done in adolescents aged 9-17 years at two clinical research centres in Bangkok and Pathum Thani, Thailand. Eligible participants were screened and randomly assigned (1:1:1) to receive one booster dose of apgen, Tdapgen, or Tdapchem vaccine. Participants were followed up until day 336 post-immunisation. The primary endpoint was non-inferior seroconversion rates in Tdapgen and Tdapchem vaccine groups, with seroconversion rate defined as the proportion of participants with at least a four-fold increase on day 28 post-immunisation relative to baseline of anti-PT and anti-FHA IgG. The non-inferiority for seroconversion rates of anti-PT and anti-FHA IgG was defined as the lower bound of the two-sided 95% CI of the seroconversion rate for Tdapgen compared with Tdapchem exceeding -10%. Immunogenicity was analysed in the per-protocol population. All safety data were collected, and the prevalence of adverse events was analysed in the intention-to-treat population. This trial was registered on the Thai Clinical Trial Registry (TCTR20181031001). FINDINGS Between June 18, and Aug 3, 2019, 450 adolescents (mean age 12·1 years, SD 2·5) were enrolled and randomly assigned (150 participants in each group). Day 28 anti-PT IgG seroconversion rates were 141 (94%) of 150 participants who received Tdapgen (95% CI 88·8-97·0) and 105 (71%) of 149 participants who received Tdapchem (62·7-77·2; p<0·0001). Day 28 anti-FHA IgG seroconversion rates were 144 (96%) of 150 participants who received Tdapgen (91·4-98·3) and 124 (83%) of 149 participants who received Tdapchem (76·4-88·4; p<0·0001). The difference in seroconversion rates was 23·5% (95% CI 15·3-31·8) for anti-PT IgG and 12·8% (6·0-19·6) for anti-FHA IgG, when comparing the Tdapgen versus the Tdapchem vaccine group. No vaccine-related serious adverse events were reported. INTERPRETATION Recombinant Tdapgen vaccine showed non-inferior immunogenicity compared with Tdapchem at day 28 in terms of seroconversion rate of anti-PT IgG and anti-FHA IgG relative to baseline. The reduced-dose approach for Tdapgen vaccines thus presents as a potentially cost-saving booster strategy to protect adolescents against pertussis. FUNDING Office of National Higher Education Science Research and Innovation Policy Council (Programme Management Unit Competitiveness), Thailand, and BioNet-Asia.

中文翻译：

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泰国青少年减剂量重组百日咳疫苗加强剂：一项 2/3 期、观察者盲法、随机对照、非劣效性试验。


背景 百日咳的卷土重来增加了对低成本疫苗的需求。本研究的目的是测试含有减剂量 （2 μg） 重组百日咳毒素 （PT） 和 5 μg 丝状血凝素 （FHA;apgen） 的加强无细胞单价百日咳疫苗对含有破伤风和减量白喉类毒素 （Tdapgen） 的 apgen 版本的免疫原性，以及含有化学解毒 PT 和 FHA 联合破伤风类毒素和减剂量白喉类毒素 （Tdapchem） 的许可疫苗。方法 这项 2/3 期、观察者盲法、随机、对照、非劣效性试验是在泰国曼谷和巴吞他尼的两个临床研究中心对 9-17 岁的青少年进行的。筛选符合条件的参与者并随机分配 （1：1：1） 接受一剂加强剂量的 apgen、Tdapgen 或 Tdapchem 疫苗。对参与者进行随访直至免疫后第 336 天。主要终点是 Tdapgen 和 Tdapchem 疫苗组的非劣效血清转化率，血清转化率定义为免疫后第 28 天相对于抗 PT 和抗 FHA IgG 基线至少增加四倍的参与者比例。抗 PT 和抗 FHA IgG 血清转化率的非劣效性定义为 Tdapgen 血清转化率与 Tdapchem 相比超过 -10% 的双侧 95% CI 的下限。在符合方案的人群中分析免疫原性。收集所有安全数据，并分析意向治疗人群中不良事件的发生率。该试验已在泰国临床试验注册库 （TCTR20181031001） 注册。 结果 在 2019 年 6 月 18 日至 8 月 3 日期间，招募了 450 名青少年 （平均年龄 12·1 岁，SD 2·5） 并随机分配 （每组 150 名参与者）。第 28 天的抗 PT IgG 血清转化率为接受 Tdapgen 的 150 名参与者中的 141 名 （94%） （95% CI 88·8-97·0） 和接受 Tdapchem 的 149 名参与者中的 105 名 （71%） （62·7-77·2;p<0·0001）。第 28 天的抗 FHA IgG 血清转化率为接受 Tdapgen 的 150 名参与者中的 144 名 （96%） （91·4-98·3） 和接受 Tdapchem 的 149 名参与者中的 124 名 （83%） （76·4-88·4;p<0·0001）。当比较 Tdapgen 与 Tdapchem 疫苗组时，抗 PT IgG 的血清转化率差异为 23·5% （95% CI 15·3-31·8），抗 FHA IgG 的血清转化率差异为 12·8% （6·0-19·6）。未报告与疫苗相关的严重不良事件。解释 重组 Tdapgen 疫苗在第 28 天时，在抗 PT IgG 和抗 FHA IgG 的血清转化率方面显示出非劣效于 Tdapchem 的免疫原性相对于基线。因此，Tdapgen 疫苗的减剂量方法是一种可能节省成本的加强策略，可以保护青少年免受百日咳的侵害。国家高等教育科学研究与创新政策委员会（项目管理单位竞争力）办公室（泰国）和 BioNet-Asia。