Miura Kazutoyo, Swihart Bruce J, Deng Bingbing, Zhou Luwen, Pham Thao P, Diouf Ababacar, Burton Timothy, Fay Michael P, Long Carole A
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Lane, Rockville, MD 20852, USA.
Vaccine. 2016 Jul 29;34(35):4145-4151. doi: 10.1016/j.vaccine.2016.06.066. Epub 2016 Jun 29.
Malaria transmission-blocking vaccines (TBVs) are potentially helpful tools for malaria eradication. The standard membrane-feeding assay (SMFA) is considered one of the "gold standard" assays for TBV development. However, lack of consensus in reporting results from SMFA has made it very challenging to compare results from different studies. Two main readouts, % inhibition in mean oocyst count per mosquito (TRA) and % inhibition in prevalence of infected mosquitoes (TBA), have been used widely. In this study, we statistically modeled the oocyst data in SMFA using data from 105 independent feeding experiments including 9804 mosquitoes. The model was validated using an independent data set that included 10,790 mosquitoes from 110 feeding studies. The model delineates a relationship between TRA, the mean oocyst count in the control mosquitoes (mo-contl), and TBA. While TRA was independent from mo-contl, TBA values changed depending on mo-contl. Regardless of monoclonal or polyclonal antibodies tested, there were strong concordances between observed TBA and predicted TBA based on the model using mo-contl and observed TRA. Simulations showed that SMFA with lower true control means had increased uncertainty in TRA estimates. The strong linkage between TBA, TRA and mo-contl inspired creation of a standardized TBA, a model-based TBA standardized to a target control mean, which allows comparison across multiple feeds regardless of mo-contl. This is the first study showing that the observed TBA can be reasonably predicted by mo-contl and the TRA of the test antibody using independent experimental data. This study indicates that TRA should be used to compare results from multiple feeds with different levels of mo-contl. If a measure of TBA is desired, it is better to report standardized TBA rather than observed TBA. These recommendations support rational comparisons of results from different studies, thus benefiting future TBV development.
疟疾传播阻断疫苗（TBVs）是根除疟疾的潜在有用工具。标准膜饲法（SMFA）被认为是TBV研发的“金标准”检测方法之一。然而，在报告SMFA结果方面缺乏共识，使得比较不同研究的结果极具挑战性。两个主要的读数，即每只蚊子平均卵囊计数的抑制率（TRA）和受感染蚊子患病率的抑制率（TBA），已被广泛使用。在本研究中，我们使用来自105项独立饲育实验（包括9804只蚊子）的数据，对SMFA中的卵囊数据进行了统计建模。该模型使用一个独立数据集进行了验证，该数据集包括来自110项饲育研究的10790只蚊子。该模型描绘了TRA、对照蚊子的平均卵囊计数（mo-contl）和TBA之间的关系。虽然TRA与mo-contl无关，但TBA值会根据mo-contl而变化。无论测试的是单克隆抗体还是多克隆抗体，基于使用mo-contl和观察到的TRA的模型，观察到的TBA与预测的TBA之间都有很强的一致性。模拟表明，真实对照均值较低的SMFA在TRA估计中具有更大的不确定性。TBA、TRA和mo-contl之间的紧密联系促使创建了一种标准化的TBA，即基于模型的TBA，标准化到目标对照均值，这使得无论mo-contl如何，都可以在多个饲育实验之间进行比较。这是第一项表明可以使用独立实验数据通过mo-contl和测试抗体的TRA合理预测观察到的TBA的研究。本研究表明，应使用TRA来比较不同mo-contl水平的多个饲育实验的结果。如果需要测量TBA，最好报告标准化的TBA而不是观察到的TBA。这些建议支持对不同研究结果进行合理比较，从而有利于未来TBV的研发。
