PDF(Pubmed)
Abstract：
BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule.
RESULTS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again).
CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups.
BACKGROUND: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).
RESULTS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again).
CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups.
BACKGROUND: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).
摘要：
背景：在许多国家，婴儿接种无细胞百日咳(aP)疫苗已取代使用更具反应性的全细胞百日咳(wP)疫苗.根据免疫学和流行病学证据，我们假设用wP疫苗替代常规疫苗接种计划中的第一个aP剂量可能对IgE介导的食物过敏具有保护作用.我们的目的是比较反应原性，免疫原性,混合wP/aP初级方案与标准aP方案的IgE介导反应。
结果：OPTIMUM是贝叶斯的，2阶段，双盲,随机试验。在第一阶段,婴儿被分配（1：1）接受第一剂五价wP联合疫苗（DTwP-Hib-HepB，PentabioPTBioFarma,印度尼西亚）或六价aP疫苗（DTaP-Hib-HepB-IPV，Infanrixhexa,葛兰素史克,澳大利亚）大约6周大。随后，所有婴儿在4个月和6个月大时接种了六价aP疫苗，在18个月大时接种了aP疫苗(DTaP-IPV，Infanrix-IPV,葛兰素史克,澳大利亚)。第二阶段正在进行中，并遵循上述随机化策略和疫苗接种时间表。在确定12个月大的过敏症患者确诊的IgE介导的食物过敏的主要临床结果之前，这里我们介绍次级免疫原性的结果，反应原性,破伤风类毒素IgE介导的免疫反应，和父母可接受性终点。血清IgG对白喉的反应，破伤风,使用基于多重荧光珠的免疫测定法测量百日咳抗原;通过ImmunoCAP测定法(ThermoFisherScientific)测量血浆中的总IgE和特异性IgE。混合时间表的免疫原性被定义为在6个月aP后1个月的百日咳毒素（PT）-IgG的几何平均浓度（GMR）比率为2/3的非劣效性不低于aP时间表。研究小组总结了引起的不良反应，包括所有接受第一剂wP或aP的儿童。使用5点Likert量表评估父母的接受度。主要分析基于意向治疗（ITT）；还进行了次要符合方案（PP）分析。该试验已在ANZCTR（ACTRN12617000065392p）注册。在2018年3月7日至2020年1月13日之间，随机分配了150名婴儿（每臂75名）。混合方案的PT-IgG反应在6个月aP剂量后约1个月不劣于仅aP方案[GMR=0·98，95％可信间隔（0·77至1·26）；概率（GMR>2/3）>0·99；ITT分析]。在7个月大的时候，在混合方案组和仅aP组,破伤风类毒素IgE定量的后中位概率均为0·22(95%可信区间0·12~0·34).尽管有排除，结果与PP分析一致。在6周大的时候，在wP(74例疫苗中的65[88%])和aP(72例疫苗中的59例[82%])疫苗接种者中,易怒是最常见的全身征求反应.在相同的年龄，在74例wP后婴儿中的14例(19%)和72例aP后婴儿中的8例(11%)中报告了严重的全身反应.在随访的前6个月内，5名参与者中有7个SAE；在盲法评估中，没有一个被认为与研究疫苗有关.父母对混合时间表和aP时间表的接受度很高（73个中的71[97％]对72个中的69[96％]同意再次使用相同的时间表）。结论与仅aP时间表相比，混合时间表诱发非劣质PT-IgG反应，与更严重的反应有关，但被父母接受了。各研究组的破伤风类毒素IgE反应没有差异。
背景：试验在澳大利亚和新西兰临床207试验注册中心注册(ACTRN12617000065392p)。https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371998&isReview=true。只有一个注册表（如上）。
结果：OPTIMUM是贝叶斯的，2阶段，双盲,随机试验。在第一阶段,婴儿被分配（1：1）接受第一剂五价wP联合疫苗（DTwP-Hib-HepB，PentabioPTBioFarma,印度尼西亚）或六价aP疫苗（DTaP-Hib-HepB-IPV，Infanrixhexa,葛兰素史克,澳大利亚）大约6周大。随后，所有婴儿在4个月和6个月大时接种了六价aP疫苗，在18个月大时接种了aP疫苗(DTaP-IPV，Infanrix-IPV,葛兰素史克,澳大利亚)。第二阶段正在进行中，并遵循上述随机化策略和疫苗接种时间表。在确定12个月大的过敏症患者确诊的IgE介导的食物过敏的主要临床结果之前，这里我们介绍次级免疫原性的结果，反应原性,破伤风类毒素IgE介导的免疫反应，和父母可接受性终点。血清IgG对白喉的反应，破伤风,使用基于多重荧光珠的免疫测定法测量百日咳抗原;通过ImmunoCAP测定法(ThermoFisherScientific)测量血浆中的总IgE和特异性IgE。混合时间表的免疫原性被定义为在6个月aP后1个月的百日咳毒素（PT）-IgG的几何平均浓度（GMR）比率为2/3的非劣效性不低于aP时间表。研究小组总结了引起的不良反应，包括所有接受第一剂wP或aP的儿童。使用5点Likert量表评估父母的接受度。主要分析基于意向治疗（ITT）；还进行了次要符合方案（PP）分析。该试验已在ANZCTR（ACTRN12617000065392p）注册。在2018年3月7日至2020年1月13日之间，随机分配了150名婴儿（每臂75名）。混合方案的PT-IgG反应在6个月aP剂量后约1个月不劣于仅aP方案[GMR=0·98，95％可信间隔（0·77至1·26）；概率（GMR>2/3）>0·99；ITT分析]。在7个月大的时候，在混合方案组和仅aP组,破伤风类毒素IgE定量的后中位概率均为0·22(95%可信区间0·12~0·34).尽管有排除，结果与PP分析一致。在6周大的时候，在wP(74例疫苗中的65[88%])和aP(72例疫苗中的59例[82%])疫苗接种者中,易怒是最常见的全身征求反应.在相同的年龄，在74例wP后婴儿中的14例(19%)和72例aP后婴儿中的8例(11%)中报告了严重的全身反应.在随访的前6个月内，5名参与者中有7个SAE；在盲法评估中，没有一个被认为与研究疫苗有关.父母对混合时间表和aP时间表的接受度很高（73个中的71[97％]对72个中的69[96％]同意再次使用相同的时间表）。结论与仅aP时间表相比，混合时间表诱发非劣质PT-IgG反应，与更严重的反应有关，但被父母接受了。各研究组的破伤风类毒素IgE反应没有差异。
背景：试验在澳大利亚和新西兰临床207试验注册中心注册(ACTRN12617000065392p)。https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371998&isReview=true。只有一个注册表（如上）。
