PDF(Pubmed)
Abstract：
BACKGROUND: Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR = 1-hazard ratio or VERR = 1-risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure.
METHODS: Power of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion.
RESULTS: In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power.
CONCLUSIONS: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis.
BACKGROUND: NCT00866619, NCT02663700, NCT02143934.
METHODS: Power of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion.
RESULTS: In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power.
CONCLUSIONS: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis.
BACKGROUND: NCT00866619, NCT02663700, NCT02143934.
摘要：
背景：早期疟疾疫苗现场试验通常通过对连续取样的血液进行PCR或浓血涂片显微镜检查来测量疟疾感染。疫苗效力（VE）是由于疫苗接种而导致的终点降低的比例，通常以VEHR=1风险比或VERR=1风险比计算。基因分型信息可以区分不同的克隆，并随着时间的推移区分多种感染，潜在增加的统计能力。本文研究了结合基因分型信息的两个替代VE终点：VEolFOI，随着时间的推移，疫苗诱导的新克隆发生率降低，和VEC,疫苗诱导的每次暴露感染克隆的平均数量减少的比例。
方法：通过模拟和分析推导，将VEolFOI和VEC的功率与VEHR和VERR的功率进行了比较，并将四种VE方法应用于三个数据集：RTS的3期试验，6912名非洲婴儿的S疟疾疫苗，在80名布基纳法索成年人中进行PfSPZ疫苗的2期试验，和一项试验比较了466名巴布亚新几内亚儿童在接受氯喹和蒿甲醚氟烷曲碱联合或不联合伯氨喹后的间日疟原虫发病率（因为这些VE方法也可以量化其他预防措施的效果）。通过摧毁冬眠的肝脏间日疟原虫，伯氨喹减少治疗完成后的后续再激活。
结果：在RTS的试验中，S疫苗，首次感染时，克隆数量显着减少，但在PfSPZ疫苗或伯氨喹的试验中情况并非如此，尽管PfSPZ试验缺乏显示减少的功效.从大型RTS中重新采样较小的数据集，模拟第二阶段试验的试验显示，与来自RTS的数据相比，来自VEC的功率增益适中，S,但在首次感染时克隆数量未减少的试验中,VEC的作用不如VEHR.VemolFOI在基于模型的模拟中最强大，但只有伯氨喹试验收集了足够的系列样本来精确估计VeholFOI。伯氨喹VEolFOI估计值在大多数对照臂肝脏阶段感染重新激活后降低（在数学上类似于减弱的疫苗），阻止VeholFOI提高动力。
结论：基因分型方法的功率增益取决于环境。由于早期相位功率计算的输入参数通常是不确定的，除非有针对性的数据分析支持,否则不建议将这些估计作为小型试验的主要终点.
背景：NCT00866619、NCT02663700、NCT02143934。
方法：通过模拟和分析推导，将VEolFOI和VEC的功率与VEHR和VERR的功率进行了比较，并将四种VE方法应用于三个数据集：RTS的3期试验，6912名非洲婴儿的S疟疾疫苗，在80名布基纳法索成年人中进行PfSPZ疫苗的2期试验，和一项试验比较了466名巴布亚新几内亚儿童在接受氯喹和蒿甲醚氟烷曲碱联合或不联合伯氨喹后的间日疟原虫发病率（因为这些VE方法也可以量化其他预防措施的效果）。通过摧毁冬眠的肝脏间日疟原虫，伯氨喹减少治疗完成后的后续再激活。
结果：在RTS的试验中，S疫苗，首次感染时，克隆数量显着减少，但在PfSPZ疫苗或伯氨喹的试验中情况并非如此，尽管PfSPZ试验缺乏显示减少的功效.从大型RTS中重新采样较小的数据集，模拟第二阶段试验的试验显示，与来自RTS的数据相比，来自VEC的功率增益适中，S,但在首次感染时克隆数量未减少的试验中,VEC的作用不如VEHR.VemolFOI在基于模型的模拟中最强大，但只有伯氨喹试验收集了足够的系列样本来精确估计VeholFOI。伯氨喹VEolFOI估计值在大多数对照臂肝脏阶段感染重新激活后降低（在数学上类似于减弱的疫苗），阻止VeholFOI提高动力。
结论：基因分型方法的功率增益取决于环境。由于早期相位功率计算的输入参数通常是不确定的，除非有针对性的数据分析支持,否则不建议将这些估计作为小型试验的主要终点.
背景：NCT00866619、NCT02663700、NCT02143934。
