Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure
Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure
复制标题
DOI：
10.1371/journal.ppat.1008157
复制
发表时间：
2019-12-01
期刊：
影响因子：
6.7
通讯作者：
Glass, Pamela J.
中科院分区：
文献类型：
--
作者：
Burke, Crystal W.;Froude, Jeffery W.;Glass, Pamela J.
目前还没有FDA批准的委内瑞拉马脑炎病毒(VEEV)的疫苗或疗法。VEEV会导致人类患上一种衰弱的急性发热性疾病，可能会发展为脑炎。以往的研究表明，小鼠和猕猴的单抗对VEEV外周攻击和气溶胶攻击具有预防和治疗作用。此外，针对E2糖蛋白的两种中和性单抗1a3b-7和1a4a-1的人源化版本单独给药，可保护小鼠免受雾化VEEV感染。然而，还没有研究证明在VEEV感染的非人灵长类动物(NHP)模型中具有保护作用。在这里，我们评估了含有人免疫球蛋白框架上小鼠可变区的嵌合抗体1a3b-7(c1A3B-7)和含有血清半衰期延长修饰(Hu-1A4A-1-YTE)的人源化抗体1A4A-1在雾化VEEV暴露的NHP中的暴露后疗效。大约在暴露后24小时，NHPs被单次静脉注射mAb。对照组NHP有VEEV感染的典型生物标志物，包括可测量的病毒血症、发热和淋巴细胞减少。相比之下，C1A3B-7治疗的NHP显著减少了病毒血症和淋巴细胞减少，平均大约减少了50%的发烧。虽然没有统计学意义，但HU-1A4A-1-YTE给药确实减少了病毒血症和发热持续时间。将c1A3B-7治疗推迟到暴露后48小时，仍然可以通过减少病毒血症和发烧来保护NHP免受严重的VEE疾病的影响。这些结果表明，暴露后给予c1A3B-7可保护猕猴免受严重VEE疾病的发展，即使在气雾剂暴露后48小时也是如此，并描述了首次对暴露后预防NHP使用的VEEV特异性单抗进行评估。在病毒暴露后24小时给予C1A3B-7治疗后，在一例NHP中发现了病毒突变。这表明，对于高效的治疗方法，基于鸡尾酒的疗法或针对不会导致病毒适应性丧失的表位突变的替代mAb可能是必要的。委内瑞拉马脑炎病毒(VEEV)在美洲流行，可通过蚊子叮咬传播给人类、马和其他动物。除了其自然流行之外，VEEV以前被开发为生物武器，使疫苗和疗法的开发成为最重要的。尽管60多年的研究确定了VEEV疾病的有效疗法，但到目前为止，没有任何抗VEEV疗法的进展超过了在小鼠模型上的临床前测试。在这里，我们提出了在非人类灵长类动物(NHP)中抗VEEV治疗的第一次评估。我们发现，在暴露于VEEV的气雾剂后一天或两天给予单抗可以预防严重的VEE疾病。我们还发现，特定抗体在体外对病毒的中和水平并不能预测NHP的疗效。重要的是，我们在治疗后发现了一个NHP中的病毒逃逸突变，强调了开发新的抗体的必要性，以包括在基于鸡尾酒的抗VEEV治疗中。
There are no FDA licensed vaccines or therapeutics for Venezuelan equine encephalitis virus (VEEV) which causes a debilitating acute febrile illness in humans that can progress to encephalitis. Previous studies demonstrated that murine and macaque monoclonal antibodies (mAbs) provide prophylactic and therapeutic efficacy against VEEV peripheral and aerosol challenge in mice. Additionally, humanized versions of two neutralizing mAbs specific for the E2 glycoprotein, 1A3B-7 and 1A4A-1, administered singly protected mice against aerosolized VEEV. However, no studies have demonstrated protection in nonhuman primate (NHP) models of VEEV infection. Here, we evaluated a chimeric antibody 1A3B-7 (c1A3B-7) containing mouse variable regions on a human IgG framework and a humanized antibody 1A4A-1 containing a serum half-life extension modification (Hu-1A4A-1-YTE) for their post-exposure efficacy in NHPs exposed to aerosolized VEEV. Approximately 24 hours after exposure, NHPs were administered a single bolus intravenous mAb. Control NHPs had typical biomarkers of VEEV infection including measurable viremia, fever, and lymphopenia. In contrast, c1A3B-7 treated NHPs had significant reductions in viremia and lymphopenia and on average approximately 50% reduction in fever. Although not statistically significant, Hu-1A4A-1-YTE administration did result in reductions in viremia and fever duration. Delay of treatment with c1A3B-7 to 48 hours post-exposure still provided NHPs protection from severe VEE disease through reductions in viremia and fever. These results demonstrate that post-exposure administration of c1A3B-7 protected macaques from development of severe VEE disease even when administered 48 hours following aerosol exposure and describe the first evaluations of VEEV-specific mAbs for post-exposure prophylactic use in NHPs. Viral mutations were identified in one NHP after c1A3B-7 treatment administered 24 hrs after virus exposure. This suggests that a cocktail-based therapy, or an alternative mAb against an epitope that cannot mutate without resulting in loss of viral fitness may be necessary for a highly effective therapeutic.Author summary Endemic in the Americas, Venezuelan equine encephalitis virus (VEEV) can be transmitted to humans, horses, and other animals through the bite of a mosquito. Beyond its natural prevalence, VEEV was previously developed as a biological weapon making the development of vaccines and therapeutics of the upmost importance. Despite over 60 years of research to identify effective therapeutics for VEEV disease, to-date no anti-VEEV therapeutics have progressed beyond pre-clinical testing in a mouse model. Here, we present the first evaluation of an anti-VEEV therapeutic in a nonhuman primate (NHP). We found that a monoclonal antibody given either one or two days after an aerosol exposure to VEEV protected from severe VEE disease. We also found the level of in vitro virus neutralization by a given antibody did not predict efficacy in NHPs. Importantly, we identified viral escape mutations in one NHP after treatment, highlighting the need for development of novel antibodies for inclusion in cocktail-based therapy against VEEV.