Lennemann Nicholas J, Herbert Andrew S, Brouillette Rachel, Rhein Bethany, Bakken Russell A, Perschbacher Katherine J, Cooney Ashley L, Miller-Hunt Catherine L, Ten Eyck Patrick, Biggins Julia, Olinger Gene, Dye John M, Maury Wendy
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA.
J Virol. 2017 Aug 10;91(17). doi: 10.1128/JVI.00479-17. Print 2017 Sep 1.
The recent Ebola virus (EBOV) epidemic in West Africa demonstrates the potential for a significant public health burden caused by filoviral infections. No vaccine or antiviral is currently FDA approved. To expand the vaccine options potentially available, we assessed protection conferred by an EBOV vaccine composed of vesicular stomatitis virus pseudovirions that lack native G glycoprotein (VSVΔG) and bear EBOV glycoprotein (GP). These pseudovirions mediate a single round of infection. Both single-dose and prime/boost vaccination regimens protected mice against lethal challenge with mouse-adapted Ebola virus (ma-EBOV) in a dose-dependent manner. The prime/boost regimen provided significantly better protection than a single dose. As N-linked glycans are thought to shield conserved regions of the EBOV GP receptor-binding domain (RBD), thereby blocking epitopes within the RBD, we also tested whether VSVΔG bearing EBOV GPs that lack GP1 N-linked glycans provided effective immunity against challenge with ma-EBOV or a more distantly related virus, Sudan virus. Using a prime/boost strategy, high doses of GP/VSVΔG partially or fully denuded of N-linked glycans on GP1 protected mice against ma-EBOV challenge, but these mutants were no more effective than wild-type (WT) GP/VSVΔG and did not provide cross protection against Sudan virus. As reported for other EBOV vaccine platforms, the protection conferred correlated with the quantity of EBOV GP-specific Ig produced but not with the production of neutralizing antibodies. Our results show that EBOV GP/VSVΔG pseudovirions serve as a successful vaccination platform in a rodent model of Ebola virus disease and that GP1 N-glycan loss does not influence immunogenicity or vaccination success. The West African Ebola virus epidemic was the largest to date, with more than 28,000 people infected. No FDA-approved vaccines are yet available, but in a trial vaccination strategy in West Africa, recombinant, infectious VSV encoding the Ebola virus glycoprotein effectively prevented virus-associated disease. VSVΔG pseudovirion vaccines may prove as efficacious and have better safety, but they have not been tested to date. Thus, we tested the efficacy of VSVΔG pseudovirions bearing Ebola virus glycoprotein as a vaccine platform. We found that wild-type Ebola virus glycoprotein, in the context of this platform, provides robust protection of EBOV-challenged mice. Further, we found that removal of the heavy glycan shield surrounding conserved regions of the glycoprotein does not enhance vaccine efficacy.
最近在西非爆发的埃博拉病毒（EBOV）疫情表明丝状病毒感染可能造成重大的公共卫生负担。目前尚无FDA批准的疫苗或抗病毒药物。为了扩大潜在可用的疫苗选择范围，我们评估了一种由缺乏天然G糖蛋白（VSVΔG）并携带埃博拉病毒糖蛋白（GP）的水疱性口炎病毒假病毒组成的埃博拉病毒疫苗所提供的保护作用。这些假病毒介导一轮感染。单剂量和初免/加强免疫接种方案均以剂量依赖的方式保护小鼠免受适应小鼠的埃博拉病毒（ma-EBOV）的致死性攻击。初免/加强免疫方案提供的保护作用明显优于单剂量方案。由于N-连接聚糖被认为会屏蔽埃博拉病毒GP受体结合域（RBD）的保守区域，从而阻断RBD内的表位，我们还测试了携带缺乏GP1 N-连接聚糖的埃博拉病毒GPs的VSVΔG是否能提供针对ma-EBOV或更远亲病毒苏丹病毒攻击的有效免疫力。采用初免/加强免疫策略，高剂量的在GP1上部分或完全去除N-连接聚糖的GP/VSVΔG保护小鼠免受ma-EBOV攻击，但这些突变体并不比野生型（WT）GP/VSVΔG更有效，也不能提供针对苏丹病毒的交叉保护。正如其他埃博拉病毒疫苗平台所报道的那样，所提供的保护作用与产生的埃博拉病毒GP特异性Ig的量相关，但与中和抗体的产生无关。我们的结果表明，埃博拉病毒GP/VSVΔG假病毒在埃博拉病毒病的啮齿动物模型中是一个成功的疫苗平台，并且GP1 N-聚糖的缺失不会影响免疫原性或疫苗接种的成功。西非埃博拉病毒疫情是迄今为止规模最大的一次，超过28000人感染。目前尚无FDA批准的疫苗，但在西非的一项试验性疫苗接种策略中，编码埃博拉病毒糖蛋白的重组感染性VSV有效预防了病毒相关疾病。VSVΔG假病毒疫苗可能同样有效且安全性更好，但迄今为止尚未进行测试。因此，我们测试了携带埃博拉病毒糖蛋白的VSVΔG假病毒作为疫苗平台的有效性。我们发现，在这个平台背景下，野生型埃博拉病毒糖蛋白能为受埃博拉病毒攻击的小鼠提供强大的保护。此外，我们发现去除糖蛋白保守区域周围的重糖链屏蔽并不会提高疫苗效力。
