委内瑞拉马脑炎病毒(VEEV)偶尔爆发。此外,VEEV具有作为生物防护剂的发展历史。然而,没有FDA批准的VEEV疾病疫苗或治疗方法。零星爆发对测试人类医疗对策(MCM)提出了挑战;因此,FDA动物规则许可需要定义明确的动物模型。食蟹猴(CM)模型已在高攻击剂量的VEEV特立尼达驴品系(>1.0×108斑块形成单位[PFU])下进行了广泛研究,剂量太高,无法代表人类剂量。基于VEEV两种亚型的病毒血症,IC,和IAB,我们发现CM感染剂量50(ID50)很低,12PFU,和6.7PFU,分别。此外,我们表征了三个临床参数的模式(病毒血症,温度,和淋巴细胞减少)在一系列剂量中确定产生一致感染迹象的攻击剂量。基于这些研究,我们建议在VEEV疾病的气溶胶CM模型中转向使用较低的攻击剂量1.0×103PFU。在这个剂量下,NHP的病毒血症最高,表现出发烧反应,并且可以证明MCM功效的完整淋巴细胞计数生物标志物有可测量的减少。
Venezuelan equine encephalitis virus (VEEV) outbreaks occur sporadically. Additionally, VEEV has a history of development as a biothreat agent. Yet, no FDA-approved vaccine or therapeutic exists for VEEV disease. The sporadic outbreaks present a challenge for testing medical countermeasures (MCMs) in humans; therefore, well-defined animal models are needed for FDA Animal Rule licensure. The cynomolgus macaque (CM) model has been studied extensively at high challenge doses of the VEEV Trinidad donkey strain (>1.0 × 108 plaque-forming units [PFU]), doses that are too high to be a representative human dose. Based on viremia of two subtypes of VEEV, IC, and IAB, we found the CM infectious dose fifty (ID50) to be low, 12 PFU, and 6.7 PFU, respectively. Additionally, we characterized the pattern of three clinical parameters (viremia, temperature, and lymphopenia) across a range of doses to identify a challenge dose producing consistent signs of infection. Based on these studies, we propose a shift to using a lower challenge dose of 1.0 × 103 PFU in the aerosol CM model of VEEV disease. At this dose, NHPs had the highest viremia, demonstrated a fever response, and had a measurable reduction in complete lymphocyte counts-biomarkers that can demonstrate MCM efficacy.