Establishment of an Aerosol Challenge Model of Tuberculosis in Rhesus Macaques and an Evaluation of Endpoints for Vaccine Testing
Establishment of an Aerosol Challenge Model of Tuberculosis in Rhesus Macaques and an Evaluation of Endpoints for Vaccine Testing
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DOI：
10.1128/cvi.00079-10
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发表时间：
2010-08-01
影响因子：
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通讯作者：
Marsh, P. D.
中科院分区：
文献类型：
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作者：
Sharpe, S. A.;McShane, H.;Marsh, P. D.
在非人灵长类动物（NHPs）中建立气溶胶激发模型用于测试针对结核分枝杆菌的疫苗将有助于全球努力优化新型疫苗接种策略。临床前挑战研究中用于确定疾病负担指标的终点需要足够准确和敏感，以便在组规模不可避免地较小时区分不同结核病（TB）疫苗方案的细微差异和益处。本研究旨在评估临床和非临床终点作为恒河猴攻毒研究中疾病负荷的潜在敏感指标，该研究采用新的M.结核评估免疫学和临床读数在疫苗评价研究中的实用性。这是第一个用恒河猴进行结核疫苗评价的例子，长期生存是主要终点之一。然而，我们发现，在NHP疫苗效力研究中，最大组数为6只动物，存活率并没有提供有价值的终点。本研究纳入了人体临床试验中用于评价γ干扰素（IFN-γ）对疫苗接种反应的两种方法（酶联免疫斑点[ELISpot]试验和酶联免疫吸附试验[ELISA]）。发现接种疫苗后诱导的IFN-γ谱与保护无关，纯化蛋白衍生物（PPD）特异性增殖的水平也与保护无关。可靠区分接种疫苗和未接种疫苗的NHP的唯一读数是在研究结束时使用磁共振（MR）成像结合体视学测定肺部病变负荷。因此，目前提出的关键标志物未显示与保护相关，只有成像提供了潜在可靠的相关性。
The establishment of an aerosol challenge model in nonhuman primates (NHPs) for the testing of vaccines against Mycobacterium tuberculosis would assist the global effort to optimize novel vaccination strategies. The endpoints used in preclinical challenge studies to identify measures of disease burden need to be accurate and sensitive enough to distinguish subtle differences and benefits afforded by different tuberculosis (TB) vaccine regimens when group sizes are inevitably small. This study sought to assess clinical and nonclinical endpoints as potentially sensitive measures of disease burden in a challenge study with rhesus macaques by using a new protocol of aerosol administration of M. tuberculosis. Immunological and clinical readouts were assessed for utility in vaccine evaluation studies. This is the first example of TB vaccine evaluation with rhesus macaques where long-term survival was one of the primary endpoints. However, we found that in NHP vaccine efficacy studies with maximum group sizes of six animals, survival did not provide a valuable endpoint. Two approaches used in human clinical trials for the evaluation of the gamma interferon (IFN-gamma) response to vaccination (enzyme-linked immunospot [ELISpot] assay and enzyme-linked immunosorbent assay [ELISA]) were included in this study. The IFN-gamma profiles induced following vaccination were found not to correlate with protection, nor did the level of purified protein derivative (PPD)-specific proliferation. The only readout to reliably distinguish vaccinated and unvaccinated NHPs was the determination of lung lesion burden using magnetic resonance (MR) imaging combined with stereology at the end of the study. Therefore, the currently proposed key markers were not shown to correlate with protection, and only imaging offered a potentially reliable correlate.