Department of Medicine, The University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, Vermont 05405-00681, USA.
Microbiol Mol Biol Rev. 2010 Jun;74(2):157-70. doi: 10.1128/MMBR.00045-09.
The arenaviruses are a family of negative-sense RNA viruses that cause severe human disease ranging from aseptic meningitis to hemorrhagic fever syndromes. There are currently no FDA-approved vaccines for the prevention of arenavirus disease, and therapeutic treatment is limited to the use of ribavirin and/or immune plasma for a subset of the pathogenic arenaviruses. The considerable genetic variability observed among the seven arenaviruses that are pathogenic for humans illustrates one of the major challenges for vaccine development today, namely, to overcome pathogen heterogeneity. Over the past 5 years, our group has tested several strategies to overcome pathogen heterogeneity, utilizing the pathogenic arenaviruses as a model system. Because T cells play a prominent role in protective immunity following arenavirus infection, we specifically focused on the development of human vaccines that would induce multivalent and cross-protective cell-mediated immune responses. To facilitate our vaccine development and testing, we conducted large-scale major histocompatibility complex (MHC) class I and class II epitope discovery on murine, nonhuman primate, and human backgrounds for each of the pathogenic arenaviruses, including the identification of protective HLA-restricted epitopes. Finally, using the murine model of lymphocytic choriomeningitis virus infection, we studied the phenotypic characteristics associated with immunodominant and protective T cell epitopes. This review summarizes the findings from our studies and discusses their application to future vaccine design.
沙粒病毒是一类负义 RNA 病毒，可引起人类严重疾病，从无菌性脑膜炎到出血热综合征不等。目前，尚无 FDA 批准的预防沙粒病毒病的疫苗，治疗方法仅限于利巴韦林和/或免疫血浆用于部分致病性沙粒病毒。在对人类具有致病性的七种沙粒病毒中观察到的相当大的遗传变异性说明了当今疫苗开发的主要挑战之一，即克服病原体异质性。在过去的 5 年中，我们的小组已经测试了几种策略来克服病原体异质性，利用致病性沙粒病毒作为模型系统。由于 T 细胞在沙粒病毒感染后保护性免疫中发挥着重要作用，我们特别专注于开发能够诱导多价和交叉保护性细胞介导免疫应答的人类疫苗。为了促进我们的疫苗开发和测试，我们在鼠、非人灵长类和人类背景下对每种致病性沙粒病毒进行了大规模的主要组织相容性复合体 (MHC) 类 I 和 II 表位发现，包括鉴定保护性 HLA 限制性表位。最后，我们使用淋巴细胞性脉络丛脑膜炎病毒感染的鼠模型研究了与免疫优势和保护性 T 细胞表位相关的表型特征。这篇综述总结了我们研究的结果，并讨论了它们在未来疫苗设计中的应用。
