Sharpe S A, McShane H, Dennis M J, Basaraba R J, Gleeson F, Hall G, McIntyre A, Gooch K, Clark S, Beveridge N E R, Nuth E, White A, Marriott A, Dowall S, Hill A V S, Williams A, Marsh P D
Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom.
Clin Vaccine Immunol. 2010 Aug;17(8):1170-82. doi: 10.1128/CVI.00079-10. Epub 2010 Jun 9.
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.
建立用于测试抗结核分枝杆菌疫苗的非人灵长类动物（NHP）气溶胶攻击模型，将有助于全球优化新型疫苗接种策略的努力。临床前攻击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）疫苗方案所带来的细微差异和益处。本研究旨在通过使用一种新的结核分枝杆菌气溶胶给药方案，评估恒河猴攻击研究中作为疾病负担潜在敏感指标的临床和非临床终点。评估了免疫和临床读数在疫苗评估研究中的效用。这是恒河猴TB疫苗评估的首个实例，其中长期生存是主要终点之一。然而，我们发现，在最大组规模为6只动物的NHP疫苗效力研究中，生存并未提供有价值的终点。本研究纳入了人类临床试验中用于评估疫苗接种后γ干扰素（IFN-γ）反应的两种方法（酶联免疫斑点[ELISpot]测定和酶联免疫吸附测定[ELISA]）。发现接种疫苗后诱导的IFN-γ谱与保护作用无关，纯化蛋白衍生物（PPD）特异性增殖水平也无关。在研究结束时，使用磁共振（MR）成像结合体视学确定肺部病变负担是唯一能够可靠区分接种和未接种NHP的读数。因此，目前提出的关键标志物未显示与保护作用相关，只有成像提供了潜在可靠的关联。
