Parsimonious Determination of the Optimal Infectious Dose of a Pathogen for Nonhuman Primate Models.
Parsimonious Determination of the Optimal Infectious Dose of a Pathogen for Nonhuman Primate Models.
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DOI：
10.1371/journal.ppat.1005100
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发表时间：
2015-08
期刊：
影响因子：
6.7
通讯作者：
Roederer M
中科院分区：
文献类型：
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作者：
Roederer M
非人灵长类动物(NHP)模型通常是测试旨在阻止艾滋病毒、结核病和疟疾等人类病原体感染的干预措施的最佳实验模型。生理模型可能需要使用有限剂量的感染剂，其中只有一小部分动物在任何给定的挑战中被感染。在这类实验中确定病原体的激发剂量对实验的成功至关重要：使用过高或过低的激发剂量可能会导致假阴性结果和过度使用动物。在这里，我定义了一个优化的方案，用于定义感染50%的时间(AID50)的病原体的剂量；其他挑战剂量，例如AID80，可以很容易地从相同的数据中计算出来。该方案将动物数量以及资源和程序降至最低，同时提供了真实值1.5倍内的AID50估计值。让非人类灵长类动物接触传染性病原体(如结核病、疟疾或相当于艾滋病毒的猿类)是测试疫苗或其他旨在预防感染或疾病的干预措施的重要模式。事实上，在开始对人类进行临床试验之前，通常需要在动物身上证明疗效。在这种测试中，一个关键变量是所使用的病原体的剂量：这个剂量应该与人类遇到的剂量相似。使用太高的剂量可能会克服干预并掩盖成功的方法；使用太低的剂量可能不相关。通常情况下，最佳剂量只会导致动物暴露在环境中的一小部分“成功”感染。因此，成功的干预实验需要使用精确校准的感染剂剂量；这种校准只能通过将动物暴露在一定剂量范围内并测量它们感染的频率来完成。在这里，我定义了执行这种校准的最简约的方法：使用最少的动物数量和程序的方法。鉴于大量新病原体正在动物模型中进行测试，采用这种简明的方案在经济和伦理上都是合理的，因此将使机构动物护理和使用委员会对拟议的动物使用数量进行有利的审查。
The nonhuman primate (NHP) model is often the best experimental model for testing interventions designed to block infection by human pathogens, such as HIV, tuberculosis, and malaria. A physiological model may require the use of a limiting dose of the infectious agent, where only a fraction of animals become infected upon any given challenge. Determining the challenge dose of the pathogen in such experiments is critical to the success of the experiment: using too-high or too-low a challenge dose may lead to false negative results and an excessive use of animals. Here I define an optimized protocol for defining the dose of pathogen that infects 50% of the time (AID50); other challenge doses, e.g. AID80, can be easily calculated from the same data. This protocol minimizes the number of animals, as well as resources and procedures, while providing an estimate of the AID50 within 1.5-fold of the true value. Exposing nonhuman primates to infectious pathogens (such as tuberculosis, malaria, or the simian equivalent of HIV) is an important model for testing vaccines or other interventions designed to prevent infection or disease. In fact, demonstrating efficacy in animals is often a requirement before clinical testing in humans can be started. A critical variable in such testing is the dose of the pathogen used: this dose should be similar to what humans would encounter. Using too-high a dose may overcome the intervention and mask a successful approach; using too-low a dose may not be relevant. Often, an optimal dose will lead to “successful” infections only a fraction of the times the animal is exposed. A successful intervention experiment therefore needs to use a precisely calibrated dose of the infectious agent; this calibration can only be done by exposing animals to a range of doses and measuring how often they become infected. Here I define the most parsimonious method for performing this calibration: one that uses the least number of animals and procedures. Given the large number of new pathogens being tested in animal models, adoption of such a parsimonious protocol is both economically and ethically warranted, and will thereby enable favorable review of proposed animal use numbers by Institutional Animal Care and Use Committees.