Martins Karen, Carra John H, Cooper Christopher L, Kwilas Steven A, Robinson Camenzind G, Shurtleff Amy C, Schokman Rowena D, Kuehl Kathleen A, Wells Jay B, Steffens Jesse T, van Tongeren Sean A, Hooper Jay W, Bavari Sina
1 Department of Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases (USAMRIID) , Frederick, Maryland.
Viral Immunol. 2015 Feb;28(1):62-70. doi: 10.1089/vim.2014.0071.
Filoviruses are causative agents of hemorrhagic fever, and to date no effective vaccine or therapeutic has been approved to combat infection. Filovirus glycoprotein (GP) is the critical immunogenic component of filovirus vaccines, eliciting high levels of antibody after successful vaccination. Previous work has shown that protection against both Ebola virus (EBOV) and Marburg virus (MARV) can be achieved by vaccinating with a mixture of virus-like particles (VLPs) expressing either EBOV GP or MARV GP. In this study, the potential for eliciting effective immune responses against EBOV, Sudan virus, and MARV with a single GP construct was tested. Trimeric hybrid GPs were produced that expressed the sequence of Marburg GP2 in conjunction with a hybrid GP1 composed EBOV and Sudan virus GP sequences. VLPs expressing these constructs, along with EBOV VP40, provided comparable protection against MARV challenge, resulting in 75 or 100% protection. Protection from EBOV challenge differed depending upon the hybrid used, however, with one conferring 75% protection and one conferring no protection. By comparing the overall antibody titers and the neutralizing antibody titers specific for each virus, it is shown that higher antibody responses were elicited by the C terminal region of GP1 than by the N terminal region, and this correlated with protection. These data collectively suggest that GP2 and the C terminal region of GP1 are highly immunogenic, and they advance progress toward the development of a pan-filovirus vaccine.
丝状病毒是出血热的病原体，迄今为止，尚无有效的疫苗或治疗方法被批准用于对抗感染。丝状病毒糖蛋白（GP）是丝状病毒疫苗的关键免疫原性成分，成功接种疫苗后可引发高水平抗体。先前的研究表明，通过接种表达埃博拉病毒（EBOV）GP或马尔堡病毒（MARV）GP的病毒样颗粒（VLP）混合物，可以实现对EBOV和MARV的保护。在本研究中，测试了用单一GP构建体引发针对EBOV、苏丹病毒和MARV的有效免疫反应的潜力。产生了三聚体杂交GP，其表达马尔堡GP2的序列，并与由EBOV和苏丹病毒GP序列组成的杂交GP1结合。表达这些构建体的VLP与EBOV VP40一起，对MARV攻击提供了相当的保护，导致75%或100%的保护率。然而，对EBOV攻击的保护因所用杂交体而异，其中一种提供75%的保护，另一种则不提供保护。通过比较总体抗体滴度和针对每种病毒的中和抗体滴度，结果表明GP1的C末端区域比N末端区域引发更高的抗体反应，这与保护作用相关。这些数据共同表明，GP2和GP1的C末端区域具有高度免疫原性，它们推动了泛丝状病毒疫苗开发的进展。
