A recombinant vesicular stomatitis virus-based vaccine provides postexposure protection against Bundibugyo ebolavirus infection

Bundibugyo virus (BDBV) is the most recently discovered pathogenic species of ebolavirus, with mortality rates of 25% and 51% reported in two identified. BDBV infection is non-uniformly lethal in macaques. The lack of uniform lethality offers the opportunity for identification of biomarkers that correlate with positive and negative outcomes following infection that can help define mechanisms of pathogenesis and potentially serve as guides for clinical care. In both the treatment and control groups, ~58% survived infection, an increase over lethality seen in historical controls. There was no differential advantage of the BDBV GP expressing vaccine, suggesting a general effect of rVSV. Our transcriptomic analysis identified strong initial responses to infection and treatment in all animals. This response returned to baseline in animals with mild disease by day 7. In animals with severe disease, fatal cases could be predicted beginning at day 5 post infection based on the expression of 5 circulating mRNAs. This study suggested a nonspecific effect of treating NHPs with VSV-based vectors as a postexposure therapy following BDBV infection and identified potential biomarkers of outcome. Overall design: Seven cynomolgus macaques were challenged by intramuscular injection in the left quadriceps with a 1,000 PFU target dose of BDBV challenge stock (the actual dose was 913 PFU). Approximately 20-23 minutes post challenge, six animals were treated with ~ 2X10^7 PFU of rVSV?G/BDBV-GP via i.m. injection. The inoculation was equally distributed between the left and right quadriceps. Animals were monitored for viremia and clinical signs of illness (temperature, weight loss, changes in blood count, and blood chemistries) during the treatment and BDBV challenge portions of the study. Blood was collected on days 0, 1, 5, 7, 9, 12, 15, 21, and 28 post challenge. Samples were also collected on the day of euthanasia.

本迪布焦病毒（Bundibugyo virus, BDBV）是埃博拉病毒属中最新发现的致病型种，在两起已确认的暴发中其病死率分别为25%与51%。BDBV感染食蟹猴时的致死性并不均一。这种致死性不均一性为鉴定与感染后转归（阳性/阴性）相关的生物标志物提供了契机，此类标志物既有助于阐明致病机制，也有望为临床诊疗提供参考。

治疗组与对照组中均有约58%的个体得以存活，该存活率高于历史对照队列中的致死率水平。表达BDBV糖蛋白（glycoprotein, GP）的疫苗并未展现出额外优势，这提示重组水疱性口炎病毒（recombinant vesicular stomatitis virus, rVSV）载体存在广谱效应。

我们的转录组学分析显示，所有受试动物均出现了针对感染与治疗的强烈初始应答。对于轻症动物，此类应答于感染后第7天恢复至基线水平。对于重症动物，可基于5种循环mRNA的表达谱，自感染后第5天起预测其是否会发生死亡。

本研究表明，以基于VSV的载体作为BDBV感染后的暴露后治疗手段，对非人灵长类动物（non-human primates, NHPs）存在非特异性效应，并鉴定出了与转归相关的潜在生物标志物。

整体实验设计：
7只食蟹猴经左侧股四头肌肌肉注射（intramuscular, i.m.）BDBV攻毒毒株，攻毒靶剂量为1000 蚀斑形成单位（plaque forming unit, PFU）（实际给药剂量为913 PFU）。攻毒后约20~23分钟，对其中6只动物经肌肉注射（intramuscular, i.m.）给予约2×10^7 PFU的rVSVΔG/BDBV-GP。疫苗接种点均匀分布于左右两侧股四头肌。在本研究的治疗与BDBV攻毒阶段，对所有动物的病毒血症及临床病症体征（体温、体重下降、血常规与血生化变化）进行监测。分别于攻毒后第0、1、5、7、9、12、15、21及28天采集血液样本。安乐死当日亦采集样本。