A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis
A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis
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DOI：
10.1371/journal.pone.0198140
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发表时间：
2018-05-25
期刊：
影响因子：
3.7
通讯作者：
Elkins, Karen L.
中科院分区：
文献类型：
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作者：
De Pascalis, Roberto;Hahn, Andrew;Elkins, Karen L.
对于任何细胞内病原体，包括引起土拉菌病的土拉热弗朗西丝菌，都没有明确的保护相关性。使用田间试验评估疫苗对兔热病等散发性疾病的效力是有问题的，因此需要测试候选疫苗如弗朗西斯菌活疫苗株（LVS）的替代策略，例如在动物中测试并应用相关测量。最近，我们描述了一个有前途的相关策略，预测疫苗诱导的保护程度的小鼠给予胃肠外的挑战，主要是当使用减毒弗朗西斯菌株。在这里，我们证明，在这种方法中使用外周血淋巴细胞（PBL）预测LVS介导的保护对呼吸挑战的Fischer 344大鼠完全毒力F。土拉菌，具有特殊的敏感性和特异性。大鼠接种一组LV衍生的疫苗，随后给予A型和F型致死性呼吸道攻击。土拉热。同时，在体外共培养试验中评价了来自接种疫苗大鼠的PBL控制巨噬细胞内弗朗西斯菌生长的功能能力。还使用在鼠研究中鉴定的大量基因评估从共培养物回收的PBL的相对基因表达。体外LVS巨噬细胞内复制的控制反映了保护的层次。此外，尽管个体之间存在变异性，但与来自接种变体LVS-R或热灭活LVS的大鼠的PBL相比，来自接种LVS的大鼠的PBL中有22个基因显著上调，而后者的保护性较差。这些基因包括IFN-γ、IL-21、N 0 S2、LTA、T-bet、IL-12 r β 2和CCL 5。最重要的是，使用多变量分析将巨噬细胞内生长控制的定量与5-7个基因表达水平相结合，以大于95%的灵敏度和特异性区分受保护的个体与未受保护的个体。因此，这些结果支持将这种方法翻译到非人灵长类动物和人类中，以评估针对弗朗西斯菌和其他细胞内病原体的新疫苗。
There are no defined correlates of protection for any intracellular pathogen, including the bacterium Francisella tularensis, which causes tularemia. Evaluating vaccine efficacy against sporadic diseases like tularemia using field trials is problematic, and therefore alternative strategies to test vaccine candidates like the Francisella Live Vaccine Strain (LVS), such as testing in animals and applying correlate measurements, are needed. Recently, we described a promising correlate strategy that predicted the degree of vaccine-induced protection in mice given parenteral challenges, primarily when using an attenuated Francisella strain. Here, we demonstrate that using peripheral blood lymphocytes (PBLs) in this approach predicts LVS-mediated protection against respiratory challenge of Fischer 344 rats with fully virulent F. tularensis, with exceptional sensitivity and specificity. Rats were vaccinated with a panel of LVS-derived vaccines and subsequently given lethal respiratory challenges with Type A F. tularensis. In parallel, PBLs from vaccinated rats were evaluated for their functional ability to control intramacrophage Francisella growth in in vitro co-culture assays. PBLs recovered from co-cultures were also evaluated for relative gene expression using a large panel of genes identified in murine studies. In vitro control of LVS intramacrophage replication reflected the hierarchy of protection. Further, despite variability between individuals, 22 genes were significantly more up-regulated in PBLs from rats vaccinated with LVS compared to those from rats vaccinated with the variant LVS-R or heat killed LVS, which were poorly protective. These genes included IFN-gamma, IL-21, NOS2, LTA, T-bet, IL-12r beta 2, and CCL5. Most importantly, combining quantifications of intramacrophage growth control with 5-7 gene expression levels using multivariate analyses discriminated protected from non-protected individuals with greater than 95% sensitivity and specificity. The results therefore support translation of this approach to non-human primates and people to evaluate new vaccines against Francisella and other intracellular pathogens.